Neuromuscular Disorders
Distal myopathies
Sep. 18, 2024
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Limb-girdle muscular dystrophies (LGMD) …
- Updated 02.15.2023
- Released 11.06.1995
- Expires For CME 02.15.2026
Limb-girdle muscular dystrophies
Introduction
Overview
The previous wastebasket term “limb girdle muscular dystrophy” has been transformed into a multitude of specific, genetically defined disorders. In 2017, the European Neuromuscular Center LGMD workshop study group met in the Netherlands to reach a consensus on the most useful nomenclature and classification of limb-girdle muscular dystrophy subtypes that is accurate, scientific, and with capacity to accommodate further discoveries of limb-girdle muscular dystrophies. The proposed definition for limb-girdle muscular dystrophy is as follows:
Limb girdle muscular dystrophy is a genetically inherited condition that primarily affects skeletal muscle leading to progressive, predominantly proximal muscle weakness at presentation caused by a loss of muscle fibres. To be considered a form of limb girdle muscular dystrophy the condition must be described in at least 2 unrelated families with affected individuals achieving independent walking, must have an elevated serum creatine kinase activity, must demonstrate degenerative changes on muscle imaging over the course of the disease, and have dystrophic changes on muscle histology, ultimately leading to end-stage pathology for the most affected muscles. |
As a result of this new classification, some previous cases of limb-girdle muscular dystrophy described in a single family were removed from this classification. Other conditions were reclassified according to the protein affected or phenotype. This article will mention the new classification as well as the old classification for clarification purposes.
Historical note and terminology
The history of limb-girdle muscular dystrophy encompasses the history of primary and secondary muscle diseases as a whole (34; 286; 473; 474; 536; 54; 246; 461). The cases categorized under the term "limb-girdle dystrophy" have varied over time and among authors. In the older literature, for example, authors tended to lump limb-girdle muscular dystrophy cases with other muscular dystrophies, polymyositis, spinal muscular atrophies, and even poliomyelitis. Recognition of a distinct mode of inheritance and distribution of weakness first helped to differentiate some muscular dystrophies from the limb-girdle syndromes. Modern techniques of investigation then allowed the recognition and separation of the inflammatory myopathies, other acquired myopathies, and neurogenic disorders into separate entities. From the residuum, the cases of congenital myopathies, dystrophinopathies, and mitochondrial and metabolic myopathies have further been culled out based on ultrastructural and biochemical studies. Later, molecular genetics drastically altered the field, initially with linkage of multiple families and syndromes to specific chromosomal loci and subsequently with a rapid succession of identified genes and gene products for many limb-girdle muscular dystrophy subtypes.
Muscular dystrophy was probably known to the ancient Egyptians, as evidenced by wall carvings in pyramids (about 2500 BC). Meryon described an entity in some of his patients that appears to be the first reported description of either limb-girdle muscular dystrophy or benign X-linked muscular dystrophy (333). Duchenne mentioned dystrophies with onset in later age and with non-X-linked modes of inheritance. In a family reviewed by Nevin, Duchenne described a relatively benign limb-girdle myopathy in a father and son pair, suggesting an autosomal dominant trait; the father's weakness began in his fifth decade (362). Clinical descriptions were long ago characterized by the distribution of weakness based on the predominant involvement of the scapulohumeral (136), pelvifemoral (287; 340), or quadriceps musculature. In subsequent classifications, these types of muscular dystrophy have maintained their identity and have been traditionally viewed as subtypes of limb-girdle muscular dystrophy. Of note, the terms "muscular dystrophy" and "muscular atrophy" were used interchangeably and without qualification at the time of these early writings. It was not until later that Erb introduced the concept of muscular dystrophy as a hereditary degenerative disease of muscle (135).
In the 20th century, an increasing number of cases of upper and lower limb-girdle dystrophy were reported. Levison reviewed 123 personal cases of muscular dystrophy from Denmark, and Stevenson investigated 60 families from Northern Ireland (286; 473; 474). These authors attempted to separate limb-girdle muscular dystrophy from other forms of dystrophies based on clinical, genetic, electrophysiologic, and histologic studies. Walton and Nattrass investigated 105 cases of muscular dystrophy from the northeast of England and proposed the most widely accepted classification of the muscular dystrophies until 1995 (536). They grouped the pelvifemoral form of Leyden and Mobius and the juvenile scapulohumeral form of Erb together with the late-onset cases of Nevin under the umbrella term "limb-girdle muscular dystrophy" in order to separate this group from X-linked disorders and fascioscapulohumeral dystrophy. However, with improved diagnostic methods, limb-girdle muscular dystrophy as described by Walton and Nattrass turned out to include a wide variety of neuromuscular disorders, such as chronic spinal muscular atrophy, polymyositis, endocrine myopathies, and some congenital and metabolic myopathies (54).
A workshop headed by Bushby reclassified limb-girdle muscular dystrophy based on mode of inheritance and chromosomal localization (64). At the time in 1995, only one dominant and four recessive loci were identified and only one protein product was known (adhalin). In later years, many of the limb-girdle dystrophies have been identified at the molecular level. As more information is gained regarding the genes and mechanisms involved for pathogenesis in limb-girdle muscular dystrophies, there has been further exploration into therapeutic targets.
Clinical manifestations
Presentation and course
Limb-girdle dystrophy occurs in both sexes, with onset between the second and sixth decade, usually in late childhood or early adulthood, although onset can occur at almost any age. Weakness in many cases begins in the pelvic girdle musculature (Leyden and Mobius type) and then spreads to the pectoral musculature. However, in the reverse pattern (Erb type), it is not unusual to see the pectoral girdle affected first. In rarer cases, both regions are affected simultaneously. Early facial, distal, or extraocular muscle involvement is not seen. The average interval before symptoms appear in the initially unaffected girdle musculature is about 5 to 10 years, although it can be longer. Autosomal dominant forms of limb-girdle muscular dystrophy tend to occur later in life and progress relatively slowly, although exceptions occur (40; 11; 343; 486; 247). Weakness is progressive, and loss of ambulation occurs earlier when the disease begins in the pelvic girdle, but progression can be slow or rapid. Eventually, virtually all muscles in the body are affected, but the relative distribution of affected and relatively spared muscles determines the characteristic clinical appearance in limb-girdle muscular dystrophy.
Although the severity and time course of weakness in individual muscles may vary, the overall pattern of involvement seems to be similar in pectoral and pelvic forms of limb-girdle muscular dystrophy. The trapezius, serratus anterior, sternal head of pectoralis major, spinati, biceps, and brachioradialis muscles are involved early in the pectoral form. The deltoid muscle may be relatively spared, but this muscle can be difficult to test when the subject is unable to fixate the scapula. The presence of weakness and atrophy in certain muscle groups, with relative sparing of others, often produces a characteristic appearance: drooped shoulders, scapular winging, characteristic anterior axillary fold (due to wasting of the sternal head of the pectoralis major), and "Popeye" arms (due to wasted arm muscles and spared deltoids); however, this pattern is more commonly demonstrated in fascioscapulohumeral muscular dystrophy (FSHD). In the pelvic form of limb-girdle muscular dystrophy, sacrospinalis, quadriceps, hamstrings, and hip muscles are especially involved, causing excessive lumbar lordosis and a waddling gait. Facial muscles are uninvolved in limb-girdle muscular dystrophy until the patient is severely disabled from limb weakness. Why muscles of one region should be selectively targeted remains unknown.
Pseudohypertrophy of calf muscles has been reported in some cases of autosomal recessive limb-girdle muscular dystrophy but is not invariably present (240; 36). Muscle tendon reflexes are preserved in the early stages but are lost as the disease progresses. Ankle jerks often can still be elicited when all other reflexes are lost. Cardiac involvement is seen late in a small minority of patients. Creatine kinase is variably raised (2x to 350x) in recessive cases and is either normal or only mildly increased (to 6x) in dominant patients (64).
The progressive clinical course may eventually lead to loss of ambulation, especially if the pelvic girdle is involved at an early stage. It is often decades before the disease produces severe physical disability and muscle contractures. In terminal stages, patients may have respiratory muscle involvement leading to respiratory failure, pneumonia, and death. Some patients with limb-girdle muscular dystrophy have axial muscle involvement and relatively early respiratory failure (479). The clinical course is variable, however, and some patients have a normal lifespan and may remain ambulatory throughout (40; 11; 343; 486; 91; 403).
Learning difficulties and mild intellectual disability are not rare in limb-girdle muscular dystrophy. Cognitive deficits in limb-girdle muscular dystrophy are thought to occur from defects in assembly and processing of dystroglycans in both muscles and neurons in dystroglycanopathy syndromes (341).
Chronic pain appears to be a prevalent problem in people with limb-girdle muscular dystrophy, with a negative impact on everyday life (532).
Prognosis and complications
Limb-girdle dystrophies, like all muscular dystrophies, are progressive disorders. The rate of progression, however, varies widely in different types of limb-girdle muscular dystrophies and between individuals. Autosomal recessive limb-girdle muscular dystrophy of childhood generally progresses more rapidly, leading to loss of ambulation in late childhood or adolescence and death in early adulthood (36; 563; 149; 14), although milder cases are also seen. Autosomal dominant forms of limb-girdle muscular dystrophy, even those that begin in early childhood, are more benign and life expectancy can be normal (40; 11; 343; 486; 247).
Physical disability in limb-girdle muscular dystrophy is dependent on the distribution and severity of muscle weakness. Not surprisingly, loss of walking ability occurs earlier when the disease begins in the pelvic girdle. The interval between onset of symptoms and inability to walk is highly variable. Muscle contractures may contribute to severe disability in later stages. Respiratory muscle impairment can occur, with muscles of forced expiration involved earlier than those of inspiration. Pulmonary function tests typically disclose a decreased vital capacity, inspiratory reserve volume, and maximum breathing capacity. Because the disease process is slow in most cases, compensatory changes occur and a normal resting minute volume is generally maintained for long periods of time. Ventilation perfusion mismatch does not occur in limb-girdle muscular dystrophy, probably because of the uniformly diffuse disease process. Respiratory components affected include diaphragmatic and intercostal muscles. Pneumonia and respiratory failure can eventually shorten the life span. Some patients with mild phenotypes, however, remain mobile and have a normal life span.
Pathological changes in the myocardium in limb-girdle muscular dystrophy are seen in some forms more than others (478) and are generally similar to, but less severe than, in Duchenne dystrophy. Clinically overt cardiac involvement, however, is rare in limb-girdle muscular dystrophy except in a few subtypes.
A study has found that the Performance of the Upper Limb module, a functional upper extremity score traditionally used for Duchenne patients, can be applied and used for patients with limb-girdle muscular dystrophy as well with adequate reliability (171).
Additionally, findings indicate that miR-206 could be a prognostic indicator of disease progression. A study found that miR-206 is associated with disease severity for those with LGMD D4, R1, and D2 (392). The expression of miR-206 was elevated in those with limb-girdle muscular dystrophy in comparison to controls as a whole but was significantly elevated in those with severe disease in the specific aforementioned subtypes. This was characterized by worsened functional impairment when the expression was 50- to 80-fold higher as well as worsened atrophy confirmed by MRI.
Biological basis
Etiology and pathogenesis
Classification of limb-girdle muscular dystrophies. A reclassification of limb-girdle muscular dystrophy was proposed by the European Neuromuscular Center LGMD workshop study group in 2017. This new classification follows the formula: “LGMD, inheritance (R or D), order of discovery (number), affected protein” (477). Because of the definition of limb-girdle muscular dystrophy that needs to have been described in at least two different families, some conditions are no longer considered limb-girdle muscular dystrophy (for gene mutations with only one family described in the literature) (Table 1). Limb-girdle muscular dystrophy type 1 is now LGMD D and limb-girdle muscular dystrophy type 2 is now LGMD R. This review will describe the limb-girdle muscular dystrophies following the new classification. The description of the conditions no longer considered in current limb-girdle muscular dystrophy will be maintained for clarification purposes.
LGMD D (previously autosomal dominant [Type 1] limb-girdle muscular dystrophies). Autosomal dominant limb-girdle muscular dystrophies are much less common than recessive forms, accounting for fewer than 10% of all cases. Many of these entities have other neuromuscular or nonmuscular abnormalities linked to the same genes and in some cases the same gene mutations (Table 2).
LGMD D1 DNAJB6-related (previously limb-girdle muscular dystrophy 1D) (7q) – DNAJ homolog, subfamily B, member 6 (DNAJB6). DNAJB6 belongs to the DNAJ/HSP40 family of proteins, and it regulates molecular chaperone activity as a cochaperone (370). DNAJB6 is ubiquitously expressed, including in skeletal muscle, though with highest expression in the brain. Its best characterized function is the participation with the heat shock protein HSP70 in preventing aggregation of misfolded or otherwise aggregation-prone proteins, including polyglutamine containing huntingtin, alpha-synuclein, TDP-43, and Abeta42, through a process involving preferential interaction with misfolding forms of these proteins. One patient (with a known Phe93Leu DNAJB6 mutation) has been reported with pathologically confirmed frontotemporal dementia and no mutation in any of the known frontotemporal dementia genes. Whether this is a coincidence or other patients with DNAJB6-myopathy will also develop frontotemporal dementia with aging remains to be seen (554).
Mutations affecting the glycine/phenylalanine-rich (G/F) domain of DNAJB6 are most commonly reported, but mutations in J domain can also cause myopathy (441). These mutations likely interfere with the interaction between DNAJB6 and HSP70, resulting in defective antiaggregate properties and altered protein degradation system in cells – in other words, the mutations contribute to aberrant chaperone function (380; 442). There may be a genotype-phenotype correlation, with mutations affecting the amino acid in the more C-terminal part of the G/F domain (Pro96 and Phe100 in this) as well as mutations causing skipping of the entire G/F domain, correlating with a more distal phenotype compared to the more N-terminal amino acids (Phe89, Phe91, and Phe93) (429).
The p.A50V mutation in J domain has been associated with a distal calf-predominant phenotype whereas p.E54A mutation leads to a more proximo-distal phenotype (380). Onset can be very early (age 6) or late (6th decade). A retrospective study of 122 patients showed a mean age of onset of 29.7 years (156). Genotype appears to impact age of onset, weakness pattern, and the median time to loss of ambulation of around 34 years. Slowly progressive leg weakness is characteristic. A posterior-dominant pattern of lower limb muscle impairment with gluteus and truncal muscle involvement is typical (271). Distal predominant weakness is another manifestation of DNAJB6 mutations. Most patients with LGMD demonstrate no cardiac involvement. Dysphagia can be present (252). A family with progressive weakness starting in distal lower limb muscles and progressing to all other muscles including bulbar muscles (sparing extraocular muscles) has been described (428). Some patients are minimally symptomatic even in the seventh decade of life (567).
EMG shows myopathic changes and some patients can display pseudomyotonic or myotonic discharges (252). Muscle pathology demonstrates cytoplasmic inclusions and rimmed vacuoles. In muscle MRI, the radiological features of patients with DNAJB6 Phe93Leu mutations include soleus, adductor magnus, semimembranosus, and biceps femoris muscles in the early stages followed by medial gastrocnemius and adductor longus and later by vasti muscles of the quadriceps. Rectus femoris, lateral gastrocnemius, sartorius, gracilis, and the anterolateral group of the lower leg muscles are spared until late senescence (428).
In a preclinical mouse model of LGMD D1 DNAJB6 knockout mice, lithium chloride improved muscle size and strength. This could be a potential therapeutic option in the future (157).
LGMD D2 TNPO3-related (previously limb-girdle muscular dystrophy 1F) (7q32) –transportin 3 (TNPO3). Transportin 3 is a nuclear import receptor. The mutation discovered in the original Italo-Spanish family was a nonstop mutation (c.2771delA). Later, a missense mutation (c.G2453A) was found in a sporadic case and a frameshift mutation (c.2767delC) was found in a Hungarian family (503; 07). The mechanism of how these mutations in TNPO3 lead to disease is unknown but it may be related to its role in transporting serine/arginine-rich proteins that control precursor-mRNA splicing (181).
Penetrance of the mutation is incomplete and increases with age (148). In this condition, both shoulder and pelvic muscles are involved, but pelvic weakness predominates, and creatine kinase is mildly increased. In the upper extremities, the deltoid and triceps muscles are more affected, whereas in the lower extremities the quadriceps and anterior leg compartment are the most involved. Phenotypes are variable within the family; some patients have adult onset in the 40s, whereas others have a juvenile form starting before age 15 years or resembling a congenital myopathy. No dysarthria, cardiac involvement, or muscle contractures are seen. There is evidence of anticipation with earlier onset in children of affected parents. Specific clinical pointers and indicators for LGMD D2 are skeletal abnormalities, such as arachnodactyly, pes cavus, and mild Achilles tendon retraction. Macroglossia, mild facial weakness, calf hypertrophy, gynecomastia, dysarthria, partial ophthalmoparesis, neck extension, and flexor weakness (181) were only occasionally observed. Dysphagia was found in 8 of 29 patients in a case series. A rapid worsening of symptoms was reported to have occurred following intense physical exercise, alcohol intake, long periods of inactivity, benzodiazepine overuse, and pregnancy in some cases.
Muscle MRI shows the atrophy is more prominent in lower than in upper extremities, preferentially in the vastus lateralis and posterior leg compartment (398).
There can be sparing of the gracilis and rectus femoris muscles (181). Muscle biopsy findings include increased fiber size variability, fiber atrophy, and acid-phosphatase-positive vacuoles (79), ragged red fibers, cytoplasmic bodies, and enlarged mitochondria with procrystalline inclusions (181). Rod-like structures and other changes suggest a derangement of the cytoskeletal network.
LGMD D3 HNRNPDL-related (previously limb-girdle muscular dystrophy 1G) (4p21) – HNRPDL. HNRNPDL is a heterogeneous ribonucleoprotein (hnRNP) family member that has been shown to function in mRNA biogenesis and mRNA metabolism, including alternative splicing, mRNA nuclear export, translational regulation, and turnover. HNRNPDs participate in the splicing of specific exons in pre-mRNA of transcripts from important muscle-related genes (524). The disease has been found in four families so far with mutations affecting the same codon (c. G1132C/A, p.D378H/N) in HNRNPDL (470; 524; 38; 480). The mutation may lead to a loss of function, impacting hnRNPDL self-assembly properties, and accelerating protein aggregation in muscle cells (26).
The phenotype includes pure limb-girdle presentation starting in lower extremity, distal lower limb weakness, and oligosymptomatic cases. Limitation of finger and toe flexion is also a characteristic of this condition, although not always present (470; 480). Weakness usually starts in the second to fifth decade. Early onset (younger than 50-years-old), cataracts, and diabetes can also be present. Myotonia is absent. In a Spanish family with a scapulo-peroneal phenotype, cognitive impairment was another characteristic (522).
Scapular winging was characteristic in a case series (38).
In Italy, a woman with a previously reported pathogenic variant c.1132G > C p.(Asp378Asn) in the HNRNPDL gene experienced diaphragmatic weakness requiring noninvasive ventilation during hours of sleep, a unique case because respiratory muscles are not usually involved in LGMD D3 (316).
Muscle MRI shows involvement of vastus muscles, with partial sparing of rectus femoris and biceps femoris and complete sparing of adductor longus (480).
Muscle biopsy shows a predominantly myopathic histopathological pattern associated with rimmed vacuoles and autophagic vacuoles (38).
LGMD D4 calpain3-related (previously limb-girdle muscular dystrophy 1I) (15q) – Calpain-3 (CAPN3). Calpain 3 mutations are one of the most common causes of limb-girdle muscular dystrophy (LGMD R1 calpain3- related or LGMD 2A in the prior classification).
Interestingly, although CAPN3 mutations usually cause autosomal recessive limb-girdle muscular dystrophy (LGMD R1), there have been reports of patients heterozygous for the c.643_663del21 mutation who presented with autosomal dominant limb-girdle muscular dystrophy (LGMD D4). These patients reported variable weakness in their 40s or 50s, with myalgia, back pain or hyperlordosis. Pelvic girdle muscles were affected with adductor and hamstring sparing (different from LGMD R1). Creatine kinase was normal to elevated, independent of weakness severity. Electromyography and muscle biopsy were normal to mildly myopathic. Western blot muscle CAPN3 expression was reduced (528; 323; 360).
Further missense mutations in CAPN3 have been characterized for LGMD D4, including c.700G> A, [p.(Gly234Arg)], c.1327T> C [p.(Ser443Pro], c.1333G> A [p.(Gly445Arg)], c.1661A> C [p.(Tyr554Ser)], and c.1706T> C [p.(Phe569Ser)] (186). Another missense variant is c.1715G>C p.(Arg572Pro) and another deletion mutation of CAPN3 discovered is c.643_663del (529).
A study using next-generation sequencing in 4656 patients with limb-girdle muscular dystrophy phenotype found an in-frame deletion c.598_612del15 in the CAPN3 gene without a second pathogenic variant in 16 patients, indicating another potential autosomal-dominant form of calpainopathy in these cases (360). For more details on CAPN3 function and clinical features, see LGMD R1 description.
LGMD D5 collagen 6-related (previously Bethlem myopathy dominant) (21q, 2q) – collagen type VI subunits alpha-1, 2, and 3 (COL6A1, COL6A2, COL6A3). This condition is caused by mutations to three genes encoding different subunits of collagen type VI. Two of them are on chromosome 21q (alpha-1, alpha-2) and one on chromosome 2q (alpha-3) (248).
In 1976, Bethlem and Van Wijngaarden described an autosomal dominant, early-onset but relatively benign limb-girdle muscular dystrophy associated with flexion contractures in many members of three unrelated Dutch families. The progression was extremely slow, with periods of arrest for several decades; the ability to walk was preserved until old age. Ankle and elbow joints seemed preferentially affected and long finger flexor contractures were usually the first signs. Serum creatine kinase was normal or slightly elevated, EMG showed a myopathic pattern, and muscle biopsy disclosed nonspecific myopathic alterations.
Onset is earlier than in typical limb-girdle muscular dystrophy; nearly all patients demonstrate weakness or contractures before 2 years of age, but progression is slow and continues into adulthood (247). More than two thirds of patients over 50 years of age are wheelchair bound (247; 264). Three family members heterozygous for c.2107A>C p.T703P mutation in the COL6A2 gene had symptom onset at 40 to 60 years of age and the diagnosis was suspected only based on characteristic muscle MRI findings (251).
Similar to other dominant limb-girdle muscular dystrophy syndromes, an allelic recessive disorder was described: Ullrich scleroatonic muscular dystrophy. This is an autosomal recessive form of congenital muscular dystrophy with distinctive proximal joint contractures, distal joint hyperextensibility, scoliosis, and normal intelligence (221; 515). Later, autosomal dominant and recessive patterns have been observed in both Ullrich and Bethlem phenotypes. Intermediate manifestations are also common (264; 71; 561). A large clinical variability, including intrafamilial variability, has been seen (121; 561). The recessive form of collagen VI-related dystrophies is designated as LGMD R22.
Muscle MRI in COL6 in patients with Bethlem myopathy and Ullrich congenital muscular dystrophy characteristic findings that aid in the diagnosis. In patients with Bethlem muscular dystrophy, the vasti muscles show a rim of hyperintensity at the periphery of the vastus lateralis and hyperintensity at the center of the rectus femoris (central shadow). There is relative sparing of the sartorius, gracillis and adductor longus muscles. In the calf, there is a rim of hyperintensity between the soleus and the gastrocnemius. The MRI findings are similar in Ullrich congenital muscular dystrophy, except for the presence of a more diffuse muscle involvement (331; 138).
The use of skin biopsy with COL6 staining is postulated to facilitate diagnosis (82). However, COL6 expression can be only mildly reduced in Bethlem myopathy and variable in Ulrich muscular dystrophy, making diagnosis difficult. Some skin physical exam findings, such as follicular hyperkeratosis and keloid formation, may provide cues to possible COL6 deficiency in the right clinical context (280).
Interestingly, mutations in COL6A3 have also been associated with a form of isolated recessive dystonia (DYT27) (301).
LGMD R (previously autosomal recessive [type 2] limb-girdle muscular dystrophies). This category includes a group of autosomal recessive disorders, although some may appear to be sporadic. Proximal muscles are more severely affected; cardiac and bulbar muscles are typically but not exclusively spared. These disorders include the majority of limb-girdle muscular dystrophy cases. There is considerable clinical overlap between entities and diagnosis on purely clinical grounds remains problematic, although some differing characteristics will be highlighted where appropriate.
LGMD R1 calpain3-related (previously limb-girdle muscular dystrophy 2A) (15q) – Calpain-3. LGMD R1 was the first muscular dystrophy shown to be caused by an enzymatic abnormality rather than a structural muscle protein defect. Calpain-3 protein likely functions as a homodimer and is a calcium-activated nonlysosomal cysteine protease that plays a role in muscle regeneration, sarcolemmal repair, sarcomere remodeling, cytoskeleton regulation, and calcium homeostasis (422; 126; 210). Calpains are found in all mammalians and many plant tissues, but the CAPN3 isoform is predominantly found in muscle.
CAPN3 can be detected in three compartments (myofibrillar, cytosolic and membrane fractions. The myofibrillar fraction is bound to titin, which stabilizes it. The cytosolic fraction is stabilized by the Platform Element for Inhibition of Autolytic Degradation (PLEIAD) protein. The membrane fraction exhibits more activity and is concentrated at the triad, where it colocalizes with a protein complex including RyR1, CaMK, and aldolase (137; 375) and works as a structural protein rather than a protease. Studies have shown that calpain-3 can cleave the C-terminus of filamin-C in vitro and that this modification may decrease the ability of filamin-C to bind to delta- and gamma-sarcoglycans (197). The secondary CAPN3 deficiency in titin gene defects (LGMD2J) suggests that the pathomechanisms of the diseases are linked. Studies in yeast have identified myospryn (linked to hereditary cardiomyopathy) as a binding partner for both M-band titin and CAPN3 (440). The protein may also play a role as a switch in muscle remodeling (108). Calpain-3 may also be related to dysferlin, the protein involved in LGMD R2, by a common protein AHNAK, which is involved in subsarcolemmal cytoarchitecture and membrane repair. Calpain-3 cleaves AHNAK, which in the fragmented form loses its affinity for dysferlin (229).
Studies in calpain-3 knockout mice have shown that lack of calpain-3 leads to reduced ryanodine receptor (RyR1) expression, abnormal calcium 2+/calmodulin-dependent protein kinase II (Ca-CaMKII)-mediated signaling, attenuated calcium release, and impaired muscle adaptation to exercise (114). Calmodulin is a positive regulator of CAPN3 activity. Calpain-3 deficient myotubes show increased degradation of sarco/endoplasmic reticulum Ca2+ ATPases (SERCA) proteins (502). Studies in muscle tissue suggest that the dystrophic processes in LGMDR1 associate with oxidative stress, increased protein ubiquitinylation, and activation of NF-kB p65. In LGMD R1 muscle protein, ubiquitinylation may occur through the activation of MuRF 1 and MAFbx. NADPH oxidase appears to be one possible source of oxidative stress in these dystrophic muscles. Calpain-3 also appears to be important for muscle regeneration, comparing LGMD R1 patient samples from others with LGMD R9 and Becker muscular dystrophy (211). In LGMD R1, frizzled related protein (FRZB) is upregulated and there appears to be a reciprocal relationship between FRZB and CAPN3 (76).
First reported in 37 affected members of two large Amish kindreds (240), this form of muscular dystrophy was later reported in families from the French Reunion Island near Madagascar (31; 150) and in Brazilian families (389). A genetic epidemiology study in northeastern Italy found a prevalence of 9.47 per million, suggesting that LGMDR1 is one of the most common autosomal recessive disorders (144). Several different mutations in the CAPN3 (calpain-3) gene have been reported in affected members of these genetically unrelated families. The entity is a common cause of limb-girdle muscular dystrophy; close to 500 distinct mutations have now been identified, although a small number of mutations underlie the majority of cases (188; 141) (Leiden muscular dystrophy database). In some populations, mutations in this gene account for 28% to 50% of limb-girdle muscular dystrophy cases if sarcoglycanopathies and dystrophinopathies are excluded (91; 147). Some particularly common mutations include the c.2120A>G mutation in the Chinese population and the c.550del in European populations (565). LGMD R1 is the most common form in France, with 10 to 70 cases per million people (315).
Age at onset ranges from 2 to 45 years; loss of ambulation occurs about 10 to 30 years after onset of weakness, from early adulthood to the seventh decade (usually between 10 and 45 years of age). There is no correlation between age of onset and time of wheelchair confinement (431). The type of mutation was not entirely predictive of disability, though patients with two null mutations seem to be less ambulatory than patients with one missense mutation. The weakness usually starts in the pelvic girdle with later involvement of the shoulder girdle, or less commonly starts in the shoulder girdle (usually milder form). The characteristic pattern is muscular atrophy of pelvic girdle sparing hip abductors even in late stages, scapular winging, abdominal laxity, frequent contractures, and preserved respiratory function (403; 65). Early involvement of hip adductors and hamstring is common. Facial and neck muscles are usually spared. Calf muscle hypertrophy and cardiac involvement are uncommon. Creatine kinase is often elevated but not to the levels seen in the sarcoglycanopathies, dysferlinopathies or dystrophinopathies. In patients with long disease duration, nonambulatory, and with normal CK levels, the frequency of respiratory dysfunction increases (up to 20%) (348). Respiratory failure usually occurs in advanced disease, although one case with marked respiratory muscle weakness in a still-ambulatory patient has been described (322). There is usually no cardiac involvement.
Pizzanelli and colleagues reported a young girl with LGMDR1 and coexistent generalized epilepsy (401). Tsao and Mendell describe a boy with absence seizures, a normal brain MRI, and partial calpain deficiency (505). There is one report of late-onset foot drop as a presenting sign (63). Because of this heterogeneity, it is currently impossible to definitively distinguish this form of dystrophy from other forms of limb-girdle muscular dystrophy on clinical features alone. Late-onset myopathy and camptocormia were described in a calpainopathy carrier (291).
There is considerable variation in disease severity, including some with isolated hyperCKemia and others with predominantly distal myopathy (147). An early and transient feature in LGMDR1 may be eosinophilic myositis, which has been documented only in young patients with increased creatine kinase (CK) levels and peripheral blood hypereosinophilia. Some patients with LGMDR1 may present with a pseudometabolic myopathy, with asthenia, myalgia, exercise intolerance, proximal muscle weakness, and excessive lactate production. Asymptomatic hyperCKemia (5 to 80 times normal values), usually observed in children or young patients, is the preclinical stage of the disease and may persist for decades. CK levels gradually decrease with the progression of muscle atrophy and weakness (140). The disease appears clinically more heterogeneous among the Amish families than among the Reunion Island families, but cases have been seen in numerous countries worldwide (403; 144; 17; 216; 366; 417; 540; 02; 397; 418; 496; 548; 230). Interestingly, the disease seems to have slower progression in the Indian population in comparison to Europeans and missense mutations seem to confer an overall better prognosis in comparison to nonsense mutations (390). Muscle MRI shows selective involvement of thigh muscles in the lower limbs, mainly of the adductors, hamstrings, and gluteus minimus. Sartorius, gracilis, quadriceps, biceps short head, and iliopsoas are relatively spared. At calf level, the involvement is predominant at the soleus muscle and of the medial head of the gastrocnemius with relative sparing of the lateral head of gastrocnemius and other muscles belonging to the anterolateral compartment of the leg. As muscle MRI may show a typical pattern of involvement even in the “contracted” phenotype of LGMD2A and may help to differentiate it from other clinically similar muscular dystrophies such as Emery-Dreifuss and Bethlem myopathy, imaging might help to tailor further genetic testing in these phenotypically similar patients (330). Like collagen VI-related disorders, a high signal observed at the central area of muscles on MRI is associated with longer and more severe disease course (21).
Muscle biopsy findings in patients with LGMDR1 can vary from the usual dystrophic pattern, with prominent lobulated fibers and scanty inflammatory infiltrates, to one with eosinophilic myositis or macrophage-rich regional inflammatory infiltrates, which can be confused for an autoimmune disease but does not respond to immunosuppressive treatment (453). Mitochondrial abnormalities with COX-negative muscles fibers, ragged red fibers and mitochondrial depletion have also been described (130).
At present, protein immunostaining of muscle biopsy samples is not highly reliable, and Western blotting or genetic testing is needed to confirm the diagnosis. In a review of 208 cases based on protein and genetic analysis, it was found that the probability of a gene defect is high with complete protein deficiency (84%) and declines with increasing protein expression (141). Whereas some calpain-3 mutations alter the level of protein expression, others alter the autocatalytic enzyme activity without affecting protein expression (145). Fanin and colleagues screened 148 muscle biopsy specimens with normal calpain-3 levels and found that 11% of samples had abnormal autolytic function (143). Some patients with limb-girdle muscular dystrophy-R1 will be missed if they are tested by immunohistochemistry or Western blotting only. Fanin and colleagues conducted a quantitative analysis of calpain-3 protein in 519 muscles from patients with unclassified limb-girdle muscular dystrophy, unclassified myopathy, and hyperCKemia as well as a functional assay of calpain-3 autolytic activity in 108 cases with limb-girdle muscular dystrophy. Coincident genetic testing found 94 LGMD2A patients, carrying 66 different mutations (6 newly identified). The probability of diagnosing calpainopathy was very high in patients showing either a quantitative (80%) or a functional calpain-3 protein defect (88%). They concluded that reduced or absent calpain-3 or lost autolytic activity had a high predictive value for a genetic diagnosis. These methods are proposed to be desirable because of the laborious task of identifying one of the multitudes of genetic defects in this condition (146). Only 70% of patients with recessive calpainopathy have quantitative calpain-3 deficiency by immunoblot. The remaining 30% of patients may have mutations that alter protein function but not quantity, manifesting with compromised autolytic calpain-3 activity (148). In a small proportion of cases, calpain-3 protein deficiency can be secondary to a primary defect of other proteins, such as dysferlin and titin, or to its artificial degradation as a consequence of inadequate tissue treatment. Many other diverse disorders have been associated with, likely secondary, calpain-related dysfunction, but are not due to gene mutations. One intriguing example is a suggested secondary deficiency of calpain-3 in patients with myoglobinuria from eating toxic quail meat (359).
Other gene defects may secondarily affect calpain-3 function and expression as well. The abnormally expressed genetic region mutated in facioscapulohumeral muscular dystrophy (FRG1) affects other downstream genes including Rbfox1 that appears to secondarily affect calpain-3 expression. Facioscapulohumeral muscular dystrophy (FSHD) and LGMD2A share some phenotypic features. In FRG1 mice and FSHD patients, the calpain-3 isoform lacking exon 6 is increased. Also, Rbfox1 knockdown and over-expression of the calpain-3 E6- isoform inhibit muscle differentiation. The results suggest aberrant expression of an altered calpain-3 protein through dysregulated splicing (400).
Interestingly, although CAPN3 mutations usually cause autosomal recessive LGMD R1, there have been reports of patients heterozygous for the c.643_663del21 mutation who presented with autosomal dominant LGMD (see LGMD D4), which tends to be less severe than the recessive form.
LGMD R2 dysferlin-related (previously limb-girdle muscular dystrophy 2B) (2p) – dysferlin. This subtype of limb-girdle muscular dystrophy is associated with defects in the DYSF gene that encodes the protein dysferlin and is expressed in adult mammalian cardiac and skeletal muscles as well as multiple nonmuscle tissues, including kidney, brain, and lung. Bashir and colleagues reported the initial linkage of this limb-girdle muscular dystrophy to 2p in Palestinian and Sicilian families (25), but patients have been identified in numerous countries. Dysferlin appears to play an important role in sarcolemmal repair, especially sarcolemmal resealing. In normal skeletal muscle cells, injury leads to a process of Ca2+-dependent membrane repair that involves membrane patches enriched in dysferlin (20). In dysferlin-null mice, this repair process is defective, and the mice develop progressive muscular dystrophy (20). A mouse model also displays early, severe, and progressive diaphragm involvement—a finding not appreciated in humans (24). Subcellular labeling of dysferlin also colocalizes with the developing T-tubule system in mice; dysferlin is necessary for correct T-tubule formation; and dysferlin-deficient skeletal muscle is characterized by abnormally configured T-tubules (269; 224). Most of the dysferlin present in mature skeletal muscle fibers concentrates in the T-tubules, where it stabilizes Ca2+ release at the triad junction when muscle is injured either in vitro or in vivo (305). Dysferlin is also thought to have a role in myogenesis, angiogenesis, microtubule dynamics, cytokine secretion, lysosome exocytosis, acid sphingomyelinase secretion, and phagocytosis (95). In mice, dysferlin deficiency confers increased susceptibility to coxsackievirus-induced cardiomyopathy (538). Dysferlin also may play a role in cholinergic signaling in the neuromuscular junction (273). There is also activation of the ubiquitin proteasome system (UPS) and autophagy programs in dysferlinopathy partly due to regeneration and an inflammatory reaction (142). Humans also produce an alternate splice variant lacking one exon (delta17), which is replaced by the full-length version during muscle development but is the predominant form in normal peripheral nerve (433).
Dysferlin is normally present in muscle membrane and is lost in limb-girdle muscular dystrophy R2. Miyoshi myopathy, a rare disorder but the most common form of distal-onset myopathy, is an allelic disorder with genetic defects not only in the same DYSF gene but also often with identical mutations (339). The defect is a common cause of distal myopathy either with severe posterior compartment (gastrocnemius) involvement in Miyoshi myopathy or with distal myopathy with anterior tibialis onset (DMAT) (433). A series of Spanish patients were found to have identical dysferlin mutations and three different phenotypes: limb-girdle muscular dystrophy, Miyoshi myopathy, and anterior compartment atrophy (525). Other clinical presentations in patients with dysferlin mutations include proximodistal weakness (more severe), exercise intolerance, and asymptomatic hyperCKemia.
LGMDR2 prevalence is 1/100 000 to 1/200 000 people. Onset is often later than in other recessive limb-girdle muscular dystrophy forms, usually after age 15 (as late as 7th decade) with early lower extremity involvement and difficulty in toe walking and running. There is preservation of hand and neck muscles at the late stage and lack of facial muscle weakness or dysphagia. There is rare cardiac dysfunction. Respiratory function declines with disease duration. Loss of ambulation occurs at a mean of 20-year disease duration (489). Joint contractures commonly affecting ankles, knees, and elbows can be present in 36% of patients. Distal lower limb muscle atrophy is seen in 71% of cases. Muscle pseudohypertrophy can be seen in 11% of cases, usually in distal lower extremity muscles. Up to 19% of patients report an above-average sporting ability before the onset of symptoms (207).
A wide variety of phenotypes have been observed in the series of DYSF mutations characterized to date (68). Ueyama and colleagues found that calf involvement with sparing of the tibialis anterior is common to both diseases but is the dominant feature in Miyoshi myopathy, whereas proximal muscle weakness dominates in limb-girdle muscular dystrophy (507). Late-onset muscular dystrophy linked to dysferlin mutations has also been reported in a 73-year-old man with proximal muscle weakness (268) and another elderly patient with isolated calf weakness and atrophy and markedly elevated creatine kinase (255). The phenotype does not appear to affect progression or prognosis (387). Interestingly, on MRI studies the adductor magnus and gastrocnemius medialis were the first to be impaired in both phenotypes. Several other phenotypes have been described.
Rarely, a rigid spine phenotype can develop. A case report from Japan describes a patient with LGMDR2 and chorea (488). An LGMDR2 patient was reported with coexisting sarcoidosis and autoimmune Addison disease, suggesting a possible link between LGMDR2 and autoimmunity (456). Another report describes a patient with LGMDR2 and minimal change nephropathy with absent dysferlin in the renal glomeruli (239). Rosales and colleagues noted some characteristic features in a cohort of 21 patients (427). A distinct "bulge" of the deltoid muscle in combination with other typical findings was noted. Respiratory weakness and cardiac involvement are atypical. However, some LGMDR2 patients progressively develop dilated cardiomyopathy with reduced left ventricular ejection fraction and interstitial fibrosis. Some patients without cardiac symptoms have mild left ventricular hypertrophy. A case misdiagnosed and treated for refractory polymyositis was reported (526).
Different phenotypes can occur within families, but affected siblings typically have the same disorder (465; 462). Fanin and colleagues found that 60% of biopsied patients with distal myopathy had a dysferlin mutation, but only 1% of patients with undiagnosed limb-girdle muscular dystrophy were positive (147). However, defects in the DYSF gene are the second most common cause of limb-girdle muscular dystrophy in some populations. Because of the prevalence of dysferlinopathies, Fanin suggests screening for dysferlin mutation-suspected carriers and for asymptomatic patients with idiopathic hyperCKemia (143).
A muscle MRI study showed that head and cervical muscles, levator scapula, trapezius, pectoralis minor, popliteus, piriformis, posterior forearm compartment, and transversus abdominis muscles are usually spared. On the other hand, subscapularis, lumbaris erector spinae, gluteus minimus, tensor fasciae latae, obturator externus, quadriceps, semimembranosus, semitendinosus, biceps femori, hip adductors, and all leg muscles (except popliteus) are usually involved (184). A case report demonstrated some unusual fatty degeneration in the lumbar paraspinalis in an LGMD R2 patient, detected on MRI (262).
Muscle biopsies may show inflammatory response more often than in other forms of limb-girdle muscular dystrophy and serum creatine kinase is typically markedly increased. These features can lead to confusion with an inflammatory myopathy. Inflammasome upregulation was demonstrated in dysferlin-deficient muscles, suggesting activation of proinflammatory cytokines, including IL-1beta and IL-18.
In addition, clinically affected heterozygotes have been reported in two Spanish mutations (234). Both patients had clinical weakness, elevated CK, and abnormal muscle biopsy and muscle MRI but normal dysferlin PCR and no coincident unrelated mutation; both had homozygous affected relatives. A different family with pauci-symptomatic (cramps, mildly elevated CK) heterozygous carriers has also been described (243).
Genetic testing should replace the need for muscle biopsy. There are currently over 250 different gene defects reported (Leiden muscular dystrophy database). In fact, new variants of DYSF gene mutations in LGMD R2 continue to be reported, including a novel heterozygous variant that involves a frameshift mutation of c.4010delT (288). Absence of the protein is diagnostic for LGMDR2 (09). However, there are patients with reduced but not absent protein, or dysfunctional dysferlin (498) and some with increased dysferlin expression in Western Blot due to a pathological retention of mutated polypeptide in the cytoplasms. For this reason, immunohistochemistry in biopsy samples can be unreliable, and DNA sequence testing is recommended. Dysferlin western blot analysis in monocytes has been proven to be highly predictive of primary dysferlinopathy provided that protein quantity is lower than 10%; the amount of dysferlin was evaluated to be less than 11% in affected patients, 24% to 78% in heterozygous carriers, and greater than 75% in healthy individuals. However, there are false-negative results (139). A nonquantitative immunoassay that may be used at centers with limited resources for detection of dysferlinopathies from peripheral blood samples has been developed (100).
Dysferlin expression in muscle can also be reduced in patients with sarcoglycan, dystrophin, caveolin, or calpain mutations. Next-generation sequencing in 90 patients with dysferlin deficiency in muscle revealed that 70% had DYSF mutations, 10% had CAPN3 mutations, 2% had CAV3 mutations, 3% had mutations in other genes (in single patients), and 16% did not have any identified mutations (238).
Many animal models are in use to search for potential treatment. In a murine model of LGMB2B, human adipose-derived stromal cells (HASCs) were inserted without immunosuppression of the animals. The dystrophic mouse muscle was able to fuse with HASCs, express human muscle proteins, and improve motor function in the animals (523). Wang and colleagues developed an in vitro assay based on the finding that membrane blebbing in a dysferlin-deficient mouse and human myocytes model in response to hypotonic shock requires dysferlin (537). Using this model and the nonsense suppression drug, ataluren (PTC124), the group was able to induce read-through of the premature stop codon in a patient with a dysferlin R1905X mutation and produce sufficient functional dysferlin (approximately 15% of normal levels) to rescue myotube membrane blebbing. Also, it has been shown that antisense oligonucleotide-triggered exon skipping is possible in myoblasts generated from control and patient MyoD transduced fibroblasts; high efficiency skipping of exon 32 was demonstrated in this model (543). This strategy may prove to be useful in other exons (284). Another approach is using peptides that might restore aberrant dysferlin function. A German group has created short peptides derived from the dysferlin protein that seem to reduce folding and aggregation errors in the endoplasmic reticulum of myoblast cells derived from patients following laser induced membrane injuries (450). In a dysferlinopathy mouse model, treatment with recombinant human MG53 protein (rhMG53) enhanced muscle membrane integrity independently of the canonical dysferlin-mediated, Ca2+-dependent pathway known to be important for sarcolemmal membrane repair, suggesting a possible therapeutic option (195). AMP-activated protein kinase (AMPK) complex was found to be a potential therapeutic target for dysferlinopathy. AMPK complex interacts with dysferlin and AMPK activator metformin was shown to improve the muscle phenotype in zebrafish and mouse models of dysferlin deficiency (374).
Conventional pharmacological treatment attempts are less encouraging. A blinded, placebo-controlled trial of deflazacort failed to show benefit in a cohort of 25 dysferlinopathy patients randomly treated for 6 months following 1 year of quantified natural decline without treatment, and there was a trend of worsening muscle strength under deflazacort treatment, which recovered after its discontinuation (535). The use of dissociative steroid compounds such as vamorolone (that retains therapeutic corticosteroid effect while reducing side effects) stabilized dysferlin- deficient muscle cell membrane and improved repair of dysferlin-deficient mouse (B6A/J) injured myofibers, indicating its potential use in future clinical trials (468). Ibuprofen was detrimental to muscle function in dysferlin-deficient mice (98).
Dysferlin-null mice exhibited a cholinergic deficit manifested by a progressive, frequency-dependent decrement in their compound muscle action potentials (CMAP) following repetitive nerve stimulation, which was reversed by pyridostigmine, suggesting a possible treatment avenue for this condition (273). Another potential treatment was diltiazem, which reduced eccentric contraction-induced t-tubule damage, inflammation, and necrosis and resulted in a concomitant increase in postinjury functional recovery in dysferlin-deficient mice (261). However, an improved study protocol did not find diltiazem to have any effect on contraction-induced muscle damage in dysferlin-deficient mice (32).
Most encouraging is work to insert a functional copy of the dysferlin gene through viral vector. The full gene is too large to insert, but a cDNA construct was transfected into a mouse model through an adeno-associated virus (AAV) gene transfer and successfully restored function (192). The approach may be suitable for human trials.
Human serum exosomes also carry dysferlin protein and improved membrane repair in dysferlin deficient myotubes. This could be a strategy to deliver dysferlin to affected muscles (120).
Another approach has been the injection of plasmids encoding dysferlin to hindlimbs of dysferlin-knockout mice (308; 193); this could potentially be applied to humans in the future.
LGMD R3, 4, 5, and 6 (previously limb-girdle muscular dystrophy 2C-F – sarcoglycanopathies). Sarcoglycans are glycoproteins needed for the stability of the muscle membrane. The four primary protein forms (alpha, beta, gamma, and delta) form a complex that provides support and signaling functions for the muscle membrane. The complex supports the association between dystrophin and beta dystroglycan (377). All four of these dystrophin-associated glycoproteins (DAGs) have been implicated in specific forms of limb-girdle muscular dystrophy. A distinct epsilon subunit replaces alpha-sarcoglycan in smooth muscle and in some striated muscle cells (476). Zeta-sarcoglycan, identified in mouse smooth and striated muscle, is another subunit of the sarcoglycan complex; levels were reduced in murine muscular dystrophy (544). This protein is also found in brain tissue. Epsilon sarcoglycan mutations lead to a form of myoclonus-dystonia syndrome. Mutations in any of the four main subunits often disrupt the sarcoglycan complex as a whole, leading to decreased biochemical function, typically loss of staining on biopsy samples, and impairment of cytoskeletal-sarcolemmal integrity (30). In fact, the disease in affected individuals is related to the level of residual function of the glycoprotein complex (06). Complete loss of the tetramer will result in earlier onset and more severe phenotype. Complete loss of sarcoglycan manifest from 3 to 15 years of age and patients are typically wheelchair-bound by age 15. Initially, this was thought to be due to underexpression of the sarcoglycan-sarcospan complex because of the mutant sarcoglycan subunits and marked by decreased immunohistochemical staining. McNally and colleagues subsequently demonstrated that loss of the gamma subunit in a knockout mouse model allowed partial retention of the alpha and beta subgroups (199). Studies by Crosbie and colleagues have shown that even when a sarcoglycan-sarcospan complex forms in the setting of a defective gamma subunit, the mutant form is not sufficient to prevent disease. This suggests an even more complex protein-protein interaction than initially thought (101). Beta-sarcoglycan appears to play an initiating role in complex formation and its association with delta-sarcoglycan is essential for proper localization of the complex to the cell membrane. Alpha-sarcoglycan is incorporated at the final stage by interaction with gamma-sarcoglycan (460).
Partial loss of sarcoglycan delays onset until the teens or early adulthood. Interestingly, the primary deficiency of dystrophin in Duchenne dystrophy can also result in secondary deficiency of dystrophin-associated glycoprotein components (369) and dystrophin must be shown to be normal before a diagnosis of sarcoglycanopathy can be made on immunohistochemical grounds. Overall mutations in the four sarcoglycans represent roughly 10% of teen- or adult-onset cases (91) with type alpha sarcoglycanopathy occurring most commonly.
Mutations of beta or delta sarcoglycan often have associated cardiomyopathy. This cardiomyopathy appears to be initiated by perturbation of the sarcoglycan complex in vascular smooth muscle cells that causes vascular constrictions and ischemic events. Notably, both the constrictions in the cardiac vasculature and the cardiomyopathy can be blunted experimentally with the calcium-channel blocker verapamil (97). In contrast, the skeletal muscle abnormalities seen in mice lacking beta or delta sarcoglycan can be rescued by adenovirus-mediated gene transfer into skeletal muscle but not vascular smooth muscle, so it appears that abnormalities of the sarcoglycan complex within skeletal muscle itself are sufficient for the resultant skeletal muscular dystrophy (127).
Muscle MRI shows similar findings in all sarcoglycanopaties: quadriceps gradient with more severe proximal involvement, adductor longus medial sparing, relative sparing of tibialis posterior, flexor digitorum longus and tensor fasciae latae, and hypertrophy of either sartorius or gracilis (492).
LGMD R3 alpha-sarcoglycan-related (previously limb-girdle muscular dystrophy 2D) (17q) – alpha-sarcoglycan (formerly known as adhalin). McNally and colleagues described a French kindred with autosomal recessive limb-girdle muscular dystrophy in which the 50-kd dystrophin-associated glycoprotein adhalin was absent in muscle fibers (326). The adhalin (alpha-sarcoglycan-SGCA) gene was initially mapped to chromosome 17q21 region and later cloned and identified. Adhalin (alpha-sarcoglycan) is an integral component of the dystrophin-associated glycoprotein complex (557). Although mostly expressed in skeletal muscle, adhalin alpha-sarcoglycan mRNA is also present in heart and lung, although Adhalin alpha-sarcoglycan in lung may reflect contamination by smooth muscle. This is the most common of the sarcoglycanopathies, with one mutation accounting for roughly half of all known cases (124).
The clinical severity of myopathy in patients with alpha-sarcoglycan mutations varies strikingly. The most severe phenotypes occur in patients homozygous for null mutations, who express no alpha-sarcoglycan in muscle fibers. Hackman and colleagues identified 11 Finnish patients with LGMD R3; 10 were homozygous for the R77C mutation and one patient was a compound heterozygote with one copy of the R77C allele (200). Patients presented between ages 5 to12 years and all were able to run as young children. They may resemble the X-linked Becker or Duchenne phenotype of dystrophinopathy, including calf hypertrophy, distribution of muscle weakness, and elevated CK; however, cardiac involvement is absent in alpha-sarcoglycanopathy. Patients from a German kindred heterozygous for a 371 T --> C mutation had clinical manifestations ranging from a severe Duchenne-like phenotype in the homozygous index case to mild or moderate weakness including scapular winging in 7 of 12 heterozygote carriers (160). Missense mutations cause relatively milder phenotypes and variable residual adhalin (alpha-sarcoglycan) expression (399). Severity may be as mild as asymptomatic hyperCKemia and patients may also present with very late-onset cases (373). A case presenting with myoglobinuria has also been described (80). Immunohistochemical staining showing alpha-sarcoglycan deficiency can confirm the diagnosis as well as mutation analysis of the SGCA gene. In countries with a high incidence of LGMD R3, SGCA gene analysis should be strongly considered in some boys and certainly in girls with a Duchenne phenotype. In some cases, immunohistochemical staining is normal but Western blot shows decreased alpha sarcoglycan levels (70).
Muscle MRI shows severe involvement of proximal lower extremity muscles and relative sparing of leg muscles until late stages (70). Paraspinal, pelvic, and glutei muscles can be preferentially affected in mild cases (187).
Gene therapy is being explored in murine models, and several promising studies have been published. Using adeno-associated virus type, Rodino-Klapac and associates injected human alpha-sarcoglycan gene into the tibialis anterior of mice using several different promoters (425). They found that sustained, nontoxic levels of alpha sarcoglycan were produced under muscle creatine kinase promoters. Mendell and colleagues conducted a double-blind, randomized controlled trial of adenovirus-associated virus gene transfer into the extensor digitorum brevis muscles of a cohort of affected patients (328). The full sarcoglycan complex was restored in all subjects, and muscle fiber size was increased in one subject at 3 months. Antibodies against the virus developed, but no signs of apoptosis were evident. Mitochondrial biogenesis was impaired in patients and mice with LGMD R3 and was associated with impaired OxPhos capacity. The histone deacetylase inhibitor trichostatin A restored mitochondrial biogenesis and enhanced muscle oxidative capacity (381).
Another possible treatment strategy is employing stem cells that may express alpha-sarcoglycan. Tedesco and colleagues have reprogrammed fibroblasts and myoblasts from patients with LGMD R3 to generate human-induced pluripotent stem cells (iPSCs) and virally transfected the cells to produce alpha-sarcoglycan. Cells transplanted into alpha-sarcoglycan-deficient mice demonstrated restoration of protein expression and reversal of the phenotype (495).
In myotubes from a patient with LGMD R3, treatment with cystic fibrosis transmembrane regulator correctors induced the proper relocalization of the whole sarcoglycan complex, with a consequent reduction of sarcolemma fragility. This is a treatment strategy that needs further investigation (73).
LGMD R4 beta-sarcoglycan-related (previously limb-girdle muscular dystrophy 2E) (4q) – beta-sarcoglycan. Cases of autosomal recessive limb-girdle muscular dystrophy among members of the old order Amish of northern and southern Indiana have been known for almost 3 decades (240). Families from northern Indiana were shown to carry calpain-3 mutations discussed above (422). The Amish families from southern Indiana were found to have mutations in the gene coding for beta sarcoglycan (295). Clinical features of beta-sarcoglycan-related limb-girdle muscular dystrophy resemble those of calpain-3-associated limb-girdle muscular dystrophy (limb-girdle muscular dystrophy R1). Both limb-girdle muscular dystrophy R4 and R6 may be associated with cardiomyopathy, probably because of abnormalities of the sarcoglycan complex in vascular smooth muscle. Beta sarcoglycan-deficient mice also demonstrate secondarily leaky ryanodine receptors, a mechanism that may underlie muscle degeneration and might provide a novel therapeutic target (05).
In a multicentric study of 32 patients with LGMD R4, there was proximal muscle weakness in all patients, but distal involvement was also observed in patients with severe disease early in the disease course. The first symptoms occurred before age 10 years in all patients with severe disease and in 4 of 12 patients with mild disease. All patients with severe disease lost independent ambulation at a mean age of 13 years (range 9 to 17 years). Age at loss of ambulation was between 23 and 59 years in five patients with mild disease (mean 40 years). Frequent clinical signs included calf hypertrophy (78% of patients), tiptoe gait pattern (56%), tendon contracture (69%), scapular winging (59%), and scoliosis (59%). Muscle pain was reported in 75% of mild cases, 40% of unknown phenotype, and in no severe cases. No rhabdomyolysis events were reported. Macroglossia was found in 31% of patients, with almost double prevalence in severe versus mild cases. Cardiac involvement was observed in 20 patients (63%) even before overt muscle involvement. Six patients had restrictive respiratory insufficiency requiring assisted ventilation (19%). There is a significant decrease in cardiac and respiratory functions over time. Ejection fraction is the biomarker that most steadily decreases with disease progression. A decrease in Cpk values is seen with disease progression as there is loss of muscle mass (319). Seventeen different mutations were identified, and three were recurrent. The c.377_384dup (13 alleles) was associated with the severe form, the c.-22_10dup (10) with the milder form, and c.341C.T (9) with both. The entire sarcoglycan complex was absent in 9 of 10 severe cases and reduced in 7 of 7 mild cases. The residual amount of sarcoglycan in muscle was a predictor of age at loss of ambulation (457).
In an LGMD R4 mouse model, after the intramuscular or intravenous injection of beta-sarcoglycan gene driven by a muscle-specific tMCK promoter (scAAVrh74.tMCK.hSGCB), 91.2% of muscle fibers in the lower limb expressed beta-sarcoglycan, restoring assembly of the sarcoglycan complex and protecting the membrane from Evans blue dye leakage (407; 408).
LGMD R5 gamma-sarcoglycan-related (previously limb-girdle muscular dystrophy 2C) (13q) – gamma-sarcoglycan (SGCG). Early works failed to distinguish this severe childhood autosomal recessive form of muscular dystrophy (SCARMD) from Duchenne dystrophy (286; 473; 536). The observation that both girls and boys in the same sibship had Duchenne-like dystrophy was clear evidence that SCARMD was a separate entity.
The locus was subsequently identified as the site of the gene coding for gamma sarcoglycan (365). LGMD R5 is the most frequent limb-girdle muscular dystrophy in North African populations as a result of the founder mutation c.525delT (129). The G787A mutation has been described in unrelated children of Puerto Rican ancestry, suggesting a founder effect (113). The first symptoms appear between 3 and 12 years of age. Pelvic girdle weakness precedes pectoral girdle weakness. However, there is considerable variability in the severity of the disease among siblings and between families. Loss of independent ambulation generally occurs in the second or third decade of life (half of the patients lose ambulation by age 12 years). Progressive scoliosis, macroglossia, and reduction of functional vital capacity are also present. Calf hypertrophy and cardiac involvement are frequent in patients from North Africa (36). Other studies suggest that the typical Tunisian mutation (delta 521T) is associated with milder cardiac manifestations whereas more severe phenotypes are seen in association with entire deletions of exon 7 (402). A wide variety of phenotypes have been reported in a large series of patients with the Tunisian 521T deletion, suggesting that other genetic factors influence the phenotype or that the phenotype responds to environmental influences (259). A case with episodic myoglobinuria is also reported, a pattern more common in metabolic myopathies or occasionally dystrophinopathies (393). A case of embolic stroke secondary to dilated cardiomyopathy has been described (153). Murine studies also suggest that the gamma-sarcoglycan mutations can cause varying phenotypes in different genetic backgrounds that suggest modifying loci that alter the dystrophic phenotype (219).
Histological features resemble those in Duchenne dystrophy, except that there are fewer hypercontracted fibers and less interstitial fibrosis. Overexpression of the gamma subunit in transgenic mice results in upregulation of alpha and beta sarcoglycans, suggesting a role for the gamma subunit in the regulation of the complex as a whole (566). Prominent eosinophilic infiltration, mimicking eosinophilic myositis was described in one patient (28). Patients with this form may also show secondary reduction of dystrophin, which complicates the diagnosis and argues for a direct association of dystrophin with the gamma subunit.
Prenatal diagnosis is possible by demonstrating absence of exon 5 of the gamma sarcoglycan gene in the fetus by chorionic villus sampling (117).
A French group has demonstrated tolerance of adenovirus-associated virus gene transfer of gamma sarcoglycan that included active mRNA and persistent gene expression after 30 days in nine patients (217). An AAV2/8-expressing gamma sarcoglycan controlled by a muscle-specific promoter has been shown efficacious in Sgcg−/− mice through intravenous injection. AAV8 serotype was more efficient in the transduction of striated muscles and gamma sarcoglycan was able to reach therapeutic levels with systemic administration (237). In a mouse model of LGMD R5, treatment with fingolimod (FTY720) produced significant functional benefit by plethysmography and significant reductions of membrane permeability and fibrosis. Furthermore, the protocol elevated protein levels of delta-sarcoglycan, a dystrophin-glycoprotein family member. This indicates that fingolimod could be useful for treatment in the future (218). In vitro, the use of morpholino oligomers to cause gamma sarcoglycan gene exons 4, 5, 6, and 7 skipping resulted in the production of a functional mini-Gamma product containing only exons 2, 3, and 8. This strategy could be used in patients with LGMD R5 affected by different mutations (552).
This multiexon skipping approach was demonstrated to be effective in correcting the aberrant reading frame in vivo using multiple exon-directed antisense oligonucleotide cocktail in a mouse model of LGMD R5 with SGCG 521delT (112).
LGMD R6 delta-sarcoglycan-related (previously limb-girdle muscular dystrophy 2F) (5q) – delta-sarcoglycan. The least common of the sarcoglycanopathies is caused by a mutation in the delta sarcoglycan gene. This mutation has been documented frequently in Brazil (125), where there is a probable founder effect as well as a high degree of consanguinity among the parents of patients with limb-girdle muscular dystrophy R6 (562). This is a very severe and quickly progressive disease characterized by generalized muscle weakness (03). Hypermobility of the interphalangeal, metacarpophalangeal, and elbow joints and delayed language development can also be present (540). In a delta sarcoglycan null mouse, prednisolone, hypothesized to improve cardiac function, actually caused further cardiac damage in animals with cardiomyopathy (27).
LGMD R7 Telethonin-related (previously limb-girdle muscular dystrophy 2G) (17q) – Telethonin. This form of limb-girdle muscular dystrophy was localized to the TCAP gene on 17q11-12 coding for telethonin, a sarcomeric protein (347). The protein, which may be important in myofiber assembly, localizes to the Z-band, where it interacts with titin. Mutations in this gene were initially documented in a few Brazilian and subsequently reported in patients originating from China, Moldavia, Portugal, India, Spain, and Turkey. Reported patients had elevated creatine kinase, onset of proximal weakness in early teens, early toe-walking, thigh atrophy, and calf hypertrophy (50% of cases) and were wheelchair-dependent by mid to late 30s. Upper extremities are minimally affected in some cases (61). Facial weakness can be present, especially after long disease duration. Even in patients with predominant proximal lower limb weakness, foot drop or frequent tripping, related to tibialis anterior involvement, are common initial or late findings (10 years after first symptoms) (99). Achilles tendon and other joint contractures, hyperlordosis, and scapular winging are common. Some patients also report myalgias. Cardiac involvement occurs in some patients, and the clinical course seems to be milder in women than in men (562). Muscle biopsy may show rimmed vacuoles or nemaline rods (379). Muscle MRI shows atrophy and fatty infiltration predominantly in glutei, hip, and thigh muscles and tibialis anterior with the typical sparing of the sartorius muscles (233; 88). Diagnosis is suggested by immunohistochemistry against telethonin in muscle tissue where it would be markedly decreased or absent; however, genetic testing is needed to confirm diagnosis as in some mutations telethonin staining of a truncated form can be present (false negative results) (65; 22). TCAP mutations also cause congenital muscular dystrophy and dilated cardiomyopathy. A Chinese study found additional pathogenic TCAP variants for LGMD R7, including an intronic variant, with the most common variant being c.165-166insG (307). The authors also provided evidence for autophagy as part of the pathophysiology for LGMD R7.
LGMD R8 TRIM 32-related (previously limb-girdle muscular dystrophy 2H) (9q) – TRIM32. TRIM32, a ubiquitin ligase, is expressed in skeletal muscle and interacts with myosin, ubiquinates actin, and likely is involved in maintenance and degradation of myofibrils during muscle remodeling (275). It was suggested that TRIM32 is involved in the ubiquitin proteosome pathway, a specialized pathway for post-translational regulation of protein levels (166; 282). The protein is localized to the Z-line in skeletal muscle and appears to regulate dysbindin; LGMD R8 and STM mutations may impair substrate ubiquitination (300). Immunostainings for desmin and myotilin, substrates of the TRIM32 E3 ligase, were seen increased in the muscle fibers of patients with LGMD R8 (384). Thin, a Drosophila protein highly analogous to TRIM32, is critical to myofibril stability. Fly mutations in this gene produce muscular degeneration (279). In particular, costameric integrin and sarcoglycan protein levels are altered in a Drosophila model for LGMD R8 (29). TRIM32 also regulates skeletal muscle stem cell differentiation and is necessary for normal adult muscle regeneration and myogenic cell proliferation and differentiation (363; 344). Mutations in this gene cause seemingly diverse diseases, including limb-girdle muscular dystrophy (LGMD R8), sarcotubular myopathy, and Bardet-Biedl syndrome type 11.
LGMD R8 has been seen in Hutterites of Manitoba (542). Onset is typically in the second to third decade with slow progression. Most patients remain ambulatory into the sixth decade, without cardiac or facial involvement. CK is mildly to moderately elevated. Rare patients can have peripheral neuropathy (TRIM32 is expressed in nerve). Muscle MRI shows predominant involvement of the posterior thigh and leg compartments, with relative sparing of the flexor digitorum longus, flexor hallucis longus, and tibialis posterior muscles (250).
Frosk and colleagues also describes a Hutterite family with two brothers homozygous for both mutations (164). The mother, father, and five sons were homozygous for a TRIM32 mutation and 2 of 5 sons were also homozygous for L276I mutations in FKRP. The double homozygous exhibited mild decrease in stamina with normal strength. The homozygous LGMD R8 (TRIM32)/heterozygous LGMD R9 (FKRP) family members were virtually asymptomatic. Other mutations have also been found. Borg and colleagues reported a large Swedish family with limb girdle muscular weakness and histological features of a microvacuolar myopathy; the index patients were compound heterozygotes. Family members with one mutation had a milder phenotype; demyelinating neuropathy was also seen in some affected family members (53). A patient with a scapuloperoneal phenotype has also been identified (293).
LGMD R9 FKRP-related (previously limb-girdle muscular dystrophy 2I) (19q) – Fukutin-related protein. Fukutin-related protein gene (FKRP) had been shown to be mutated in severe forms of congenital muscular dystrophy (MDC1C). FKRP gene mutations have also been demonstrated in patients with limb-girdle muscular dystrophy R9, making limb-girdle muscular dystrophy 2I and MDC1C are allelic disorders. FKRP and Fukutin, a protein mutated in Fukuyama congenital muscular dystrophy, share sequence similarities with proteins involved in modifying cell surfaces. FKRP encodes a glycosyltransferase in the Golgi apparatus that is involved in alpha-dystroglycan glycosylation. FKRP transfers ribitol-5-phosphate to alpha-dystroglycan from cytidine diphosphate-ribitol, which is synthesized by isoprenoid synthase domain-containing protein (ISPD) (254). Dimer form of FKRP is important for substrate recognition and its enzymatic activity. Mutations that cause deficiency in oligomerization or enzymatic function of FKRP may lead to dystroglycanopathy (215; 278). There is also some evidence of metabolic impairments in FKRP-deficient skeletal muscles (516). Downregulating FKRP expression in zebrafish by two different morpholinos resulted in embryos that had developmental defects and glycosylation deficiency similar to those observed in human muscular dystrophies associated with mutations in FKRP (256). In this model, co-injection of fish or human FKRP mRNA restored normal development, alpha-dystroglycan glycosylation, and laminin-binding activity of alpha-dystroglycan in the morphants. Mutations in either protein result in secondary lamin alpha 2 and alpha dystroglycan deficiency (57). Moreover, there appears to be a correlation between residual alpha-dystroglycan expression and phenotype. However, in the zebrafish model, FKRP-associated dystroglycanopathy does not completely phenocopy dystroglycan-deficiency (16). A study showed that there was an elevation of autophagy markers and downregulation of a negative autophagy regulator mTORC1 in LGMD R9, indicating an activation of autophagy (163). There was also an increased expression of endoplasmic reticulum stress markers.
Brown and colleagues have identified three broad categories of human FKRP disorders:
(1) Severe congenital patients (MDC1C) were found to be compound heterozygotes with either a null allele and missense mutation or two missense mutations and correspondingly profound alpha-dystroglycan depletion (59).
(2) Patients with limb-girdle muscular dystrophy with a Duchenne-like severity typically had moderate alpha-dystroglycan reduction and were compound heterozygotes for a common FKRP mutation L276I (c.826C> A) and either a missense or a nonsense mutation. Schwartz and colleagues screened samples for the L276I mutation from sporadic, male patients who were referred for dystrophinopathy and had no dystrophin deletions (454). Thirteen cases were found, all with the L276I point mutation. All patients had CK levels ranging from 1000 to 5000 and calf hypertrophy. About one third had loss of ambulation by age 36 and others had cardiac and respiratory deficits. A man who had originally been diagnosed with Duchenne muscular dystrophy based on his phenotype was discovered to actually have LGMD R9, with genes heterozygous for FKRP variants: c.169G>A (p.Glu57Lys) and c.692G>A (p.Trp231*) (371).
(3) Individuals with a milder form of limb-girdle muscular dystrophy 2I were almost invariably homozygous for the common L276I (c826C> A) FKRP mutation and showed a variable but subtle alteration in alpha-dystroglycan immunolabeling. A database review of these patients found that they tended to have a better prognosis in terms of age of diagnosis as well as milder symptoms in comparison to the other subgroups of FKRP mutations, although they still had high rates of cardiac involvement and many still required assistive ventilation at some point (358).
Although variable phenotypic severity has been partly attributed to the differences in the mutations, there has been significant phenotypic variation reported among individuals with the same FKRP mutation (472). The modifiers are unknown. Mouse models of FKRP mutations also show a wide range of disease phenotypes (47).
There have been founder mutations in FKRP reported in European (c.826C> A, LGMD R9), Tunisian (c.1364C> A, congenital muscular dystrophy with brain involvement), Chinese (c. 545A> G, asymptomatic), South African Afrikaner (c.1100C> T, LGMD R9), and Mexican (c.1387A> G congenital muscular dystrophy without brain involvement) populations (304; 165; 167; 351; 283).
LGMD R9 was originally described in a large consanguineous Tunisian family and linked to 19q (122). Poppe and colleagues described the clinical features of limb-girdle muscular dystrophy R9 patients, most of whom had the same C826A mutation. The phenotype included calf hypertrophy, marked creatine kinase elevation, and frequent cardiac and respiratory involvement (405). Over half had cardiac abnormalities, and half of these developed heart failure (404). Forced vital capacity was below 75% in 44% of patients. Oddly, heterozygotes developed cardiac involvement earlier than homozygotes. Isolated dilated cardiomyopathy without limb weakness has been reported in three siblings who were homozygous for the L276I (c826C> A) mutation (354).
The most common FKRP mutation, L276I (c826C> A) in the Hutterite families discussed earlier, is also found in many non-Hutterite families in multiple European countries, Canada, and Brazil, suggesting a founder effect dispersed throughout populations of European origin (165). It is thought to be the most common form of autosomal recessive limb-girdle muscular dystrophy in northern Europe, especially in Denmark, with a reported 38% prevalence of LGMD R9 in the adult recessively inherited limb-girdle muscular dystrophy population, which is a 3- to 4-fold higher prevalence than in other regions (485).
A different mutation in FKRP, A455D, was identified in Tunisian patients with a severe MDC1C phenotype and mental retardation, microcephaly, and cerebellar abnormalities (304). Another phenotype presents as an acute myositis, mimicking viral myositis in infants (531). Of clinical importance, diaphragmatic involvement may cause respiratory insufficiency in patients who remain ambulant (65). Two patients with severe congestive heart failure (severe enough to require cardiac transplantation) but mild muscular findings have been described (320).
Boito and colleagues screened 214 Italian patients with muscular dystrophy and normal dystrophin, alpha-sarcoglycan, calpain-3, and dysferlin immunohistochemistry; FKRP mutations were identified in 6% of patients (13/214) and about one third of these patients had the L276I (c.826C> A) mutation (49). Patients exhibited phenotypic variability within families and among the entire cohort. One homozygote and another heterozygote were completely asymptomatic whereas others had severe cardiac and pulmonary disease. Most patients had predominant hip girdle weakness and calf hypertrophy. In a reported family, some heterozygous carriers of the c.826C> A mutation showed symptoms including calf pseudohypertrophy, scapular winging, and cardiomyopathy (451). Myalgias are also common. A case of LGMD2I and unilateral cataracts (556) and metacarpophalangeal joint hypermobility have been described 539).
Mutations located in the intron of FKRP may also be pathogenic. A case of early-onset LGMD R9 with compound heterozygous c.-253+4A>G and c.826C> A has been reported (445). Willis and colleagues described a novel mutation of single nucleotide insertion (c.948_949insC) and an 18-nucleotide duplication (c.999_1017dup18) in FKRP associated with LGMD R9 (546). Muscle MRI shows that the glutei muscles, adductors, biceps femoris, vastus intermedius, and vastus lateralis are more affected. The rectus femoris, sartorius, and gracilis are relatively spared (540; 553). Cases with only mild adductor magnus fatty infiltration also exist (540). Fat fraction measurement using 3‐point Dixon MRI technique has been shown to be a sensitive marker of disease progression and may be used as a primary outcome measure alongside functional assessments in clinical trials in the future (357).
In a study of nine patients with LGMD R9 after 50 cycling sessions of 30 minutes each over a 12-week period (achieving 65% of their maximal oxygen uptake), the patients had improved exercise capacity and showed no significant increase in CK levels or altered muscle morphology, supporting the benefit of moderate-intensity endurance training in this particular phenotype (484).
In a study of eight patients with LGMD R9, all patients showed abnormal ON/OFF bipolar cell responses and sawtooth 30 Hz flicker waveforms on full-field electroretinogram (202). Further studies are needed to confirm whether this is a specific finding for LGMD R9.
Treatment with prednisolone has been described in two patients with a Duchenne type presentation; both had good response (107). Another patient with necrotizing myopathy in muscle biopsy showed response to steroids, azathioprine, and intravenous immunoglobulin (482). A single-dose treatment of AAV9-FKRP in FKR PP448L mutated mice after disease onset significantly improved the pathology and functional activity over an extended period of time and was even able to extend the lifespan of mice in advanced stages of disease progression (517). In a mouse model homozygous for the P448L mutation that presents as congenital muscular dystrophy, the oral administration of ribitol restored therapeutic levels of functional alpha dystroglycan in skeletal and cardiac muscles. Furthermore, ribitol, given before and after the onset of disease phenotype, reduced skeletal muscle pathology, decreased cardiac fibrosis, and improved skeletal and respiratory function. Ribitol could potentially be used for other FKRP mutations (78).
ISPD overexpression alone and in combination with ribitol has also been shown to improve dystrophic phenotype in a FKRP mutant mouse model (77). Mouse myoblast line and human iPSCs derived from patients with FKRP mutations have been used to screen for compounds that significantly augmented glycosylation of α-dystroglycan and may facilitate drug development for dystroglycanopathies (263).
LGMD R10 titin-related (previously limb-girdle muscular dystrophy 2J) (2q)--titin. Tibial muscular dystrophy, an autosomal dominant adult-onset distal myopathy, was described in a large Finnish pedigree and associated with defects in the protein titin (201). Titin, the biggest single peptide in humans (greater than 38 KDa), stretches from the M-line to the Z-line. Titin has mechanical, developmental, and regulatory functions in striated muscle, and has multiple ligand binding sites, including calpain-3, telethonin, and alpha-actinin (201). Titin is thought to stabilize calpain-3 and protect it from autolytic degradation; in fact, some patients with tibial muscular dystrophy had secondary calpain-3 deficiency (206), supporting the interaction between titin and calpain-3 discussed earlier. Allelic titin disorders include dilated cardiomyopathy without skeletal muscle disease, arrhythmogenic right ventricular cardiomyopathy (ARVC) and monogenic restrictive cardiomyopathy (RCM), familial hypertrophic cardiomyopathy, early onset myopathy with fatal cardiomyopathy (EOMFC), hereditary myopathy with early respiratory failure (HMERF), childhood-onset Emery Dreiffus-like phenotype without cardiomyopathy, multiminicore disease with heart disease, congenital centronuclear myopathy, and young- or early adult-onset recessive distal myopathy.
A mouse model with muscular dystrophy and myositis also shows a deletion in the titin gene likely at the calpain-3 binding site and may be a useful animal model (176). Targeted deletion of the C-terminal end of titin, which contains a kinase domain that phosphorylates telethonin, results in impaired myofibrillogenesis in organizing muscle sarcomeres (336).
Heterozygotes (autosomal dominant) have late onset, slowly progressive distal myopathy, especially of the anterior compartment, and lesser proximal weakness. Cardiac involvement has not been described.
A single titin mutation, Finnish FINmaj, is an 11bp insertion-deletion mutation exchanging four amino acids in the 363rd and last exon of TTN (Mex6), which encodes the C-terminal immunoglobulin domain M10 of M-line titin. It was found in 211 of 386 affected Finnish patients, and there was considerable phenotypic variation (506). The vast majority (91%) had the tibial muscular dystrophy phenotype consisting of late-onset (older than 35 years of age), slowly progressive distal myopathy, especially in the anterior compartment, and lesser proximal weakness with sparing of the short toe extensor digitorum brevis muscle. Nine percent had atypical presentations that included proximal weakness, bulbar weakness, asymmetric weakness, and childhood-onset weakness. Biopsy findings include fiber size variability, central nuclei, necrosis, presence of fibroadipose tissue and rimmed vacuoles. Electron microscopy showed autophagic vacuoles without membrane and very rare inclusions of 15 to 18 nm filaments. Muscle imaging (CT or MRI) is very informative with selective fatty replacement in the muscles of the anterior compartments of the lower legs starting in the anterior tibial muscle and represents a useful clinical tool to address the diagnosis (444). In congenital titinopathies, muscle MRI usually shows fatty infiltration or atrophy at paraspinal, gluteal, and hamstring muscles, whereas the adductors, sartorius, and gracilis are usually spared or hypertrophied (367; 560).
In the original Finnish pedigree, a few patients were affected in childhood with more severe limb-girdle muscular dystrophy and were found to be homozygous for titin mutations; parents of these homozygotes were not affected (206). The homozygous phenotype was adopted as autosomal recessive LGMD R10 (562). Only 2 of 211 patients were homozygous for FINmaj, and neither of these had the tibial muscular dystrophy phenotype. LGMD R10 is a severe childhood onset disease causing proximal muscle weakness in the first or second decade and progresses over the next 20 years to wheelchair confinement. Because the TTN mutation affects the A band, cardiac problems may occur first or may overlap with or follow skeletal muscle weakness (421). LGMD R10 shows a secondary CAPN3 defect. Most biopsied muscles of patients homozygous for the FINmaj variant show dystrophic findings with end-stage pathology without rimmed vacuoles although a case with rimmed vacuoles has also been reported.
A study of muscle biopsy in patients with different titin mutations found that findings depend on the phenotype. Autosomal recessive congenital myopathy showed defects in oxidative staining with prominent nuclear internalization. Autosomal recessive Emery-Dreifuss-like and autosomal recessive adult-onset distal myopathy phenotypes showed necrotic/regenerative fibers associated with endomysial fibrosis and rimmed vacuoles. Hereditary myopathy with early respiratory failure showed cytoplasmic bodies as a predominant finding (13).
A French family with an autosomal-dominant, late-onset distal myopathy of the tibial muscular dystrophy phenotype has been described (394). One deceased patient in the family proved to be homozygous for the C-terminal truncating titin mutation because of consanguinity. A patient presenting with inflammatory infiltrates in muscle biopsy resembling polymyositis refractory to different immunosuppressants has also been described (104).
Measurement of urinary N-terminal fragment of titin/creatinine ratio has been shown to have good 100% sensitivity and 92% specificity in diagnosing cardiomyopathy secondary to muscular dystrophies versus other etiologies (558).
Diagnosis of titinopathy can be difficult because genetic testing can find different variants that may not be causing disease. Savarese and colleagues proposed a workflow for interpreting titin variants (443). If a previously reported, disease-causing mutation is found, the diagnosis is made. Identifying two truncating variants on both the alleles results in a diagnosis of titinopathy. A single heterozygous protein truncating variant is not sufficient for a diagnosis of titinopathy. Missense variants can lead to a diagnosis of titinopathy only when there is sufficient evidence supporting their pathogenicity (functional studies, Western blot, etc.) (443).
LGMD R11 POMT1-related (previously limb-girdle muscular dystrophy 2K) (9q) – POMT1. POMT1 along with POMT2 gene products act to transfer O-mannosyl glycan chains onto alpha-dystroglycan.
An autosomal recessive limb-girdle muscular dystrophy with mental retardation was reported in six Turkish families (116). The consensus phenotype in the eight published cases was mild proximal weakness starting early (age of onset ranged from 1 to 6 years old), mild calves or thigh pseudohypertrophy, elevated CK (range 9 to 40 times normal), microcephaly (range of head circumference 3rd to 50th percentile), and mental retardation (range of IQ 50 to 76). Other than microcephaly, neuroimaging studies were normal. Immunohistochemical analysis of muscle biopsy samples revealed decreased alpha-dystroglycan expression. In five of the Turkish patients (116), Balci and colleagues (18) identified the culprit gene as POMT1 (O-mannosyltransferase), the same gene involved in 7% to 20% of patients with Walker-Warburg syndrome (35; 102) and congenital muscular dystrophy with mental retardation. Haberlova reported two sisters with POMT1 mutations in whom psychiatric symptoms including psychosis preceded the onset of limb girdle weakness (198).
Walker-Warburg syndrome is more severe than LGMD R11 and is characterized by severe cerebral malformations leading to type II lissencephaly, cerebellar and pontine hypoplasia, hydrocephalus, and congenital muscular dystrophy. Another allelic variant presents as severe motor impairment, leg hypertrophy, and mental retardation without brain or eye malformations (103). A dermal fibroblast-based assay of enzyme activity on the glycosylation status of alpha-dystroglycan, protein O-mannosyltransferase activity, and the stability of the mutant POMT1 protein was directly correlated with the severity of the clinical phenotype and inversely correlated with POMT activity (303).
To date, more than 76 disease-associated POMT1 mutations have been reported in the literature (228). Geis and colleagues described 35 POMT1 patients (including eight previously published cases) from 27 independent families of various ethnic origins. Fifteen patients had Walker-Warburg syndrome, one patient had muscle-eye-brain disease-like phenotype, and 19 patients were categorized as LGMD with mental retardation phenotype. There is genotype-phenotype correlation of POMT1-related disorders. Biallelic mutations leading to premature protein truncation result in a severe Walker-Warburg syndrome phenotype. A missense mutation might result in a milder phenotype if not located in a protein domain essential for the catalytic enzyme activity (178).
LGMD R12 Anoctamin5-related (previously limb-girdle muscular dystrophy 2L) (11p) – ANO5. ANO5 is a putative calcium-activated chloride channel and is involved in muscle membrane function and repair (190), but its function is not completely understood (297). ANO5 mutations have been discovered to cause defective annexin coordination during cellular repair (161). Mouse models have also demonstrated that ANO5 mutations cause cytosolic calcium overload with plasma membrane injury, which compromises muscle fiber repair (84). It is expressed in human bone and cardiac and skeletal muscles. Defects in this gene are also associated with the rare skeletal disorder gnathodiaphyseal dysplasia. Despite the relatively late discovery of this gene, it may be more common than others; ANO5-associated limb-girdle muscular dystrophy is reported to be the third most common type of limb-girdle muscular dystrophy in Northern and central Europe, possibly because of a founder effect. This gene was found to be 2% of an Italian cohort of limb-girdle muscular dystrophy and Miyoshi-like patients (220; 312). A Finnish group found eight different mutations in 25% of a varied cohort that included 75% Finnish and varied other origin patients (396). The most common ANO5 variants are c.191dupA in exon 5 and c.2272C>T in exon 20. Testing of these two exons is sufficient for molecular diagnosis in a majority of cases, particularly in individuals of northern or central European descent. LGMD2L was relatively rare among Asians. No recurrent mutation has been identified in Asian populations so far (69).
Anoctamin 5 (ANO5) mutations can present as LGMD R12 (LGMD2L) (50), Miyoshi-like distal myopathy type 3, asymptomatic hyperCKemia, and myoglobinuria after exercise (385).
Asymmetrical weakness and atrophy of quadriceps, biceps brachii and calf muscles as well as myalgia and elevated serum creatine kinase (CK) levels are common clinical features of anoctaminopathy. Some patients have calf hypertrophy (227). Onset of weakness can vary from the second to seventh decade (average 35 years of age). Female patients seem to have a milder phenotype than male patients (294), although early onset of weakness was reported in a woman who did heavy exercise training, which may have caused more sarcolemmal membrane injury (46). Jarry and colleagues described 14 patients from eight different families with asymmetric quadriceps femoris atrophy that evolved into a limb-girdle muscular dystrophy phenotype (244). Creatine kinase levels ranged from normal to 6000; age of presentation ranged from less than 20 to 60 years of age, but average age of onset is around 30 years. Phenotypes varied among individual family members and across different families. Manifesting ANO5 mutation carriers with mildly elevated CK, myalgias, and without muscle weakness have also been described (253). Some patients are also asymptomatic despite elevated CK levels (447). Patients with hypertrophic or dilated cardiomyopathy of possible association have been reported. Cardiac arrhythmia, including bradycardia, paroxysmal atrial fibrillation, and paroxysmal supraventricular tachycardia, is also present in some patients (512). Possible association with macular dystrophy in one patient has also been postulated because ANO5 transcripts have been identified in the retinal pigment epithelium, choroid, and fetal eye (519).
Muscle MRI may show asymmetric muscle involvement, but the pattern was not found to distinguish this phenotype from others such as Bethlem myopathy (438). Predominant involvement of the gluteus minimus muscle and both the posterior segment muscles of the thigh and calf with relative sparing of the gracilis muscle similar to dysferlin mutation is seen (497). A reported patient had isolated semitendinosus involvement in MRI (491). EMG can show electrical fibrillations, positive sharp waves, myopathic motor units, and electrical myotonia without clinical myotonia (294). Muscle biopsy can show rare rimmed vacuoles and also amyloid deposition (ANO5 is not present in those deposits) in the walls of the intramuscular blood vessels and in the endomysium and often surrounding perifascicular muscle fibers. A case with biopsy findings of necrotizing myopathy unresponsive to immunosuppression has also been reported (449). ANO5 mutation-related myopathy is the second most common cause of amyloid myopathy after immunoglobulin light-chain amyloidosis (292). There is no difference in the mutation location or the clinical presentation between patients with intramuscular interstitial amyloid deposits (53% of cases) and those without that finding (04).
In six patients with LGMD R12, home-based, pulse-watch monitored, moderate-intensity exercise on a cycle ergometer for 30 minutes, 3 times weekly for 10 weeks resulted in improvements in maximum oxygen uptake (VO2max) and time in the five-repetitions-sit-to-stand test (FRSTST) without any changes in CK levels (527).
LGMD R13 Fukutin-related (previously limb-girdle muscular dystrophy 2M) (9q) – Fukutin (FKTN). Three patients (Israeli and Indian origin) from two nonconsanguineous families demonstrating abnormal alpha-dystroglycan on muscle biopsy were studied. The patients’ weakness began at less than 1 year of age. Legs were affected more than arms, and calf hypertrophy was seen. CKs ranged from 9000 to 60,000 with inflammatory features seen on biopsy suggestive of polymyositis. All three patients had episodes of deterioration with febrile illnesses. Steroids led to improvement and subsequent stabilization. All patients were able to walk. Mutations were found in the Fukutin gene, the same gene that causes Fukuyama congenital muscular dystrophy (182). Fukutin acts as a ribitol phosphate transferase in the Golgi apparatus to catalyze the biosynthesis of tandem ribitol phosphate structures on alpha-dystroglycan by sequential action with fukutin-related protein (254). Reduced glycosylation on alpha-dystroglycan may disrupt the link between the intracellular cytoskeleton to the extracellular basement membrane through the dystrophin-glycoprotein complex, affecting cardiac muscles, skeletal muscles, and brain (508; 504).
Onset of weakness in LGMD R13 is usually between 4 months to 7 years (although a patient with late onset at 14 years of age has been reported). Calf hypertrophy, lumbar lordosis, joint contractures, scapular winging, and rigid spine can be seen in these patients. A patient with Wolff-Parkinson-White syndrome and LGMD R13 has been described (424). The CK values decreased with steroid treatment in one patient (466).
Fukuyama congenital muscular dystrophy, described in 1960, presents as generalized weakness, severe brain damage, epilepsy, and abnormal eye structure or function and is the second most common muscular dystrophy in Japan after Duchenne muscular dystrophy (168). Another allelic variant presents as dilated cardiomyopathy with little or no muscle involvement (356). Defects in this gene are a recognized cause of childhood onset muscular dystrophy without mental retardation (411) and can also present with asymptomatic hyperCKemia (159).
LGMD R14 POMT2-related (previously limb-girdle muscular dystrophy 2N) (14q) – POMT2. Protein O-mannosyltransferase 2 (POMT2) is a protein involved in alpha dystroglycan glycosylation. Mutations in POMT2 have been identified in patients with congenital muscular dystrophy and brain involvement, either characterized by a Walker-Warburg or muscle-eye-brain phenotype or by microcephaly, mental retardation, and cerebellar hypoplasia. In 2007, Biancheri reported a 5-year-old girl with POMT2 mutation and limb-girdle muscular dystrophy phenotype, calf hypertrophy, elevated CK (3350), and macrophage inflammation in muscle biopsy. She received steroids with resultant reduction in CK levels. She had no mental retardation, eye problems, or brain MRI abnormality (43).
A case series of 12 patients provides a better description of LGMD R14 (LGMD2N) manifestations; onset varied from birth to age 55 years. Patients with birth onset still walked unassisted at 18 years of age. Symptoms at onset include walking difficulty, learning impairment, and myalgias. Four patients had reduced Mini Mental Exam (MMSE) scores. One patient had dilated cardiomyopathy, and other had decreased left ventricular ejection fraction. Functional vital capacity was reduced in all patients at an average of 66%. Hip and knee flexors and extensors were the weakest. Calf hypertrophy was seen in some patients. Scapular winging was seen in three patients. CK was elevated (from 398 to 5000). Brain MRIs were abnormal in 3 of the 10 patients in whom brain imaging was carried out, showing mild ventricular enlargement due to central and cortical atrophy, periventricular hyperintensities, and frontal atrophy of the left hemisphere. Muscle MRI revealed a pattern of selective muscle involvement, most strikingly affecting the hamstring (worst), paraspinal, and gluteal muscles. In the leg, the posterior compartment muscles were more affected (376).
Three siblings with congenital muscular dystrophy caused by POMT2 mutations, significant dilatation of the aortic root, and depressed left ventricular systolic function or left ventricular wall motion abnormalities have been described. For this reason, frequent cardiac surveillance is recommended in patients with POMT2 mutations (321). Other features that have been described in patients with POMT2 mutations include polycystic kidneys, atrial ventricular septal defects, left ventricular hypertrophy, ventricular arrhythmias, scoliosis, café-au-lait spots, axillary freckling, and skin hyperpigmentation (158).
Muscle biopsy shows dystrophic changes with selective reduction of alpha-dystroglycan immunostaining (60).
LGMD R15 POMGnT1-related (previously limb-girdle muscular dystrophy 2O) (1p) – POMGnT1. Protein-O-mannose-_1,2-Nacetylglucosaminyltransferase 1 (POMGnT1) is a glycosyltransferase gene involved in the glycosylation of dystroglycan and is responsible for the transfer of N-acetylglucosamine (GlcNAc) to mannose (318; 222). Mutations have been described in patients with muscle-eye-brain disease, Walker-Warburg syndrome, retinitis pigmentosa 76, and LGMD R15. Clement and colleagues described a girl with onset of proximal upper and lower extremity weakness at the age of 12 years, with calf hypertrophy and lumbar hyperlordosis. She had myopia and surgery to correct convergent squint. Her CK level was elevated (up to 12,000). Muscle biopsy specimen exhibited dystrophia with abnormal variation in fiber size, necrosis, increased endomysial connective tissue and fat, and basophilic fibers, some of which were granular and had vacuoles (94).
Raducu and colleagues described a patient with delayed motor milestones, hypotonia, generalized amyotrophy, lumbar hyperlordosis, and mild CK elevation. Brain MRI and eye examination were normal (414).
LGMD R16 Alpha-dystroglycan-related (previously limb-girdle muscular dystrophy 2P) (3p) – Dystroglycan 1. Dystroglycan is a central component of the dystrophin-glycoprotein complex, which links the cytoskeleton and extracellular matrix through sarcolemma. Dystroglycan has important roles in the development and maintenance of skeletal muscle, the CNS, and other organs. DAG1 mutations cause primary dystroglycanopathy in limb-girdle muscular dystrophy and muscle-eye-brain disease. In 2003, Dincer and colleagues reported a girl with limb-girdle muscular dystrophy and mental retardation. The gene was identified in 2011. Symptoms included progressive proximal muscle weakness at age 3 years, mild calf enlargement, lumbar hyperlordosis, and ankle contractures. Her intellectual development was slow, and she said her first few words at 7 years; at 16 years of age, she only used 2-word sentences. CK was elevated (4000s). Brain MRI was normal (116; 204).
A mild, late-onset limb-girdle muscular dystrophy presentation is also possible (105). A boy with DAG1 mutations and asymptomatic hyperCKemia, calf pseudohypertrophy, and mild dystrophic changes in muscles has also been described (119).
DAG1 mutations are also associated to congenital muscular dystrophy (dystroglycanopathy) with Walker-Warburg syndrome with tectocerebellar dysraphia (285).
LGMD R17 Plectin-related (previously limb-girdle muscular dystrophy 2Q (8q) – Plectin (PLEC). Plectin is a large intermediate filament-binding protein that helps maintain cytoskeleton stability and neuromuscular junction integrity (549). PLEC mutations can cause LGMD R17, different types of epidermolysis bullosa simplex, and congenital myasthenic syndrome (549; 185). Plectin isoform 1f is associated with the sarcolemma whereas isoform 1a is associated with keratin intermediate filaments in basal keratinocytes. Tissue-specific expression and isoform-dependent deficiency of plectin may explain the various phenotypes (420).
There are reports of patients showing myasthenic symptoms as well as epidermolysis bullosa simplex with muscular dystrophy, which are called EBS-MDMys. Regarding limb-girdle muscular dystrophy, Turkish patients with muscular dystrophy but no skin changes were found to have a deletion in this gene (194). Early onset disease that later plateaued was characteristic. Other patients without skin involvement and with limb-girdle muscular dystrophy pattern of weakness, bilateral eyelid ptosis, diplopia, facial weakness, and elevated CK have also been described. Single-fiber EMG was normal, and there was no response to pyridostigmine (152). Pyloric atresia and cardiomyopathy have also been associated with PLEC mutations. Other features include alopecia, onychodystrophy, abnormal dentition, laryngeal webs, respiratory complications, urethral strictures, and mild bilateral hydronephrosis (10; 510).
Togawa and colleagues found heterozygous variants in PLEC gene (c.2668C> T, p.R890C) and ST3GAL6 gene (c.421G> C, p.V141L) in a family with atypical familial amyotrophic lateral sclerosis with slowly progressing lower extremities-predominant late-onset muscular weakness and atrophy. It is unclear whether these variants are pathogenic (500).
Some Turkish women were identified with a c.1_9del mutation in the PLEC gene, with a presentation somewhat similar to a myasthenic syndrome characterized by progressive limb-girdle weakness, muscle biopsy dystrophy, ptosis, facial weakness, fatiguability, and muscle cramps (349). They had clinical improvement with pyridostigmine and salbutamol and also had a common 3.8 Mb haplotype.
LGMD R18 TRAPPC11-related (previously limb-girdle muscular dystrophy 2S) (4q) – trafficking protein particle complex, subunit 11 (TRAPPC11). Transport protein particle (TRAPP) is a multiprotein complex involved in endoplasmic reticulum-to-Golgi trafficking and possibly other membrane trafficking steps. It also plays a role in autophagy (335; 469). TRAPPC11 mutations are associated with congenital muscular dystrophy with fatty liver and infantile onset cataract and also myopathy and intellectual disability, including cerebral atrophy, scoliosis, achalasia, and alacrima (a form of triple A syndrome) (270).
LGMD presentation was described in eight Syrian and Hutterite patients with progressive weakness that started in school age. CK was elevated (9- to 16-fold). There was moderate intellectual disability, infantile hyperkinetic movements, and ataxia. In all affected individuals, the shoulder girdle muscles are less severely involved than the hip girdle musculature. Skeletal findings, present in all affected individuals, included hip dysplasia and scoliosis. Microcephaly, mild bilateral cataract, strabismus convergens, and slight enlargement of the right cardiac ventricle were present in some patients. Respiratory muscle weakness was seen in one patient. Other patients with TRAPPC11 muscular dystrophy have been described with associated retinopathy and natural killer cell dysfunction (281).
Brain MRI showed mild cerebral atrophy in two patients (48; 155) and multifocal diffusion abnormalities in other cases (281). Muscle MRI shows preferential involvement of the posterior leg compartment (281).
LGMD R19 GMPPB-related (previously limb-girdle muscular dystrophy 2T) (3p) – GMPPB. GDP-mannose pyrophosphorylase B (GMPPB) catalyzes the formation of GDP-mannose, which is required for the glycosylation of lipids and proteins. Mutations in GMPPB can lead to hypoglycosylation of alpha‐dystroglycan (75). GMPPB c.803T>C and GMPPB c.1060G>A, associated with LGMD 2T, were found to form cytoplasmic aggregates and were degraded by autophagy-lysosome pathway. These mutations cause abnormal GMPPB distribution and reduced expression (499).
In eight pediatric patients with a dystroglycanopathy due to mutations in GMPPB, all of them presented by 4 years of age. The phenotype ranged from severe congenital muscular dystrophy to limb-girdle muscular dystrophy. Common associated features were hypotonia, epilepsy (40%), intellectual disability (80%), cataracts (40%) and cardiomyopathy (25%); in 30% of patients, brain MRI showed cerebellar hypoplasia (75). Some patients present with congenital myasthenic syndromes with decrement of motor response with 3 Hz nerve stimulation and positive response to pyridostigmine (306; 346).
Other patients have proximal weakness, elevated CK (greater than 17,000), hypertrophic calves, some of them with cardiac involvement including right bundle branch block, sinoatrial block, long QT interval, left ventricular dilatation, and aberrant ventricular conduction. Loss of ambulation was seen by the sixth to seventh decade. Some of them had scapular winging and restrictive respiratory pattern. Episodic rhabdomyolysis as the only symptom was also reported (67). Asymptomatic hyperCKemia and pseudometabolic myopathy or exercise intolerance have also been described (245; 383). Late onset cases (30 to 40 years of age) without brain involvement and with slow progression are also present (19). Patients with GMPPB mutations can have centronuclear myopathy on biopsy and combined pre- and post-synaptic defects of neuromuscular transmission on EMG (364).
Muscle MRI in patients with LGMD R19 shows consistent findings of a preferential affection of paraspinal and hamstring muscles (368).
A case report of a child with GMPPB muscular dystrophy treated with oral prednisone for 3 months showed improvement in muscle strength and function scores and decrease in CK value (154). This could be a future therapy option.
LGMD R20 ISPD-related (previously limb-girdle muscular dystrophy 2U) (7p) – ISPD. ISPD, a gene located on chromosome 7p21, encodes the isoprenoid synthase domain-containing protein and has been implicated in the initial step of the O-mannosylation of alpha dystroglycan. Mutations in this gene have been associated to Walker-Warburg syndrome and muscle-eye-brain disease. ISPD mutations have also been associated with limb-girdle muscular dystrophy of childhood onset with or without cerebellar involvement, white matter changes, or mental retardation. In some cases, patients had calf and tongue hypertrophy, oculomotor apraxia, strabismus, CK elevation, decreased respiratory function, and cardiac ejection fraction (93; 493).
LGMD R21 POGLUT1-related (previously limb-girdle muscular dystrophy 2Z) (3q) – POGLUT1. POGLUT1 (protein O-glucosyltransferase 1), an enzyme involved in Notch posttranslational modification and function, is important for satellite cell regeneration. Four of five siblings from a Spanish family presented with limb-girdle muscular dystrophy. They exhibited muscle weakness predominantly in the proximal lower limbs, with onset during the third decade. The disease course was progressive, leading to scapular winging and wheelchair confinement. Serum creatine kinase level was normal in three patients and mildly elevated in 1. Muscle biopsies from all four affected siblings revealed histological features ranging from very mild myopathic changes to classic dystrophic pathology. Muscle MRI of the legs revealed a striking pattern of muscle involvement, with early fatty replacement of internal regions of thigh muscles that spared the external area (459). Later, Servian-Morilla and colleagues reported a cohort of 15 patients with LGMD R21, from nine unrelated families coming from different countries (458). Age of onset age varied from adult to congenital and infantile onset. Muscle imaging was consistent with previously described "inside-to-outside" fatty degeneration. Patients’ muscle biopsies showed decreased level of the NOTCH1 intracellular domain, reduction of satellite cells, and alpha dystroglycan hypoglycosylation. Their in vitro and in vivo experiments showed POGLUT1 mutations lead to reduced enzymatic activity and/or protein stability. Myogenic activities from transgenic Drosophila and satellite cell-derived myoblasts from patients' muscle samples were reduced. Therefore, muscular dystrophy in patients with LGMD R21 is likely caused by alterations in satellite cell biology from reduced Notch1 signaling, with possibly additional contribution from α-dystroglycan hypoglycosylation (458).
POGLUT1 mutations are also associated with Dowling-Degos disease, an autosomal-dominant hereditary pigmentation disorder that causes varying degrees of progressive reticulate hyperpigmentation, primarily affecting the flexures, large skin folds, trunk, face, and extremities (415). Galli-Galli disease, an acantholytic variant of Dowling-Degos disease, has also been reported with POGLUT1 mutations (272).
LGMD R22 Collagen6-related (previously Bethlem myopathy recessive) (21q, 2q) – collagen type VI subunits alpha-1, 2, and 3. In 1976, Bethlem and Van Wijngaarden described an autosomal dominant, early-onset, but relatively benign limb-girdle muscular dystrophy associated with flexion contractures in many members of three unrelated Dutch families. The progression was extremely slow, with periods of arrest for several decades; the ability to walk was preserved until old age. Ankle and elbow joints seemed preferentially affected and long finger flexor contractures were usually the first signs. Serum creatine kinase was normal or slightly elevated, EMG showed a myopathic pattern, and muscle biopsy disclosed nonspecific myopathic alterations. The defect was mapped to three genes encoding different subunits of collagen type VI. Two of them are on chromosome 21q (alpha-1, alpha-2) and one on chromosome 2q (alpha-3) (248). Onset is earlier than in typical limb-girdle muscular dystrophy; nearly all patients demonstrate weakness or contractures before 2 years of age, but progression is slow and continues into adulthood (247). More than two thirds of patients over 50 years of age are wheelchair bound (247).
An allelic recessive disorder exists—Ullrich scleroatonic muscular dystrophy. This rare autosomal recessive form of congenital muscular dystrophy with distinctive proximal joint contractures, distal hyperextensibility, and normal intelligence has been associated with different mutations in collagen VI subunits (221; 515). The use of skin biopsy with COL6 staining is postulated to facilitate diagnosis (82).
The autosomal dominant form of collagen VI-related dystrophies is designated as LGMD D5 as discussed above.
Interestingly, mutations in COL6A3 have also been associated with a form of isolated recessive dystonia (DYT27) in addition to LGMD R22 (301). A mild phenotype of LGMD R22 caused by the COL6A3 mutation has been discovered that is secondary to aberrant assembly of vWF and for which MRI appears to be more diagnostic than muscle biopsy (471).
LGMD R23 laminin alpha-2-related – LAMA2. LAMA 2 encodes the extracellular matrix protein laminin alpha-2, a subunit of laminin 2 (merosin), the most abundant laminin isoform in the basement membrane of skeletal muscle cells. Laminin alpha-2 is expressed in the cardiac and skeletal muscles, central and peripheral nervous system, and skin.
Recessive mutations in LAMA2 cause a severe form of congenital muscular dystrophy (MDC1A). A limb-girdle muscular dystrophy presentation is associated with mutations causing reduced rather than absent levels of laminin alpha-2 on muscle biopsy. Patients present with mild mental retardation, white matter changes in brain MRI, dilated cardiomyopathy, and even peripheral neuropathy (83; 302; 118; 208), usually demyelinating. Migraines and epilepsy are other common presentations (313). Onset of symptoms in limb-girdle muscular dystrophy ranges from childhood to adulthood and some patients have independent ambulation and only mild symptoms (118).
Muscle MRI shows signal abnormalities in the adductor magnus and biceps femoris and concentric atrophy of muscles similar to that observed in collagen-VI related disorders, with outer area more affected than the center (in mild cases) (475; 83). The sartorius and gracilis muscles were spared. Besides muscle tissue, diagnosis can also be made with skin biopsy that will show absence or reduction of laminin alpha-2 at the dermal-epidermal junction. Brain MRI shows diffuse leukodystrophy but usually patients do not exhibit central nervous system symptoms. Symmetric high signal in the bilateral globus pallidus has also been described (208). Of note, patients with nonspecific brain MRI abnormalities and very subtle laminin alpha-2 staining have been described, making the diagnosis challenging in these cases (437).
Gene replacement using AAV9 vectors carrying the mini-agrin, which is an homologous functional substitute for mutated laminin alpha2 in dyw/dyw mice (LAMA2 muscular dystrophy model) partially amended nerve pathology as evidenced by improved motor function and sensorimotor processing, partial restoration of myelination, partial restoration of basement membrane via EM examination, as well as decreased regeneration of Schwann cells (412). Much research has been concentrated on MDC1A, but some results are likely applicable to LGMD R23 as well (177; 242; 260; 01; 205).
LGMD R24 POMGNT2-related – POMGNT2. O-linked mannose β-1,4-N-acetylglucosaminyltransferase 2 (POMGNT2) is also involved in glycosylation of alpha dystroglycan. Glycosylation of alpha dystroglycan is important for linking intracellular cytoskeleton to the extracellular matrix. POMGNT2 selectively catalyzes the first step toward the functional matriglycan structure of alpha dystroglycan based on the primary amino acid sequence in proximity to the site of O-mannosylation (203). Patients with POMGNT2 mutations have mild intellectual disability without brain malformation (133).
LGMD R25 blood vessel epicardial substance related – BVES. A homozygous nonsense variant of BVES in two Japanese patients caused loss of ambulation by midlife, cardiac involvement with symptomatic AV block, and severely affected posterior compartments of lower limbs and paraspinal muscles (235).
LGMD R26 Popeye domain-containing protein 3 related – POPDC3. This muscular dystrophy is related to dysfunction of Popeye domain-containing protein involved in modulating membrane trafficking of interacting proteins (564). These proteins are expressed in skeletal muscles and myocardium. Patients have proximal weakness in upper and lower extremities with mildly elevated CK. They can exhibit kyphosis deformity. Typical dystrophy in muscles may be absent. Calf hypertrophy is present (509). Myogenic changes are detected on EMG. MRI can show fat replacement in the gastrocnemius and paraspinals. Cardiac dysfunction is not usually seen.
LGMD R (number pending) - PYROXD1. This is a mild form of limb-girdle muscular dystrophy characterized by facial weakness, normal CK, and slow progression of weakness. The causative mutations include a homozygous missense variant c.464A>G, p.Asn155Ser, as well as a compound heterozygous frameshift variant c.329_332delTCTG, p.Leu112Valfs*8. It can be either child or adult onset. Cardiac involvement is present in some compound heterozygous cases (106).
Reclassified conditions (no longer considered in the current limb-girdle muscular dystrophy classification)
Myofibrillar myopathy (previously limb-girdle muscular dystrophy 1A) (5q) – myotilin. Myotilin is a thin-filament-associated protein located in the Z-band and binds alpha-actinin, gamma-filamin, and F-actin, and appears to help stabilize and anchor thin filaments during sarcomere assembly (434). Mutations in myotilin have also been documented in cases of myofibrillar myopathy, cardiomyopathy, peripheral neuropathy, and distal myopathy (455).
Mutations in myotilin were found in a West Virginian family of German descent with autosomal dominant limb-girdle muscular dystrophy previously linked to chromosome 5q. Affected members have a distinctive, nasal dysarthric speech pattern and involvement of both shoulder and pelvic muscles, starting in proximal lower more than upper extremities and progressing to distal muscles (213). A second family from Argentina with a myotilin mutation at Ser55Phe developed proximal limb weakness that spread to distal muscles with onset by age 42 to 58 years; 2 of 4 living patients had dysarthric speech, similar to the North American family (212). A novel myotilin mutation was found to underlie the defect in a large family with spheroid body myopathy (162). In a Spanish family, six patients were identified from three families who had clinical and pathologic findings that were intermediate between LGMD and myofibrillar myopathy (372). Myotilinopathy can also be unmasked by statin treatment (416).
Electromyography shows myopathic changes and abundant complex repetitive discharges in affected muscles. Muscle MRI shows hyperintensity in soleus and medial gastrocnemius. Muscles biopsy can show COX-negative fibers (416).
In a mouse model, myotilin mutations promote myofibrillar aggregation and subsequent contractile dysfunction (175). In this mouse model, overexpression of myotilin causes severe muscle degeneration, enhanced myofibrillar aggregation, and earlier onset of aggregation (174). This suggests that lowering total myotilin levels may be a therapeutic option in the future.
Emery-Dreifuss muscular dystrophy (EDMD) (previously limb-girdle muscular dystrophy 1B) (1q) – lamin A/C. Lamins are nuclear envelope proteins, as is emerin, the protein mutated in the more common X-linked form of Emery-Dreifuss muscular dystrophy. Lamin A is essential for anchoring emerin to the inner nuclear membrane and lamin C to the lamina, providing a possible link between the different forms of muscular dystrophies with cardiac involvement (518). Thus, defective assembly of the nuclear lamina is one common feature of all these diseases. The “structural” hypothesis suggests that mutated A-type lamins or the associated nuclear envelope proteins disrupt the integrity of the cell nuclear membrane, resulting in nuclear breakage and cell death in tissues exposed to mechanical stress, such as muscle fibers. The “gene regulation hypothesis” suggests that A-type lamins are crucial in tissue-specific gene expression. Indeed, in Emery-Dreifuss muscular dystrophy muscle, the transcriptional regulation is defective, likely due to a focal loss and disorganization of heterochromatin in fibroblast and muscle fiber nuclei (310). The amount of lamin A/C appears to correlate with phenotypic severity. Ho and colleagues found that both lamin A/C and emerin regulate a downstream protein mechanosensitive transcription factor megakaryoblastic leukemia 1 (MKL1), a myocardin family member that is pivotal in cardiac development and function, based on mouse models and mutant cell lines (223). Lamin A/C and emerin may regulate gene expression through modulation of nuclear and cytoskeletal actin polymerization.
Lamins A and C are alternate splice forms from the same LMNA gene. These proteins have a role in several cellular processes, and mutations in LMNA are associated with a wide range of disease phenotypes, from neuromuscular, cardiac, and metabolic disorders to premature aging syndromes; however, no clear genotype-phenotype correlation is described in the current literature. Even within patients with muscle involvement, different phenotypes have been reported: limb-girdle muscular dystrophy (formerly LGMD1B), autosomal dominant Emery-Dreifuss muscular dystrophy 2, and a form of congenital muscular dystrophy.
Onset of weakness is usually in the 3rd or 4th decade (but as early as 1st decade) with predominant weakness of pelvic muscles. Facial weakness and scapular winging can be present. In a large Italian case series, contractures, traditionally associated with Emery-Dreifuss muscular dystrophy 2, were observed in 24 of 37 patients. In 13 patients, contractures were localized at multiple sites and in 10 developed before obvious clinical signs of muscle weakness (311). Hypermobility of the interphalangeal and metacarpophalangeal joints can also be present (539). The primary differentiating feature from other forms of limb-girdle muscular dystrophy is cardiac involvement, including conduction disturbances, arrhythmias, and syncope (513) with risk of sudden cardiac death, requiring pacemaker, defibrillator placement, or heart transplantation in some cases. Embolic ischemic stroke secondary to cardiac arrhythmia can be the presentation (87). A case of late onset (65 years of age) with paraspinal muscle pseudohypertrophy has also been reported (170).
Some LMNA mutation patients present initially with dilated cardiomyopathy or familial cardiac conduction disease (514). A particularly malignant mutation of the LMNA gene (c.908-909delCT) can cause rapid atrioventricular conduction abnormalities and sudden death (08). Other LMNA mutation patients can have an atypical phenotype characterized by isolated humeral, peroneal, or quadriceps weakness, in some cases with contractures or head drop syndrome (311).
Similar to other forms, there is phenotypic variability. In a study of four patients with mutations in the same LMNA exon 11 codon, one patient had congenital onset; another had severe, early cardiac involvement; a third patient had cardiac involvement that long predated skeletal muscle weakness; and the last patient had mild, late-onset limb-girdle muscular dystrophy presentation (329).
Muscle MRI shows that the adductor magnus, semimembranosus, and short and long head of the biceps femoris are the most frequently involved muscles in laminopathies whereas the gracilis and sartorius are less involved. The vasti muscles are usually involved, with sparing of the rectus femoris (296).
Muscle biopsy can show myocardial fibrosis or unspecific inflammatory signs in microscopic examination of heart or skeletal muscle in some patients (309). Fiber-type disproportion (430) and myopathic, dystrophic and myofibrillar changes with desmin accumulation have also been described (311).
Lamin defects are also implicated in a form of inherited dilated cardiomyopathy with conduction defect (CMD1A), familial partial lipodystrophy (151), mandibuloacral dysplasia, Hutchinson Gilford progeria (110), and a form of hereditary axonal motor and sensory neuropathy (CMT type 2) (111; 85). Overlapping phenotypes have been reported. Vital and colleagues described a patient with a phenotypic and pathologic combination of axonal polyneuropathy and myopathy caused by a dominant missense lamin A/C mutation, E33D (530). Another report described a young girl with progeria, congenital myopathy, and cardiac involvement due to a de novo missense mutation in the LMNA gene (S143F) (265).
Rippling muscle disease (previously limb-girdle muscular dystrophy 1C) (3p25) – caveolin 3. Mutations in the CAV3 gene were found in two families with dominant limb-girdle muscular dystrophy linked to chromosome 3p25 (338). Caveolins are major structural components of caveolae that serve as signaling hubs and membrane reservoirs at the cell surface. They also function as scaffolding proteins that organize and enrich caveolin-interacting proteins and lipids. During muscle contraction, caveolae are passively flattened and compensate plasma membrane stretch by extending the cell surface. Caveolin-3, a 21- to 24-kDa protein mainly expressed in muscle fibers, is the principal structural protein of caveolar membrane domains in skeletal, smooth, and heart muscle; it localizes at the sarcolemma within caveolae, associates with the dystroglycan complex, and binds to dysferlin.
Symptoms often begins around 5 years of age with cramping, mild weakness, and calf hypertrophy, but mild cases with clinical weakness are also seen (72). Percussion-induced muscle mounding can also be seen (386).
Caveolin 3 mutations also produce other phenotypes besides limb-girdle muscular dystrophy. The CAV3 gene has been implicated in nondystrophic rippling muscle disease, idiopathic and familial isolated hyperCKemia, a form of distal myopathy, long QT syndrome, and hypertrophic cardiomyopathy (72; 42; 332; 494; 550; 452). An autosomal recessive phenotype has also been reported in a 57-year-old woman with a novel homozygous intronic mutation in the CAV3 gene (352). Myalgia, exertion intolerance, and recurrent rhabdomyolysis are features associated with CAV3 mutations. Rippling muscle contraction and percussion-induced rapid muscle contractions (PIRCs) are important clinical clues indicative of caveolinopathies (446). In patients with CAV3-related distal myopathy, atrophy can be symmetric or asymmetric, usually in lower extremities (although cases with hand involvement have been described) (89).
Muscle MRI of patients with rippling muscle disease can be normal or show preferential and early involvement of rectus femoris (sometimes with peripheral hyperintensity), semitendinosus, and gastrocnemius (236). EMG can show electrical myotonic discharges (337).
One screen of 663 patients with a variety of neuromuscular phenotypes found CAV3 mutations in roughly 1% (169). The same group found that, in contrast to diminished levels in most fibers, CAV3 overexpression in regenerating fibers appears to lead to multiple misfolded oligomers in the Golgi complex but improved membrane immunostaining. Caveolin-3 appears to interact with dysferlin; accordingly, in some patients with dysferlinopathy there is a secondary reduction in the levels of caveolin-3 (534). A toxic gain of function exerting stress on the endoplasmic reticulum may underlie the disease mechanism based on a transgenic mouse model (276).
Myofibrillar myopathy (previously limb-girdle muscular dystrophy 1E) (2q) – desmin. This subtype is associated with cardiac failure and conduction system disease and previously was descriptively named "familial dilated cardiomyopathy with conduction disease and myopathy." Later onset patients generally present before 25 years of age and remain ambulatory (334). Creatine kinase is typically elevated. The genetic defect is determined to be due to an intron splice donor site mutation of the desmin gene located on chromosome 2q35 (189). Desminopathies usually manifest in the second to the fourth decade of life. The main features are lower and later upper limb muscle weakness slowly spreading to involve truncal, neck flexor, facial, bulbar, and respiratory muscles. The patients may have arrhythmias and restrictive, dilated, or hypertrophic cardiomyopathy. Desmin myopathies are a diverse group of disorders representing a subcategory of myofibrillar myopathies and some other entities such as Kaeser scapuloperoneal syndrome, myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy (ARVD7), myofibrillar myopathy (MFM1), and dilated cardiomyopathy (1F and 1I). A recessive form of limb girdle muscular dystrophy without cardiomyopathy or myofibrillar myopathy has also been described (81).
Unconfirmed (previously limb-girdle muscular dystrophy 1H) (3p23-25) – Unknown protein product. A novel form of autosomal dominant limb-girdle muscular dystrophy associated with rimmed vacuoles is proposed to be type 1H. Bisceglia and colleagues investigated a novel Italian family with 11 of 19 affected members (45). Five subjects presented with slowly progressive proximal arm and leg weakness beginning during the fourth to fifth decade. Earlier disease onset was observed in a group of patients presenting with muscle weakness or calf hypertrophy, or occasionally high creatine kinase and lactate serum levels. Two muscle biopsies showed morphological findings compatible with muscular dystrophy associated with subsarcolemmal accumulation of mitochondria and the presence of multiple mitochondrial DNA deletions. Several candidate genes in the region identified were excluded (45).
Myofibrillar myopathy (previously limb-girdle muscular dystrophy 2R) (2q) – Desmin. Desmin is a type III intermediate filament found near the Z disk in sarcomeres. Desminopathies usually manifest in the second to the fourth decade of life with lower and later upper limb muscle weakness slowly spreading to involve truncal, neck flexor, facial, bulbar, and respiratory muscles. The patients may have arrhythmias and restrictive, dilated, or hypertrophic cardiomyopathy. Desminopathies are inherited with an autosomal dominant pattern or result from de novo mutations; autosomal recessive mutations are rare. In muscle biopsy, there are findings of myofibrillar myopathy with presence of pleomorphic amorphous abnormal fiber areas containing aggregates, including desmin and other proteins such as dystrophin, plectin, alpha B-crystallin, gelsolin, actin, and ubiquitin. In addition, an autosomal dominant form also exists (see above). In a Turkish family with two affected siblings, onset of weakness varied from 15 to 27 years of age, with progressive severe proximal more than distal weakness and mild facial weakness. One became wheelchair-bound at age 33 years. There was scapular winging but no respiratory involvement or scoliosis. No cardiac symptoms were reported, but one patient had abnormal EKG. CK was normal. Muscle biopsy showed dystrophic changes but no changes of myofibrillar myopathy, different from other desminopathy phenotypes. The c.1289-2A>G mutation identified in these two patients is postulated to interfere with desmin-lamin B interactions (81).
Pompe disease (previously limb-girdle muscular dystrophy 2V) (17q) – GAA. GAA encodes the lysosomal enzyme acid alpha glucosidase, and mutations are the cause of Pompe disease. Late-onset Pompe disease can present as limb-girdle muscular dystrophy. The red flags for diagnosis of Pompe disease in patients with limb-girdle muscular dystrophy are: (1) mild, nondystrophic, myopathic features on muscle biopsy, often missing the typical vacuoles and glycogen accumulation; (2) CK levels below 1000; and (3) disproportionate axial and respiratory muscle involvement in comparison with limb muscle involvement. Myotonic discharges in paraspinal muscles are also suggestive of this diagnosis. Some patients present with idiopathic hyperCKemia (410; 196).
LIMS2-related myopathy (2q) – LIMS2. LIMS is an evolutionarily conserved protein, critical for muscle attachment. LIMS, along with integrin linked kinase (ILK) and parvin, is part of a ternary complex known as ILK–Pinch–Parvin (IPP), a core component of the integrin-actin cytoskeleton, and functions as a signaling mediator that transmits mechanical signals to downstream effectors. Two siblings with limb-girdle muscular dystrophy have been described. Weakness started at 5 years of age and progressed to wheelchair dependence by age 12 years. Dilated cardiomyopathy and macroglossia less severe at the tip with an appearance of a triangular tongue was also noted. CK was elevated. On cardiac MRI, both siblings also demonstrated a subepicardial rim of delayed enhancement predominantly in the inferolateral wall, likely representing fibrosis (86).
POPDC1-related myopathy (6q) – POPDC1. POPDC1, which is also known as BVES, is a member of the Popeye domain-containing (Popdc) gene family, encoding transmembrane proteins, which is highly expressed in cardiac and skeletal muscle in an overlapping manner. POPDC proteins possess the evolutionarily conserved Popeye domain, which functions as a high-affinity cAMP-binding site. POPDC proteins are localized primarily at the plasma membrane and in T-tubules, although they have also been found at the nuclear envelope of striated muscle cells. Mutation in this gene in four family members with limb-girdle muscular dystrophy and cardiac arrhythmia, including AV block, bradycardia-causing syncope, has been described. CK was elevated. Onset of weakness in one patient was in the fifth decade (448).
TOR1AIP1-related myopathy (previously limb-girdle muscular dystrophy 2Y) (1q) – TOR1AIP1. TOR1AIP1 encodes lamina-associated polypeptide-1 (LAP1B) and is a type II integral protein localized to the inner nuclear membrane through a single transmembrane domain. LAP1B has been shown to interact with the nuclear envelope protein emerin, and loss of LAP1B is associated with dystrophic changes on muscle biopsy and early lethality in knockout mice.
Reported cases present with proximal and distal weakness and atrophy, rigid spine, and contractures of the proximal and distal interphalangeal hand joints. Onset of weakness is in the first or second decades. Additionally, cardiomyopathy and respiratory involvement were noted. CK is mildly elevated. Cardiac failure can be severe, requiring heart transplant (257; 179).
Classification of limb-girdle muscular dystrophies. A reclassification of limb-girdle muscular dystrophy was proposed by the European Neuromuscular Center (ENMC) LGMD workshop study group. This new classification follows the formula: “LGMD, inheritance (R or D), order of discovery (number), affected protein” (477). Because of the definition of limb-girdle muscular dystrophy, that needs to have been described in at least two different families, some conditions are no longer considered limb-girdle muscular dystrophy (only one family described in the literature). Table 1 includes the new and previous classification for clarity purposes. Distinguishing clinical features (if they exist) are also included in the table.
Table 1. Classification of Limb-Girdle Muscular Dystrophy
New nomenclature | Old nomenclature | Gene | Distinguishing clinical features | Reason for exclusion in new classification |
LGMD D1 DNAJB6-related | LGMD 1D | 7q36 DNA JB6 | Foot drop, rimmed vacuoles, myofibrillar aggregates, myotonia in EMG (some cases) | |
LGMD D2 TNP03-related | LGMD 1F | 7q32.1-q32.2 TNPO3-- | Early contractures, arachnodactyly, macroglossia, dysarthria, pes cavus, calf hypertrophy, gynecomastia, worsening of weakness (after intense exercise, alcohol use, pregnancy), ophthalmoparesis, rimmed vacuoles, acid phosphatase vacuoles, cytoplasmic inclusions, ragged red fibers, mitochondrial paracrystaline inclusions | |
LGMD D3 HNRNPDL-related | LGMD 1G | 4q21 HNRNPDL-- | Limited finger and toe flexion, cataracts, scapular winging, rimmed vacuoles, autophagic vacuoles | |
LGMD D4 calpain3-related | LGMD 1I | 15q CAPN3 | Calpainopathy; scapular winging, abdominal hernia, severe hip adductor weakness, toe walking, ankle contractures, absence of calf hypertrophy, myalgia, British, Southern or Eastern European, or Brazilian ancestry, asymmetry | |
LGMD D5 collagen 6-related | Bethlem myopathy dominant | 21q, 2q COL6A1, COL6A2, COL6A3 | Early onset with contractures, distal joint hyperlaxity, keratosis pilari, keloids | |
LGMD R1 calpain3-related | LGMD 2A | 15q CAPN3 | Calpainopathy; abdominal hernia, severe hip adductor weakness, toe walking, ankle contractures, scapular winging, absence of calf hypertrophy, British, Southern or Eastern European, or Brazilian ancestry, asymmetry | |
LGMD R2 dysferlin-related | LGMD 2B | 2q DYSF | Dysferlinopathy biceps lump and diamond on quadriceps, high CK, dysferlin—calf atrophy and asymmetry | |
LGMD R3 α-sarcoglycan-related | LGMD 2D | 17q SGCA | Alpha-sarcoglycan/adhalin--variable severity, cardiac respiratory involvement, hip adductor weakness, and muscle hypertrophy, high CK | |
LGMD R4 β-sarcoglycan-related | LGMD 2E | 4q SGCB | Beta-sarcoglycan--cardiac, respiratory involvement, hip adductor weakness, muscle hypertrophy, macroglossia, high CK | |
LGMD R5 γ -sarcoglycan-related | LGMD 2C | 13q SGCG | Gamma-sarcoglycan severe childhood limb-girdle muscular dystrophy--macroglossia, ankle contractures, scoliosis, cardiac, respiratory involvement, hip adductor weakness, muscle hypertrophy, high CK | |
LGMD R6 δ-sarcoglycan-related | LGMD 2F | 5q SGCD | Delta-sarcoglycan--cardiac respiratory involvement, hip adductor weakness, muscle hypertrophy high CK | |
LGMD R7 telethonin-related | LGMD 2G | 17q TCAP | Telethoninopathy—calf hypertrophy, cardiac involvement, rimmed vacuoles | |
LGMD R8 TRIM 32-related | LGMD 2H | 9q TRIM32 | Hutterites, scapular winging | |
LGMD R9 FKRP-related | LGMD 2I | 19q FKRP | Northern European ancestry, scapular winging, calf hypertrophy, early cardiorespiratory involvement, and myoglobinuria | |
LGMD R10 titin-related | LGMD 2J | 2q TTN | Finnish and French populations, rimmed vacuoles | |
LGMD R11 POMT1-related | LGMD 2K | 9q34.1 POMT1 | ||
LGMD R12 anoctamin5-related | LGMD 2L | 11p ANO5 | Calf atrophy and myoglobinuria | |
LGMD R13 Fukutin-related | LGMD 2M | 9q FKTN | CNS involvement, learning difficulties, and muscle hypertrophy | |
LGMD R14 POMT2-related | LGMD 2N | 1p POMT2 | CNS involvement, learning difficulties, and muscle hypertrophy | |
LGMD R15 POMGnT1-related | LGMD 2O | 14q POMGnT1 | CNS involvement, learning difficulties, and muscle hypertrophy | |
LGMD R16 α-dystroglycan-related | LGMD 2P | 3p DAG1 | ||
LGMD R17 plectin-related | LGMD 2Q | 8q PLEC | Epidermolysis bullosa | |
LGMD R18 TRAPPC11-related | LGMD 2S | 4q TRAPPC11 | CNS involvement, movement disorders, alacrima, achalasia, cataracts, and hepatic steatosis | |
LGMD R19 GMPPB-related | LGMD 2T | 3p GMPPB | CNS involvement, neuromuscular transmission defects, cataracts rhabdomyolysis | |
LGMD R20 ISPD-related | LGMD 2U | 7p ISPD | CNS involvement, calf hypertrophy, and scapular winging | |
LGMD R21 POGLUT1-related | LGMD 2Z | 3q POGLUT1 | ||
LGMD R22 collagen 6-related | Bethlem myopathy recessive | 21q, 2q COL6A1, COL6A2, COL6A3 | Early onset with contractures | |
LGMD R23 laminin α2-related | Laminin α2-related muscular dystrophy | LAMA2 | ||
LGMD R24 POMGNT2-related | POMGNT2-related muscular dystrophy | POMGnT2 | ||
LGMD R25 BVES-related | Blood vessel epicardial substance | BVES | Loss of ambulation, AV block, posterior compartment of lower limbs and paraspinals | |
LGMD R26 Popeye domain-containing protein 3 related | Popeye domain-containing protein 3 related | POPDC3 | Proximal weakness, fatty replacement in the gastrocnemius and paraspinals | |
Reclassified conditions (no longer included in the new LGMD classification) | ||||
Myofibrillar myopathy | LGMD 1A | 5q MYOT | Nasal dysarthria, hypophonia, asymmetric muscle weakness and atrophy rimmed vacuoles, occasional nemaline rod-like inclusions | Distal weakness |
Emery–Dreifuss muscular dystrophy (EDMD) | LGMD 1B | 1q LMNA | Contractures, cardiac involvement, cardiac conduction abnormalities, and humeroperoneal weakness | High risk of cardiac arrhythmias; EDMD phenotype |
Rippling muscle disease | LGMD 1C | 3p CAV3 | Rippling muscles, percussion-induced rapid contractions, prominent muscle cramps, and calf hypertrophy | Main clinical features rippling muscle disease and myalgia |
Myofibrillar myopathy | LGMD 1E | 6q DES | Foot drop, cardiac conduction abnormalities | Primarily false linkage; distal weakness and cardiomyopathy |
? | LGMD 1H | Not confirmed | False linkage | |
Myofibrillar myopathy | LGMD 2R | 6q DES | Foot drop, cardiac conduction abnormalities | Distal weakness |
Pompe disease | LGMD 2V | 17q GAA | Axial and respiratory muscle involvement | Known disease entity, histological changes |
PINCH-2 related myopathy | LGMD 2W | PINCH2 | Reported in one family | |
BVES related myopathy | LGMD 2X | BVES | Reported in one family | |
TOR1AIP1 related myopathy | LGMD 2Y | LGMD 2Y | Reported in one family | |
Table 2. Allelic Disorders with Limb-Girdle Muscular Dystrophy Gene Product Mutations
New nomenclature | Old nomenclature | Gene | Allelic disorders |
LGMD D1 DNAJB6-related | LGMD 1D | 7q36 DNA JB6 | Distal dystrophy with rimmed vacuoles and cardiomyopathy susceptibility |
LGMD D2 TNP03-related | LGMD 1F | 7q32.1-q32.2 TNPO3-- | |
LGMD D3 HNRNPDL-related | LGMD 1G | 4q21 HNRPDL-- | |
LGMD D4 calpain3-related | LGMD 1I | 15q CAPN3 | HyperCKemia |
LGMD D5 collagen 6-related | Bethlem myopathy dominant | 21q, 2q COL6A1, COL6A2, COL6A3 | Ullrich congenital muscular dystrophy |
LGMD R1 calpain3-related | LGMD 2A | 15q CAPN3 | HyperCKemia |
LGMD R2 dysferlin-related | LGMD 2B | 2q DYSF | Miyoshi myopathy HyperCKemia |
LGMD R3 α-sarcoglycan-related | LGMD 2D | 17q SGCA | Exercise intolerance |
LGMD R4 β-sarcoglycan-related | LGMD 2E | 4q SGCB | |
LGMD R5 γ -sarcoglycan-related | LGMD 2C | 13q SGCG | |
LGMD R6 δ-sarcoglycan-related | LGMD 2F | 5q SGCD | Dilated cardiomyopathy 1L |
LGMD R7 telethonin-related | LGMD 2G | 17q TCAP | Dilated cardiomyopathy 1N Congenital muscular dystrophy |
LGMD R8 TRIM 32-related | LGMD 2H | 9q TRIM32 | Sarcotubular myopathy Bardet-Biedl syndrome type 11 |
LGMD R9 FKRP-related | LGMD 2I | 19q FKRP | Congenital muscular dystrophy with muscle hypertrophy and normal CNS Myopathy with abnormal merosin |
LGMD R10 titin-related | LGMD 2J | 2q TTN | Dominant: Distal myopathy (Finnish) |
LGMD R11 POMT1-related | LGMD 2K | 9q34.1 POMT1 | Walker-Warburg syndrome |
LGMD R12 anoctamin5-related | LGMD 2L | 11p ANO5 | Nondysferlin Miyoshi myopathy Gnathodiaphyseal dysplasia |
LGMD R13 Fukutin-related | LGMD 2M | 9q FKTN | Fukuyama muscular dystrophy Cardiomyopathy |
LGMD R14 POMT2-related | LGMD 2N | 1p POMT2 | Walker-Warburg syndrome Congenital muscular dystrophy with mental retardation |
LGMD R15 POMGnT1-related | LGMD 2O | 14q POMGnT1 | Muscle eye brain disease Congenital muscular dystrophy |
LGMD R16 α-dystroglycan-related | LGMD 2P | 3p DAG1 | Asymptomatic high CK Congenital muscular dystrophy |
LGMD R17 plectin-related | LGMD 2Q | 8q PLEC | Congenital muscular dystrophy with familial junctional epidermolysis bullosa Muscular dystrophy and myasthenic syndrome |
LGMD R18 TRAPPC11-related | LGMD 2S | 4q TRAPPC11 | |
LGMD R19 GMPPB-related | LGMD 2T | 3p GMPPB | Walker-Warburg syndrome Congenital muscular dystrophy |
LGMD R20 ISPD-related | LGMD 2U | 7p ISPD | Congenital muscular dystrophy Limb-girdle muscular dystrophy with cerebellar involvement |
LGMD R21 POGLUT1-related | LGMD 2Z | 3q POGLUT1 | |
LGMD R22 collagen 6-related | Bethlem myopathy recessive | 21q, 2q COL6A1, COL6A2, COL6A3 | Ullrich congenital muscular dystrophy |
LGMD R23 laminin α2-related | Laminin α2-related muscular dystrophy | LAMA2 | |
LGMD R24 POMGNT2-related | POMGNT2-related muscular dystrophy | POMGnT2 | |
Reclassified conditions (no longer included in the new LGMD classification) | |||
Myofibrillar myopathy | LGMD 1A | 5q MYOT | Myofibrillary myopathy Distal myopathy |
Emery–Dreifuss muscular dystrophy (EDMD) | LGMD 1B | 1q LMNA | Autosomal dominant Emery-Dreifuss muscular dystrophy Cardiomyopathy (CMD1A) |
Rippling muscle disease | LGMD 1C | 3p CAV3 | Rippling muscle disease Distal myopathy |
Myofibrillar myopathy | LGMD 1E | 6q DES | Dominant myopathies (Kaeser scapuloperoneal syndrome Myofibrillar myopathy |
? | LGMD 1H | Not confirmed | |
Myofibrillar myopathy | LGMD 2R | 6q DES | Dominant myopathies (Kaeser scapuloperoneal syndrome, myofibrillar myopathy, distal myopathy, cardiomyopathy, and autophagic vacuoles); Dominant cardiomyopathies (dilated cardiomyopathy 1F and 1I, ARVD7) |
Pompe disease | LGMD 2V | 17q GAA | |
PINCH-2 related myopathy | LGMD 2W | PINCH2 | |
BVES related myopathy | LGMD 2X | BVES | |
TOR1AIP1 related myopathy | LGMD 2Y | 1q TOR1AIP1 |
Mechanisms of disease brought about by the alterations in the numerous genes thus far identified are complex and vary between subtypes. Muscular dystrophy can result from diverse defects in proteins of different muscle cell compartments including extracellular matrix (collagen VI, merosin), cell membrane (dystrophin, sarcoglycans, caveolin-3, dysferlin, integrins), nuclear envelope (lamins, emerin), and with different functions, such as cellular enzymes (calpain-3), and organelle or sarcomere structural integrity (telethonin and others). Ongoing work is aimed at determining how previously known and recently uncovered gene defects and proteins affect myofiber physiology and ultimately lead to muscle cell death. Also awaiting explanation is why cell death occurs at a particular age, in predisposed muscles, and to variable degrees in different subtypes and individuals. There is evidence that the final pathways include apoptosis and muscle necrosis, but the processes that lead to this end remain to be determined. Other general processes that can be disrupted include structural integrity of the membrane, other signaling properties, cellular trafficking, myofiber assembly, nuclear envelope function, connective tissue structure, and likely a number of others.
Epidemiology
Most limb-girdle muscular dystrophies are inherited as autosomal recessive traits; autosomal dominant limb-girdle muscular dystrophy is relatively uncommon.
Limb-girdle muscle dystrophy is considered the fourth most common muscular dystrophy with a pooled prevalence of 1.63 per 100,000 (range 0.56-5.75 per 100,000) after dystrophinopathies, myotonic dystrophies, and fascioscapulohumeral muscular dystrophy (314).
Autosomal dominant limb-girdle muscular dystrophy is relatively rare and has been reported primarily in isolated families (362; 473; 40; 11; 92; 343; 486; 382). Although the exact incidence of autosomal dominant limb-girdle muscular dystrophy is unknown, no more than 5% to 10% of all limb-girdle dystrophies are presumed to be dominant (64).
In the United States, a study using next-generation sequencing in 4656 patients established diagnosis in 27% of cases (1259 patients). The major contributing genes to limb-girdle muscular dystrophy phenotypes were CAPN3 (17%), DYSF (16%), FKRP (9%), and ANO5 (7%) (360). Calpainopathy (LGMD R1, CAPN3 mutation) is the most common limb-girdle muscular dystrophy in American and European countries except Denmark, where limb-girdle muscular dystrophy FKRP mutations are the most common. An epidemiological study found that Norway has a relatively high rate of limb-girdle muscular dystrophy in comparison to the rest of Europe, at a rate of 12.8 cases per 100,000 people, with CAPN3, ANO5, and FKRP mutations as the most common (353).
Prevention
All limb-girdle dystrophies are inherited diseases involving skeletal muscle, and in some cases additional organ systems. Typically, no risk factor exists in the environment; however, the mechanisms that determine the severity and expression of many of the disorders have yet to be determined, such as whether secondary genetic factors or as yet other unknown influences play a role. To prevent the birth of an affected child in families with known defective genes, appropriate genetic counseling is advocated if possible. Judging from the current pace of research, specific and reliable diagnostic tests for limb-girdle muscular dystrophy should be available in the near future for effective prenatal disease detection. In families with autosomal recessive limb-girdle muscular dystrophy, consanguineous marriages must obviously be discouraged.
Differential diagnosis
Duchenne dystrophy and Becker dystrophy and female manifesting heterozygotes for Duchenne dystrophy can be indistinguishable from autosomal recessive limb-girdle muscular dystrophy and must be excluded, especially in sporadic limb-girdle muscular dystrophy cases. In fact, the diagnosis of sporadic limb-girdle muscular dystrophy should not be made unless dystrophinopathy has been excluded by appropriate laboratory tests (51; 521; 299). DNA analysis for dystrophin gene mutations and staining for dystrophin in muscle biopsy specimens are both important means to identify the various dystrophinopathies, including manifesting carriers. This condition is especially relevant in girls with a limb-girdle muscular dystrophy pattern and no manifesting male dystrophinopathy relatives. Golla and colleagues identified five such cases (183). The electrocardiogram, if abnormal, may also help in identifying female carriers of Duchenne dystrophy (131; 55), although it can be abnormal in some limb-girdle muscular dystrophy phenotypes.
X-linked Emery-Dreifuss muscular dystrophy differs from limb-girdle muscular dystrophy in inheritance (X-linked), characteristic humeroperoneal distribution of weakness, early contractures, and cardiac abnormalities (132). This dystrophy is caused by alterations in the emerin gene mapped to the chromosome Xq-locus (44; 267). However, the rarer dominant form, secondary to mutations in the lamin A/C gene, may be confused with some dominant forms of limb-girdle muscular dystrophy (52; 350).
Facioscapulohumeral dystrophy is inherited as an autosomal dominant trait, and, unlike limb-girdle muscular dystrophy, facial muscles are affected early in the course of the disease. Asymmetric scapular weakness associated with distal lower limb weakness, pronounced lower abdominal weakness, and lumbar hyperlordosis are suggestive of facioscapulohumeral muscular dystrophy in the differential diagnosis with limb-girdle muscular dystrophy. Diagnosis by genetic analysis is now widely available. Scapuloperoneal syndrome is a heterogeneous disorder, but the distinctive distribution of weakness distinguishes it from limb-girdle muscular dystrophy (258). In familial neurogenic scapuloperoneal syndrome, EMG and muscle biopsy typically show a neurogenic process (490). Myotonic dystrophy is usually evident on the basis of the characteristic topography of muscle weakness, myotonia, and multisystem involvement although myotonic dystrophy type 2 can have subtle clinical findings and absent clinical or electrical myotonia in some cases.
Many congenital myopathies, including centronuclear myopathy (464; 56), nemaline rod myopathy (463), central core disease (123), multicore disease (134), congenital fiber-type disproportion (58), desmin myopathy (225), and myopathy with tubular aggregates (426) may present with proximal muscle weakness in childhood or adult life. The weakness in congenital myopathies may be gradually progressive or relatively static and may be confused with some forms of limb-girdle muscular dystrophy. A core-rod myopathy mimicking limb-girdle muscular dystrophy secondary mutations in KBTBD13 starting at age 50 has also been described (173). Careful histochemical studies of muscle specimen will clarify the diagnosis of congenital myopathies and usually identify the form.
Patients with congenital myasthenic syndromes can also be misdiagnosed with limb girdle muscular dystrophy or congenital muscular dystrophies. This distinction is important as congenital myasthenic syndromes are often treatable (249). Electrophysiological examination with repetitive nerve stimulation is valuable in confirming this diagnosis. Genetic testing is available for most of the subtypes.
The glycogenoses and the lipid myopathies may also present with proximal muscle weakness in different age groups, but these are usually differentiated from limb-girdle muscular dystrophy by histological and biochemical studies of muscle (115).
The mitochondrial myopathies represent a large and heterogeneous group of disorders that may have various morphological and biochemical characteristics (115). Although some mimic limb-girdle muscular dystrophy, most mitochondrial syndromes are multisystemic, and specific molecular tests are available for many forms.
In some cases, it may be difficult to separate spinal muscular atrophies from muscular dystrophies. In particular, Kugelberg-Welander spinal muscular atrophy can closely mimic limb-girdle dystrophy (277). The presence of fasciculations, relatively diffuse weakness, normal serum enzymes, and classic neurogenic findings on EMG and muscle biopsy differentiate the spinal muscular atrophies from muscular dystrophies.
Limb-girdle muscular dystrophy may be misdiagnosed as idiopathic inflammatory myopathy as the symptoms and MRI findings overlap among them (378). Although the fatty replacement in limb-girdle muscular dystrophy and muscular edema are expected to be present in idiopathic inflammatory myopathy as characteristic findings, it has been noted that fatty replacement and edema can coexist in limb-girdle muscular dystrophy and idiopathic inflammatory myopathy. A study by Hsu and colleagues showed that fatty replacement is more prevalent in limb-girdle muscular dystrophy (226). MRI, particularly of the adductor magnus, in all patients with limb-girdle muscular dystrophy showed fatty replacement with no edema (226). Larger studies are needed to confirm that the adductor magnus muscle could provide a biosignature to categorizing limb-girdle muscular dystrophy. Another study highlighted that abundant p62 staining and muscle edema affecting the adductor magnus on MRI seem to be good markers for immune-mediated necrotizing myopathy (555). Once a limb-girdle muscular dystrophy syndrome is suspected, a combination of muscle biopsy analysis, analysis of protein components of muscle (Western blot), and molecular genetics is usually needed for definitive confirmation of a particular subtype. In rare cases a limb-girdle muscular dystrophy syndrome is highly suspected in an individual family, but no linkage to any known site is seen. Such new pedigrees are highly sought in order to identify and further characterize new genes and disease mechanisms.
Confusing conditions
Proximal muscle weakness is the common clinical hallmark of most hereditary and acquired myopathies, and many can mimic limb-girdle muscular dystrophy. Laboratory findings in limb-girdle muscular dystrophy are not specific and resemble those of other muscular dystrophies. The large number of apparently isolated cases may obscure autosomal recessive pattern of inheritance.
Therapeutically, important disorders to differentiate from limb-girdle muscular dystrophy include polymyositis and dermatomyositis. In most cases, specific clinical and laboratory features identify an inflammatory muscle disease. Relatively rapid evolution, more generalized weakness (often involving muscles of the neck and pharynx), abundant spontaneous activity on EMG, inflammatory changes on muscle biopsy, and response to immunosuppressive therapy are all important distinguishing features. Exceptions occur, however, because some cases of polymyositis lack a few or many characteristic clinical and laboratory features and can simulate limb-girdle muscular dystrophy. A high index of suspicion, close clinical monitoring, and adequate clinical trial of corticosteroid therapy in suspected cases of polymyositis are important discriminators. The presence of myositis specific antibodies, such as Jo-1, SRP, MDA5, etc., is highly specific for myositis and not for genetic disease (317).
Myopathy associated with anti-HMGCR (3-hydroxy-3-methylglutarylcoenzyme A reductase) antibodies can mimic limb-girdle muscular dystrophy or present with asymptomatic hyperCKemia. Testing for anti-HMGCR antibodies should be considered in patients with limb-girdle muscular dystrophy or asymptomatic hyperCKemia phenotype, and negative genetic testing as immunotherapy is associated with clinical improvement (342).
Dysferlinopathy is probably most likely to simulate a steroid-resistant inflammatory myopathy, in part because of the high CK levels and inflammatory changes in muscle biopsy. Another treatable condition that can present with limb-girdle weakness is acid maltase deficiency (adult onset Pompe disease). This can be confirmed with measurement of the alpha-glucosidase activity in dry blood spot and with genetic testing. LGMD R1 and R2 are easily misdiagnosed as inflammatory myopathies as they are very similar in clinical manifestation and muscle pathology (378; 541).
Inclusion-body myositis is an inflammatory myopathy that may be confused with limb-girdle muscular dystrophy. Although the disease typically presents later in life, childhood-onset cases have been described (423). Familial inclusion-body myopathy is generally a more distal quadriceps-sparing process (481), but proximal weakness in limb-girdle distribution can occur; the gene for this disorder, a sialic acid synthesis enzyme, is now known (324; 128). Similar to muscular dystrophy, but unlike polymyositis or dermatomyositis, hypertrophied muscle fibers can be a feature in inclusion-body myositis (520). Inclusion-body myositis is differentiated from limb-girdle muscular dystrophy by pattern of weakness and characteristic histopathological changes including rimmed vacuoles with beta-amyloid inclusions (501; 520).
Various endocrine and toxic myopathies are other treatable disorders that must be differentiated from limb-girdle muscular dystrophy (54; 461). Myopathies due to treatment with chloroquine (545) and cholesterol-lowering agents (533) are examples of toxic myopathies, but these compounds are not usually taken at the most common ages of onset for limb-girdle muscular dystrophy.
Diagnostic workup
Blood chemistry. Routine blood counts, serum chemistry, and urinalysis are unhelpful in diagnosing limb-girdle muscular dystrophy. Sedimentation rate may be elevated in inflammatory muscle diseases.
The principal biochemical abnormality in limb-girdle muscular dystrophy, as also in other muscular dystrophies and myopathies, is elevation in the serum concentration of various muscle enzymes (355; 395). Serum creatine kinase is the most widely used enzymatic test for the detection of muscle disease. Creatine kinase is typically elevated in all cases of limb-girdle muscular dystrophy but especially in autosomal recessive severe forms; the creatine kinase levels in severe childhood autosomal recessive muscular dystrophy can be as high as in Duchenne dystrophy (ie, up to over 50 times normal). In other forms of limb-girdle muscular dystrophy, creatine kinase is usually mildly to moderately elevated. In general, creatine kinase levels are less elevated in autosomal dominant forms of slowly progressive limb-girdle muscular dystrophy, and they tend to decrease with the age of the patient and with the duration of the disease. Overall creatine kinase is raised roughly 2x to 350x in recessive cases and is normal to increased 6x in dominant patients (64).
Creatinuria and hypercreatinemia suggest decrease in muscle mass in limb-girdle muscular dystrophy and other dystrophies. Although their value as indicators of muscle disease is limited, they can still be useful in assessing those patients with long-standing limb-girdle muscular dystrophy in whom the serum enzymes are normal.
Electromyography. Electromyographic features in limb-girdle muscular dystrophy are typical of primary muscle disease and are similar to those in other myopathies. The principal findings on needle EMG are short duration, low-amplitude motor unit potentials, an increased proportion of polyphasic potentials, and early recruitment with a full interference pattern in clinically weak muscles. Abnormal spontaneous activity in the form of fibrillation potentials and positive sharp waves can occur in more rapidly progressive limb-girdle muscular dystrophy with prominent muscle fiber necrosis and regeneration, such as severe childhood autosomal recessive muscular dystrophy (214). In the latter setting, fibrillation and positive sharp waves do not result from primary denervation but from segmental necrosis of muscle fibers leading to isolation of a portion of muscle from its myoneural junction. Progressive muscle fibrosis may also result in increased mechanical resistance to insertion of the needle electrode and decreased insertional activity.
Nerve conduction studies, including amplitude of sensory and motor-evoked potentials and conduction velocities of both sensory and motor fibers, are typically normal in limb-girdle muscular dystrophy. However, evoked motor amplitudes can be reduced in muscles with severe atrophy.
Muscle ultrasound. Muscle ultrasound is a safe, noninvasive, and cheap diagnostic tool that can assess muscle thickness and echogenicity to identify atrophic changes and fatty degeneration. It has been helpful in targeted muscle biopsy, but, based on some studies, it can be used as a screening tool for muscular dystrophies. Its main limitation is that it is operator dependent with restricted visualization of deeper structures. In a study by Ibrahim and colleagues, ultrasound images of upper and lower extremities were obtained and visually graded semi-quantitatively using the 4-point Heckmatt scale (232). In muscular dystrophies, there was an increased and diffuse echo from the muscle substance and reduced echo from the bone. The increase in the ultrasound echo correlated with alteration in gross muscle architecture. A total Heckmatt score at a cutoff point greater than two predicted patients with dystrophy, with good (89%) accuracy and with sensitivity and specificity of 100% and 75%, respectively.
Muscle MRI. Muscle MRI can be used to identify patterns of muscle involvement, sparing, and peculiar characteristics of different muscular dystrophies and serves as an easy and fast technique to support a diagnosis. This can aid in the differential and can support pathogenicity of variants of unknown significance. MRI of the thigh and lower leg was found to have high sensitivity for assessing disease progression in LGMD R9 as well as other limb-girdle muscular dystrophies, in particular by detecting global muscle segment fat percentage (419). Table 3 shows MRI findings in different limb-girdle muscular dystrophies.
Table 3. MRI Findings in Different Limb-Girdle Muscular Dystrophies
New nomenclature | Old nomenclature | Gene | Muscles affected | Muscles spared | Characteristic findings |
LGMD D1 DNAJB6-related | LGMD 1D | 7q36 DNA JB6 | Early stages: soleus, adductor magnus, semimembranosus, biceps femoris Later involvement: medial gastrocnemius, adductor longus, vastii | Rectus femoris, lateral gastrocnemius, sartorius, gracilis, anterolateral lower leg muscles (very late involvement) | |
LGMD D2 TNP03-related | LGMD 1F | 7q32.1-q32.2 TNPO3-- | Vastus lateralis, sartorius, posterior leg compartment | Gracilis, rectus femoris | |
LGMD D3 HNRNPDL-related | LGMD 1G | 4q21 HNRPDL-- | Vastus muscles, posterior thigh compartment | Rectus femoris, adductor longus | |
LGMD D4 calpain3-related | LGMD 1I | 15q CAPN3 | Paraspinals, glutei, hamstring, medial gastrocnemius | ||
LGMD D5 collagen 6-related | Bethlem myopathy dominant | 21q, 2q COL6A1, COL6A2, COL6A3 | Sartorius, gracilis, adductor longus | Vastus lateralis: rim of hyperintensoty at the periphery Rectus femoris: hyperintensity at the center of the muscles (central shadow) Rim of hyperintensity between the soleus and gastrocnemius | |
LGMD R1 calpain3-related | LGMD 2A | 15q CAPN3 | Gluteus maximus, semimembranosus, biceps femoris, adductors, soleus, medial gastrocnemius, serratus anterior, lumbar erector spinae | Vastus lateralis, sartorius, gracilis, lateral gastrocnemius | |
LGMD R2 dysferlin-related | LGMD 2B | 2q DYSF | Subscapularis, lumbaris erector spinae, gluteus minimus, tensor fasciae latae, obturator externus, quadriceps, semimembranosus, semitendinosus, biceps femori, hip adductors, all leg muscles (except popliteus) | Head and cervical muscules, levator scapula, trapezius, pectoralis minor, popliteus, piriformis, posterior forearm compartment, transversus abdominis, gracilis, sartorius | |
LGMD R3 α-sarcoglycan-related | LGMD 2D | 17q SGCA | Proximal lower extremity muscles, anterior thigh compartment Quadriceps gradient (more affected proximally than distally), adductor longus medial sparing, hypertrophy of either sartorius or gracilis Paraspinal, pelvic and gluteu muscles can be affected in mild cases | Relative sparing of leg muscles until late stages Tensor fasciae latae, tibialis posterior, flexor digitorum longus | |
LGMD R4 β-sarcoglycan-related | LGMD 2E | 4q SGCB | Proximal lower extremity muscles, anterior thigh compartment Quadriceps gradient (more affected proximally than distally), adductor longus medial sparing, hypertrophy of either sartorius or gracilis | Relative sparing of leg muscles until late stages Tensor fasciae latae, tibialis posterior, flexor digitorum longus | |
LGMD R5 γ -sarcoglycan-related | LGMD 2C | 13q SGCG | Proximal lower extremity muscles, anterior thigh compartment Quadriceps gradient (more affected proximally than distally), adductor longus medial sparing, hypertrophy of either sartorius or gracilis | Relative sparing of leg muscles until late stages Tensor fasciae latae, tibialis posterior, flexor digitorum longus | |
LGMD R6 δ-sarcoglycan-related | LGMD 2F | 5q SGCD | Proximal lower extremity muscles, anterior thigh compartment Quadriceps gradient (more affected proximally than distally), adductor longus medial sparing, hypertrophy of either sartorius or gracilis | Relative sparing of leg muscles until late stages Tensor fasciae latae, tibialis posterior, flexor digitorum longus | |
LGMD R7 telethonin-related | LGMD 2G | 17q TCAP | Glutei, hip, thigh and tibialis anterior | Sartorius | |
LGMD R8 TRIM 32-related | LGMD 2H | 9q TRIM32 | Posterior thigh and posterior leg compartments | Flexor digitorum longus, flexor hallucis longus, tibialis posterior | |
LGMD R9 FKRP-related | LGMD 2I | 19q FKRP | Glutei (maximus> medius), adductors, biceps femoris, vastus intermedius, vastus lateralis, medial gastrocnemius, soleus Mild cases with only adductor magnus involvement | Rectus femoris (late), sartorius, gracilis, tibialis anterior | |
LGMD R10 titin-related | LGMD 2J | 2q TTN | Anterior leg and thigh compartment | ||
LGMD R11 POMT1-related | LGMD 2K | 9q34.1 POMT1 | |||
LGMD R12 anoctamin5-related | LGMD 2L | 11p ANO5 | Gluteus minimus, posterior thigh and posterior leg compartments Isolated semitendinosus involvement | Gracilis | |
LGMD R13 Fukutin-related | LGMD 2M | 9q FKTN | |||
LGMD R14 POMT2-related | LGMD 2N | 1p POMT2 | Hamstring, paraspinals, glutei, posterior leg compartment | ||
LGMD R15 POMGnT1-related | LGMD 2O | 14q POMGnT1 | |||
LGMD R16 α-dystroglycan-related | LGMD 2P | 3p DAG1 | |||
LGMD R17 plectin-related | LGMD 2Q | 8q PLEC | Posterior leg compartment | ||
LGMD R18 TRAPPC11-related | LGMD 2S | 4q TRAPPC11 | |||
LGMD R19 GMPPB-related | LGMD 2T | 3p GMPPB | Paraspinal and hamstring | ||
LGMD R20 ISPD-related | LGMD 2U | 7p ISPD | |||
LGMD R21 POGLUT1-related | LGMD 2Z | 3q POGLUT1 | Early fatty replacement of internal regions of thigh muscles that spared the external area | ||
LGMD R22 collagen 6-related | Bethlem myopathy recessive | 21q, 2q COL6A1, COL6A2, COL6A3 | |||
LGMD R23 laminin α2-related | Laminin α2-related muscular dystrophy | LAMA2 | Adductor magnus, biceps femoris | Sartorius, gracilis | Hyperintensity in periphery of thigh muscles |
LGMD R24 POMGNT2-related | POMGNT2-related muscular dystrophy | POMGnT2 | |||
LGMD R26 Popeye domain-containing protein 3 related | Popeye domain-containing protein 3 related | POPDC3 | Vastus lateralis, gastrocnemius, medial head | Fatty replacement in affected muscles and paraspinals | |
Reclassified conditions (no longer included in the new LGMD classification) | |||||
Myofibrillar myopathy | LGMD 1A | 5q MYOT | Soleus, medial gastrocnemius, sartorius | ||
Emery–Dreifuss muscular dystrophy (EDMD) | LGMD 1B | 1q LMNA | Adductor magnus, semimembranosus, short and long head of the biceps femoris, quadriceps (except rectus femoris) | Gracilis, sartorius, rectus femoris | |
Rippling muscle disease | LGMD 1C | 3p CAV3 | Rectus femoris, semitendinosus, gastrocnemius | Peripheral hyperintensity in rectus femoris | |
Myofibrillar myopathy | LGMD 1E | 6q DES | Semitendinosus, sartorius, gracilis, peroneal muscles, tibialis anterior | ||
? | LGMD 1H | Not confirmed | |||
Myofibrillar myopathy | LGMD 2R | 6q DES | |||
Pompe disease | LGMD 2V | 17q GAA | |||
PINCH-2 related myopathy | LGMD 2W | PINCH2 | |||
BVES related myopathy | LGMD 2X | BVES | |||
TOR1AIP1 related myopathy | LGMD 2Y | 1q TOR1AIP1 |
Muscle biopsy. Muscle biopsy of a clinically involved but not yet end-stage muscle in limb-girdle muscular dystrophy cases shows typical findings of primary muscle disease with additional signs pointing to a dystrophy. In most patients, the EMG and muscle biopsy findings are concordant (62). Muscle biopsy samples in general are characterized by a number of nonspecific pathological changes similar to those observed in other dystrophies (391). The severity of pathological changes and the tempo of progression are highly variable. Although the changes in the severe childhood form of autosomal recessive limb-girdle muscular dystrophy are similar to those observed in Duchenne patients, the findings in other forms are not as severe. No morphological features with routine histological stains differentiate one limb-girdle dystrophy from another or from other muscular dystrophies (391; 12).
In cross-section, there is a wide spectrum of muscle fiber sizes, ranging from large, hypertrophied fibers to small atrophic fibers in the same fascicle. Individual muscle fibers typically lose their polygonal shape and become rounded, and the nuclei often occupy central areas. The endomysial connective tissue increases with progression of the disease process. A nonspecific but wide range of degenerative changes include fiber splitting, ring-fibers, and lobulated fibers (41), and individual muscle fibers showing hyalinization, vacuolation, necrosis, and phagocytosis may be observed. Regenerating fibers with prominent nucleoli and basophilic sarcoplasm are often seen. There are occasional mononuclear cellular infiltrates near necrotic muscle fibers notably in the dysferlinopathies, but these are neither prominent nor widespread. Degenerating muscle fibers are eventually replaced by adipose or connective tissue. Some of these pathologic features have been seen in one syndrome more than another, but as with many of the clinical features there is too much overlap to rely on any one as a differentiating feature. Although next-generation sequencing is typically the diagnostic method of choice, muscle biopsy still has a role when the genetic diagnosis is complicated as it can help to assess changes to dystrophin complex properties (109).
Histochemical studies disclose nonspecific changes typical of primary muscle disease (96). Whorled fibers, moth-eaten fibers, and lobulated fibers, if present, are better appreciated when oxidative enzymes are used.
There have been few ultrastructural studies of muscle in limb-girdle muscular dystrophy. Most authors have described findings in "muscular dystrophy" as a group without specifying the type of dystrophy (391; 436). Most reported ultrastructural reactions involve the myofibrils and mitochondria and are nonspecific. Focal myofibrillar degeneration and Z-disk streaming are common in limb-girdle muscular dystrophies, as in other muscular dystrophies. Sarcoplasmic masses, autophagic vacuoles, small focal collections of glycogen, and scattered lipid droplets are also occasionally encountered.
Immunostaining for specific proteins, however, is highly useful, especially with the sarcoglycanopathies, and has improved the ability to diagnose some of the specific disorders short of molecular genetics. Staining for dystrophin in both males and females is essential to exclude affected individuals and manifesting carriers. Although adhalin (alpha-sarcoglycan) is a marker of the dystrophin-associated glycoprotein complex, specific antibodies for each subunit are available. Staining for merosin is useful in congenital cases. Antibodies for other proteins are increasingly available but vary between neuropathological centers.
Specific genetic tests. All known forms, including those only linked to chromosomal regions, can be theoretically screened by molecular genetics; however, some genes are more complex than others. For example, in excess of 500 mutations of the calpain-3 gene are known even though most cases are caused by a single mutation (188; 141). The most current information can be found on this frequently updated website: Genetic Testing Registry. However, many cases and families diagnosed as limb-girdle muscular dystrophy on clinical grounds remain unconfirmed and unclassified.
Currently, the best approach to obtain a genetic diagnosis in cases of limb-girdle muscular dystrophy is the use of next-generation sequencing so that patients can be screened using custom DNA capture via neuromuscular disease-related gene panels or by whole exome sequencing (180). This approach increases diagnostic yield and leads to discovery of new genes and phenotypes (266; 345; 444; 209; 417; 559). It is worth mentioning that repeat disorders such as fascioscapulohumeral muscular dystrophy or myotonic dystrophy should be excluded first before doing next-generation sequencing. Although this approach increases diagnostic yield, there will still be a group of patients who remain undiagnosed (from 25% to 70%). In a study, a genetic diagnosis was obtained in 53% of families using a multigene next generation sequencing panel as a first-tier approach in the investigation of muscular dystrophy (547). If next-generation sequencing is negative or unclear, further work up with neurophysiological and imaging studies, respiratory and cardiac investigations, and biopsy and protein immunoanalysis come into play. It is expected that with improvement of genetic testing and patient registries, more mutations and new phenotypes of known pathogenic genes will be described.
Management
No specific therapy to halt or delay progression of the primary muscle disease is presently known for any of the limb-girdle muscular dystrophies. Glucocorticoids have shown to improve muscle strength in Duchenne and Becker muscular dystrophy; however, no improvement has been observed in most patients with limb-girdle muscular dystrophy when treated with a 6-month course of prednisone (231). However, there have been small reports of improvement in LGMD R6 and LGMD R9. In LGMD R2, dysferlin-related, a case report of a patient using 15 mg prednisone orally in alternate days showed an increment of elbow and knee flexion strength over the follow-up time of 17 years (487). In mouse models with mutations for LGMD R2 and LGMD R5, they found that use of steroids was associated with better sarcolemmal repair. This effect was most prominent for vamorolone, however, the relationship between anti-inflammatory and functional improvement is still not completely clear as it was not examined in this study. Two siblings with LGMD R4 were treated with 0.9 mg/kg/day of deflazacort and demonstrated improvement in muscle testing at 22 months. Prednisone has also been used with some clinical benefit in LGMD R6. However, for LGMD R2, deflazacort was used for daily therapy and was associated with decreased muscle strength. There are some ongoing trials utilizing daily deflazacort in LGMD R9 with 4-stair climb times (4SCT) as a primary outcome and another study is using weekly prednisone in patients with all LGMD forms, measuring safety and muscle function improvement as the outcomes (413).
In LGMD R9 and LGMD R1, low-intensity training resulted in an increase in endurance and strength in a small study (483). Antigravity training improved walking capacity and postural balance in LGMD R9 (39). A mouse model for LGMD R2 compared the effects of concentric muscle contractions to those of eccentric contractions and found that concentric training conferred exercise benefits without inducing the damage that eccentric training did (33).
Myostatin inhibition therapy was attempted for patients with LGMD R1 that resulted in muscle hypertrophy, actually creating a loss of oxidative capacity and unfortunately no increase in muscle function or exercise tolerance (274). In dysferlin deficient mice, N-acetylcysteine supplementation reduced oxidative damage to muscles and also improved the animals’ grip strength, indicating that this antioxidant could be of benefit to patients with LGMD R2 (172).
In one patient with dominantly inherited calpainopathy (c.643_663del21 mutation), an open label treatment with low-dose recombinant human growth hormone (somatropin) over a period of 4.5 years improved muscle strength measure with dynamometer and stabilized walking ability (measured by 6-minute walk test). This suggests a possible role of human growth hormone in limb-girdle muscular dystrophy treatment (409).
Cell based therapeutic approaches could be another option that may prove suitable in the near future. Stem cell transplantation promoted muscle regeneration in a mouse model by returning alpha DG glycosylation to mice who were FKRP deficient, mimicking the LGMD R9 state (15). Another study used human induced pluripotent stem cells to generate healthy muscle cells and neurons in vitro in the presence of the LGMD R1 mutation (325).
Additionally, small molecule inhibition has been investigated for mice with LGMD D1 states. Treatment of these mice with an inhibitor for the DNAJ-HSP70 complex remobilized HSP70 away from the Z disc and corrected myopathology (37). A phase 1 clinical trial with safety measurement for the antiapoptotic compound omigapil was conducted for LGMD R23, characterized by LAMA2 gene mutations (439). For the sarcoglycanopathies (LGMD R3, 4, 5, 6), CFTR correctors successfully removed defective sarcoglycan-complexes in vitro when the mutations were missense (74).
The rapidly advancing insights into the mechanisms of muscle cell death have opened the way for genetic interventions. Strategies include the use of viral vectors (such as adeno-associated virus vector) to deliver the mutated genes.
For LGMD R5, an experiment using vivo-PMOs (anti-sense oligonucleotide) mediated-exon skipping demonstrated successfully expressed sarcoglycan proteins; however, these studies have not been performed yet in therapeutic trials. A clinical trial has been done for AAV (adeno-associated viral vectors) gene transfer therapy showing no adverse effects for these patients and also that there was a dose-dependent response for how much gamma sarcoglycan was expressed (90).
In LGMD R4 (LGMD2E), three children treated with systemic administration of the investigational gene therapy MYO-101 (scAAVrh74.MHCK7.hSGCB) showed increment of beta-sarcoglycan expression in muscle (mean of 51% of positive fibers exceeding the predefined measure for success of 20%) at 2 months with 90% reduction of creatine kinase. The vector promoter (MHCK7) was chosen for its ability to generate significant protein levels in the heart, which can be affected in LGMD2E patients. A phase I/IIa study cohort of six patients is ongoing with an estimated completion date at the end of 2020.
In LGMD R3 (LGMD2D), a phase I/IIa study of alpha-sarcoglycan gene delivery using a self-complementary adeno-associated virus vector, scAAVrh74.tMCK.hSGCA (MYO-102), was done using isolated limb infusion. One nonambulant adult received the treatment in one leg. Once confirmed to be safe, five ambulatory children received the drug in both legs. They were followed up for a total of 2 years. Following treatment, four of the children had increased levels of alpha-sarcoglycan in muscles. Two of the children had changes in thigh muscle strength. However, the 6-minute walk test worsened or remained the same in all subjects (327). The authors explained that lack of delivery to more proximal hip muscles affected the ability to improve ambulation, so a trial of systemic administration was conducted on a mouse model in 2020, which led to expression of the deficient protein (alpha sargoclycan) without findings of vector toxicity and conferred some benefit to the mice (191).
In LGMD R2 (LGMD2B) patients, a phase I study of intramuscular administration of dysferlin gene using AAVrh.74.Dysferlin.DV (dual vectors) (MYO-201) was completed. In this approach, two viral vectors will be administered to reconstitute the full-length dysferlin gene. This approach was previously successful in dysferlin-deficient mice (467; 406).
For calpainopathy LGMD (types R1 and D4), recombinant AAV-mediated calpain 3 transfer has demonstrated improvement in animal studies, but gene therapy clinical trials are yet to occur (315). An animal study also demonstrated AAV CAPN3 gene therapy in a mouse that resulted in significant, robust improvement in functional outcomes and muscle physiology independent of age (432).
Other gene replacement therapies in the horizon, all using AAV vectors, include MYO-103 (LGMD2C or gamma-sarcoglycan), MYO-301 (LGM2L or ANO-5), and LGMD2A (CAPN3).
In a mouse model of LGMD R9, long-term ribitol treatment has shown improved muscle pathology and function and increased lifespan without serious side effects (551). In addition to the 2017 reclassification, Barton and colleagues suggested the consideration of functional clusters for limb-girdle muscle dystrophies: dystroglycanopathies, mechanical signaling defects, and mitochondrial dysfunction, a grouping that could eventually inform potential therapies that are not just gene therapies (23). The glycosylation cluster includes LGMD R9, R11, R13, R14, R19, R20, R24, for which experimental treatments are being investigated on the effects of augmenting glycosylation through overexpression of LARGE, or ISPD, which are dystroglycanopathy genes. The mechanical signaling defects cluster includes LGMD R1, R2, R5, R6, for which treatments with proteins modulating the phosphorylation state of sarcoglycans could be of benefit, as could suppression of P-p38 vs disinhibition of p38 activity to allow for proper tuning of this signaling pathway when an aberrancy exists. The mitochondrial dysfunction group includes LGMD R1, R2, R3, R5, R6, for which treatments could involve mitochondrial-targeting strategies (23).
In particular, treatment with the AMPMP compound for an in vivo model of LGMD R1 activates signaling of defective CaMKIIbeta, which lends support for this as a potential future therapeutic option (298). Similarly, recombinant human galectin-1, a soluble carbohydrate binding protein was found to increase myogenic potential in dysferlin deficient cells, suggesting a potential therapeutic target for LGMD R2 (511). Another study used GW501516 (a PPARδ agonist) to improve mitochondrial biogenesis in vivo in 7-month-old calpain-3-deficient mice (241). This treatment improved satellite cell activity and sarcolemmal repair, reduced serum CK levels, and reduced muscle fatiguability, lending this is a potential therapy for LGMD R1.
Nonspecific therapeutic measures to improve residual muscle strength and to help preserve optimum function are advocated. Primary goals are to prevent contractures and deformities and to maintain upright posture and ambulation as long as possible. Passive stretching exercises, judicious use of orthopedic procedures and bracing, and active exercises against graded resistance are all important measures in the care of these disorders.
Genetic counseling is always a sensitive issue, particularly in families with limb-girdle muscular dystrophy. Counseling should take into account the possibility of considerable interfamilial and intrafamilial variation in the severity of the disease and possible founder effects. It can be difficult to convince family members that the risk of having a relatively severely affected child may be as high for mildly as for severely affected parents.
The cardiopulmonary manifestations are managed by conventional means. Early and severe diaphragmatic involvement may lead to chronic alveolar hypoventilation characterized by early-morning headache, excessive daytime sleepiness, fatigue, and altered cognition. Assisted nocturnal ventilation may provide sustained relief from these symptoms. Periodic assessment of respiratory function is important for early recognition and timely management of respiratory insufficiency. Cardiac evaluation should be done for patients with myotylin, lamin, desmin, DNA JB6, sarcoglycans, FKRP, titin, TRIM32, telethonin, POMT1, POMT2, fukutin, PMGnT1, and dystroglycan mutations or if patient has abnormal EKG, syncope, near-syncope, or palpitations (361). In particular, for the c.826C>A variant for those with FKRP mutations (LGMD R9), Libell and colleagues have suggested that homozygotes have echocardiogram monitoring every 2 to 3 years in childhood/adulthood whereas other FKRP genotypes should undergo this annually as cardiomyopathy tends to develop earlier in these groups (290). A study suggested surveillance with cardiac MR for limb-girdle muscular dystrophy patients, as MR can detect cardiac involvement earlier than echo or EKG, especially because patients with limb-girdle muscular dystrophy whose cardiac function is affected may manifest with preserved LV volume and LVEF despite dilated cardiomyopathy (435). Characteristic findings can include subepicardial late gadolinium enhancement in the inferior and inferolateral walls or mid-myocardial late gadolinium enhancement in the basal septum.
Pashun and associates have estimated that LGMD R4 is associated with cardiomyopathy in approximately 50% to 67% of patients, in whom intramyocardial fat infiltration, ischemic events, and early cardiac death can occur (388). Although there are no formally established guidelines yet for the routine surveillance of these patients, early cardiac imaging is important and ECG, Holter monitoring, and echocardiogram can be considered at a frequency of every 2 to 5 years to prevent complications associated with the cardiac damage that commonly occurs in LGMD R4 patients. Cardiac MR is the gold standard for myocardial tissue characterization to demonstrate scarring; however, cardiac CT can be used with more ease and can also detect intramyocardial fat, so it could, therefore, serve as an important means of surveillance as well. LGMD R4 is associated with abnormalities of the sarcoglycan complex in vascular smooth muscle and mouse models have revealed a role for verapamil initiation to alleviate vascular constriction and potentially prevent cardiomyopathy before it occurs in these patients (388).
Regarding swallowing function, patients with dysphagia, frequent aspiration, or weight loss should be referred for swallowing evaluation or gastroenterology evaluation to assess and manage swallowing function and aspiration risk and to teach patients techniques for safe and effective swallowing (eg, chin tuck maneuver or altered food consistencies) as well as to consider placement of a gastrostomy or jejunostomy tube for nutritional support.
Muscular dystrophy patients with musculoskeletal spine deformities should be evaluated by an orthopedic spine surgeon for monitoring and surgical intervention if it is deemed necessary in order to maintain normal posture, assist mobility, maintain cardiopulmonary function, and optimize quality of life.
As a whole, patients with muscular dystrophy should have access to a multidisciplinary clinic where they can be evaluated by multiple specialties (physical therapy, occupational therapy, respiratory therapy, speech and swallowing therapy, cardiology, pulmonology, orthopedics, and genetics) in order to receive efficient and effective long-term care.
Attending to the emotional needs of patients with disabling muscular dystrophy is an exceedingly important aspect of the overall management.
Special considerations
Pregnancy
Some forms of disease have been successfully diagnosed prenatally through chorionic villus sampling.
A study examined pregnancy outcomes for women with LGMD R9 (289). They had higher rates of labor induction and were found to be significantly more likely to require assisted vaginal delivery and some also experienced a progression of weakness during their pregnancy, at times without a return to their prior baseline.
Anesthesia
Patients with advanced limb-girdle muscular dystrophy and a compromised cardiopulmonary status may be at increased risk for perioperative morbidity and mortality.
References
- 01
- Accorsi A, Cramer ML, Girgenrath M. Fibrogenesis in LAMA2-related muscular dystrophy is a central tenet of disease etiology. Front Mol Neurosci 2020;13:3. PMID 32116541
- 02
- Alcantara-Ortigoza MA, Reyna-Fabián ME, González-Del Angel A, et al. Predominance of dystrophinopathy genotypes in Mexican male patients presenting as muscular dystrophy with a normal multiplex polymerase chain reaction DMD gene result: A study including targeted next-generation sequencing. Genes (Basel) 2019;10(11):856. PMID 31671740
- 03
- Alonso-Perez J, González-Quereda L, Bruno C, et al. Clinical and genetic spectrum of a large cohort of patients with δ-sarcoglycan muscular dystrophy. Brain 2022;145(2):596-606. PMID 34515763
- 04
- Anandan C, Milone M, Liewluck T. Intramuscular interstitial amyloid deposition does not impact anoctaminopathy-5 phenotype. Muscle Nerve 2019;59(1):133-7. PMID 30320887
- 05
- Andersson DC, Meli AC, Reiken S, et al. Leaky ryanodine receptors in β-sarcoglycan deficient mice: a potential common defect in muscular dystrophy. Skelet Muscle 2012;2(1):9. PMID 22640601
- 06
- Angelini C, Fanin M, Freda P, Duggan DJ, Siciliano G, Hoffman EP. The clinical spectrum of sarcoglycanopathies. Neurology 1999;52:176-9. PMID 9921870
- 07
- Angelini C, Marozzo R, Pinzan E, et al. A new family with transportinopathy: increased clinical heterogeneity. Ther Adv Neurol Disord 2019;12:1756286419850433. PMID 31217819
- 08
- Antoniades L, Eftychiou C, Kyriakides T, Christodoulou K, Katritsis DG. Malignant mutation in the lamin A/C gene causing progressive conduction system disease and early sudden death in a family with mild form of limb-girdle muscular dystrophy. J Interv Card Electrophysiol 2007;19(1):1-7. PMID 17605093
- 09
- Aoki M, Liu J, Richard I, et al. Genomic organization of the dysferlin gene and novel mutations in Miyoshi myopathy. Neurology 2001;57:271-8. PMID 11468312
- 10
- Argyropoulou Z, Liu L, Ozoemena L, et al. A novel PLEC nonsense homozygous mutation (c.7159G > T; p.Glu2387*) causes epidermolysis bullosa simplex with muscular dystrophy and diffuse alopecia: a case report. BMC Dermatol 2018;18(1):1. PMID 29352809
- 11
- Arts WF, Bethlem J, Volkers WS. Further investigations on benign myopathy with autosomal dominant inheritance. J Neurol 1978;217:201-6. PMID 75955
- 12
- Astrom KE. Adams RD. The pathological reactions of the skeletal muscle fiber. In: Vinken PJ, Bruyn GW, editors. Handbook of Clinical Neurology. Vol. 40. Diseases of muscle. Part 2. Amsterdam: North-Holland Publ, 1979:197-274.
- 13
- Avila-Polo R, Malfatti E, Lornage X, et al. Loss of sarcomeric scaffolding as a common baseline histopathologic lesion in titin-related myopathies. J Neuropathol Exp Neurol 2018;12(77):1101-14. PMID 30365001
- 14
- Azibi K, Chaouch M, Reghis A, et al. Linkage analysis of 19 families with Maghrebien autosomal recessive myopathy [abstract]. Cytogenet Cell Genet 1991;58:1907.
- 15
- Azzag K, Ortiz-Cordero C, Oliveira NAJ, et al. Efficient engraftment of pluripotent stem cell-derived myogenic progenitors in a novel immunodeficient mouse model of limb girdle muscular dystrophy 2I. Skelet Muscle 2020;10(1):10. PMID 32321586
- 16
- Bailey EC, Alrowaished SS, Kilroy EA, et al. NAD+ improves neuromuscular development in a zebrafish model of FKRP-associated dystroglycanopathy. Skelet Muscle 2019;9(1):21. PMID 31391079
- 17
- Balci B, Aurino S, Haliloglu G, et al. Calpain-3 mutations in Turkey. Eur J Pediatr 2006;165(5):293-8. PMID 16411092
- 18
- Balci B, Uyanik G, Dincer P, et al. An autosomal recessive limb girdle muscular dystrophy (LGMD2) with mild mental retardation is allelic to Walker-Warburg syndrome (WWS) caused by a mutation in the POMT1 gene. Neuromuscul Disord 2005;15(4):271-5. PMID 15792865
- 19
- Balcin H, Palmio J, Penttila S, et al. Late-onset limb-girdle muscular dystrophy caused by GMPPB mutations. Neuromusc Dis 2017;27:627-30. PMID 28478914
- 20
- Bansal D, Miyake K, Vogel SS, et al. Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature 2003;423(6936):168-72. PMID 12736685
- 21
- Barp A, Laforet P, Bello L, et al. European muscle MRI study in limb girdle muscular dystrophy type R1/2A (LGMDR1/LGMD2A). J Neurol 2020;267(1):45-56. PMID 31555977
- 22
- Barresi R, Morris C, Hudson J, et al. Conserved expression of truncated telethonin in a patient with limb-girdle muscular dystrophy 2G. Neuromuscul Disord 2015;25(4):349-52. PMID 25724973
- 23
- Barton ER, Pacak CA, Stoppel WL, Kang PB. The ties that bind: functional clusters in limb-girdle muscular dystrophy. Skelet Muscle 2020;10(1):22. PMID 32727611
- 24
- Barton ER, Wang BJ, Brisson BK, Sweeney HL. Diaphragm displays early and progressive functional deficits in dysferlin-deficient mice. Muscle Nerve 2010;42(1):22-9. PMID 20544921
- 25
- Bashir R, Strachan T, Keer S, et al. A gene for autosomal recessive limb-girdle muscular dystrophy maps to chromosome 2p. Hum Mol Genet 1994;3:455-7. PMID 8012357
- 26
- Batlle C, Yang P, Coughlin M, et al. hnRNPDL phase separation is regulated by alternative splicing and disease-causing mutations accelerate its aggregation. Cell Rep 2020;30(4):1117-28.e5. PMID 31995753
- 27
- Bauer R, Macgowan GA, Blain A, Bushby K, Straub V. Steroid treatment causes deterioration of myocardial function in the{delta}-sarcoglycan-deficient mouse model for dilated cardiomyopathy. Cardiovasc Res 2008;79(4):652-61. PMID 18495669
- 28
- Baumeister SK, Todorovic S, Milic-Rasic V, Dekomien G, Lochmuller H, Walter MC. Eosinophilic myositis as presenting symptom in gamma-sarcoglycanopathy. Neuromuscul Disord 2009;19(2):167-71. PMID 19167890
- 29
- Bawa S, Gameros S, Baumann K, et al. Costameric integrin and sarcoglycan protein levels are altered in a Drosophila model for Limb-girdle muscular dystrophy type 2H. Mol Biol Cell 2021;32(3):260-73. PMID 33296226
- 30
- Beckmann JS. Genetic studies and molecular structures: the dystrophin associated complex. Hum Mol Genet 1996;5(7):865-7. PMID 8817320
- 31
- Beckmann JS, Richard I, Hillaire D, et al. A gene for autosomal recessive limb-girdle muscular dystrophy maps to chromosome 15 by linkage. C R Acad Sci III 1991;312:141-8. PMID 1901754
- 32
- Begam M, Collier AF, Mueller AL, Roche R, Galen SS, Roche JA. Diltiazem improves contractile properties of skeletal muscle in dysferlin-deficient BLAJ mice, but does not reduce contraction-induced muscle damage. Physiol Rep 2018;6(11):e13727. PMID 29890050
- 33
- Begam M, Roche R, Hass JJ, et al. The effects of concentric and eccentric training in murine models of dysferlin-associated muscular dystrophy. Muscle Nerve 2020;62(3):393-403. PMID 32363622
- 34
- Bell J. The treasury of human inheritance. Vol. IV. Nervous disease and muscular dystrophies. Cambridge: Cambridge Univ Press, 1943.
- 35
- Beltran-Valero de Bernabe D, Currier S, Steinbrecher A. et al. Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet 2002;71(5):1033-43. PMID 12369018
- 36
- Ben Hamida M, Fardeau M, Attia N. Severe childhood muscular dystrophy affecting both sexes and frequent in Tunisia. Muscle Nerve 1983;6:469-80. PMID 6633560
- 37
- Bengoechea R, Findlay AR, Bhadra AK, et al. Inhibition of DNAJ-HSP70 interaction improves strength in muscular dystrophy. J Clin Invest 2020;130(8):4470-85. PMID 32427588
- 38
- Berardo A, Lornage X, Johari M, et al. HNRNPDL‑related muscular dystrophy: expanding the clinical, morphological and MRI phenotypes. J Neurol 2019;266(10):2524-34. PMID 31267206
- 39
- Berthelsen MP, Husu E, Christensen SB, Prahm KP, Vissing J, Jensen BR. Anti-gravity training improves walking capacity and postural balance in patients with muscular dystrophy. Neuromusc Dis 2014;24(6):492-8. PMID 24684860
- 40
- Bethlem J, Van Wijngaarden GK. Benign myopathy with autosomal dominant inheritance, a report of three pedigrees. Brain 1976;99:91-100. PMID 963533
- 41
- Bethlem J, Van Wijngaarden GK, DeJong J. The incidence of lobulated fibers in the facioscapulohumeral type of muscular dystrophy and the limb-girdle syndrome. J Neurol Sci 1973;18:351-8. PMID 4698315
- 42
- Betz RC, Schoser BG, Kasper D, et al. Mutations in CAV3 cause mechanical hyperirritability of skeletal muscle in rippling muscle disease. Nat Genet 2001;28:218-9. PMID 11431690
- 43
- Biancheri R, Falace A, Tessa A, et al. POMT2 gene mutation in limb-girdle muscular dystrophy with inflammatory changes. Biochem Biophys Res Commun 2007;363(4):1033-7. PMID 17923109
- 44
- Bione S, Maestrini E, Rivella S, et al. Identification of a novel X-linked gene responsible for Emery-Dreifuss muscular dystrophy. Nat Genet 1994;8:323-7. PMID 7894480
- 45
- Bisceglia L, Zoccolella S, Torraco A, et al. A new locus on 3p23-p25 for an autosomal-dominant limb-girdle muscular dystrophy, LGMD1H. Eur J Hum Genet 2010;18(6):636-41. PMID 20068593
- 46
- Blackburn PR, Selcen D, Jackson JL, et al. Early-onset limb-girdle muscular dystrophy-2L in a female athlete. Muscle Nerve 2017;55(5):E19-E1. PMID 27862037
- 47
- Blaeser A, Keramaris E, Chan YM, et al. Mouse models of fukutin-related protein mutations show a wide range of disease phenotypes. Hum Genet 2013;132(8):923-34. PMID 23591631
- 48
- Bogershausen N, Shahrzad N, Chong JX, et al. Recessive TRAPPC11 mutations cause a disease spectrum of limb girdle muscular dystrophy and myopathy with movement disorder and intellectual disability. Am J Hum Genet 2013;93(1):181-90. PMID 23830518
- 49
- Boito CA, Melacini P, Vianello A, et al. Clinical and molecular characterization of patients with limb-girdle muscular dystrophy type 2I. Arch Neurol 2005;62(12):1894-9. PMID 16344347
- 50
- Bolduc V, Marlow G, Boycott KM, et al. Recessive mutations in the putative calcium-activated chloride channel Anoctamin 5 cause proximal LGMD2L and distal MMD3 muscular dystrophies. Am J Hum Genet 2010;86(2):213-21. PMID 20096397
- 51
- Bonilla E, Samitt CE, Miranda AF, et al. Duchenne muscular dystrophy: deficiency of dystrophin at the muscle cell surface. Cell 1988;54:447-52. PMID 3042151
- 52
- Bonne G, Di Barletta MR, Varnous S, et al. Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy. Nat Genet 1999;21:285-8. PMID 10080180
- 53
- Borg K, Stucka R, Locke M, et al. Intragenic deletion of TRIM32 in compound heterozygotes with sarcotubular myopathy/LGMD2H. Hum Mutat 2009;30(9):E831-44. PMID 19492423
- 54
- Bradley WG. The limb-girdle syndrome. In: Vinken PJ, Bruyn GW, editors. Handbook of Clinical Neurology. Vol 40. Diseases of muscle. Part I. Amsterdam: North-Holland Publ, 1979:433-69.
- 55
- Bradley WG, Jones MZ, Mussini JM, Faucett PR. Becker-type muscular dystrophy. Muscle Nerve 1978;1:111-32. PMID 571527
- 56
- Bradley WG, Price DL, Watanabe CK. Familial centronuclear myopathy. J Neurol Neurosurg Psychiatry 1970;33:687-93. PMID 5478951
- 57
- Brockington M, Yuva Y, Prandini P, et al. Mutations in Fukutin-related protein gene (FKRP) identify limb-girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C. Hum Mol Genet 2001;10(25):2851-9. PMID 11741828
- 58
- Brooke MH. Congenital fiber type disproportion. In: Kakulas BA, editor. Clinical Studies in Myology. Amsterdam: Excerpta Medica, 1973:147-59.
- 59
- Brown SC, Torelli S, Brockington M, et al. Abnormalities in alpha-Dystroglycan expression in MDC1C and LGMD2I Muscular Dystrophies. Am J Pathol 2004;164(2):727-37. PMID 14742276
- 60
- Brun BN, Willer, T, Darbro, et al. Uniparental disomy unveils a novel recessive mutation in POMT2. Neuromuscul Disord 2018;28(7):595-6. PMID 29759639
- 61
- Brusa R, Magri F, Papadimitriou D, et al. A new case of limb girdle muscular dystrophy 2G in a Greek patient, founder effect and review of the literature. Neuromuscul Disord 2018;28(6):532-37. PMID 29759638
- 62
- Buchthal F, Kamieniecka Z. The diagnostic yield of quantified electromyography and quantified muscle biopsy in neuromuscular disorders. Muscle Nerve 1982;5:265-80. PMID 7099194
- 63
- Burke G, Hillier C, Cole J, et al. Calpainopathy presenting as foot drop in a 41 year old. Neuromuscul Disord 2010;20(6):407-10. PMID 20580976
- 64
- Bushby KM. Diagnostic criteria of the limb-girdle muscular dystrophies: report of the ENMC consortium on limb-girdle dystrophies. Neuromuscul Disord 1995;5:71-4. PMID 7719146
- 65
- Bushby KM. Diagnosis and management of the limb girdle muscular dystrophies. Pract Neurol 2009;9(6):314-23. PMID 19923111
- 66
- Bushby KM, Beckmann JS. The limb-girdle muscular dystrophies--proposal for a new nomenclature. Neuromuscul Disord 1995;5:337-43. PMID 7580247
- 67
- Cabrera-Serrano M, Ghaoui R, Ravenscroft G, et al. Expanding the phenotype of GMPPB mutations. Brain 2015;138(Pt 4):836-44. PMID 25681410
- 68
- Cagliani R, Fortunato F, Giorda R, et al. Molecular analysis of LGMD-2B and MM patients: identification of novel DYSF mutations and possible founder effects in the Italian population. Neuromuscul Disord 2003;13(10):788-95. PMID 14678801
- 69
- Cai S, Gao M, Xi J, et al. Clinical spectrum and gene mutations in a Chinese cohort with anoctaminopathy. Neuromuscul Disord 2019;29(8):628-33. PMID 31350120
- 70
- Cantero D, Hernandez-Lain A, Gonzalo Martinez JF, et al. Milder forms of α-sarcoglicanopathies diagnosed in adulthood by NGS analysis. J Neurol Sci 2018;394:63-7. PMID 30218921
- 71
- Caria F, Cescon M, Gualandi F, et al. Autosomal recessive Bethlem myopathy: a clinical, genetic and functional study. Neuromuscul Disord 2019;29(9):657-63. PMID 31471117
- 72
- Carbone I, Bruno C, Sotgia F, et al. Mutation in the CAV3 gene causes partial caveolin-3 deficiency and hyperCKemia. Neurology 2000;54:1373-6. PMID 10746614
- 73
- Carotti M, Marsolier J, Soardi M, et al. Repairing folding-defective a-sarcoglycan mutants by CFTR correctors, a potential therapy for limb-girdle muscular dystrophy 2D. Hum Mol Genet 2018;27(6):969-84. PMID 29351619
- 74
- Carotti M, Scano M, Fancello I, et al. Combined use of CFTR correctors in LGMD2D myotubes improves sarcoglycan complex recovery. Int J Mol Sci 2020;21(5):1813. PMID 32155735
- 75
- Carss KJ, Stevens E, Foley AR, et al. Mutations in GDP-mannose pyrophosphorylase B cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of a-dystroglycan. Am J Hum Gen 2013;93:29-41. PMID 23768512
- 76
- Casas-Fraile L, Cornelis FM, Costamagna D, et al. Frizzled related protein deficiency impairs muscle strength, gait and calpain 3 levels. Orphanet J Rare Dis 2020;15(1):119. PMID 32448375
- 77
- Cataldi MP, Blaeser A, Lu P, Leroy V, Lu QL. ISPD overexpression enhances ribitol-induced glycosylation of α-dystroglycan in dystrophic FKRP mutant mice. Mol Ther Methods Clin Dev 2019;17:271-80. PMID 31988979
- 78
- Cataldi MP, Lu P, Blaeser A, Lu QL. Ribitol restores functionally glycosylated α-dystroglycan and improves muscle function in dystrophic FKRP-mutant mice. Nat Commun 2018;9(1):3448. PMID 30150693
- 79
- Cenacchi G, Peterle E, Fanin M, Papa V, Salaroli R, Angelini C. Ultrastructural changes in LGMD1F. Neuropathology 2013;33(3):276-80. PMID 23279333
- 80
- Cerabolo F, Messina S, Rodolico C, et al. Myoglobinuria as first clinical sign of a primary alpha-sarcoglycanopathy. Eur J Pediatr 2014;173(2):239-42. PMID 23989969
- 81
- Cetin N, Balci-Hayta B, Gundesli H, et al. A novel desmin mutation leading to autosomal recessive limb-girdle muscular dystrophy: distinct histopathological outcomes compared with desminopathies. J Med Genet 2013;50(7):437-43. PMID 23687351
- 82
- Chakrabarty B, Sharma MC, Gulati S, Sarkar C. Skin biopsy for diagnosis of Ullrich congenital muscular dystrophy: an observational study. J Child Neurol 2017;32(14):1099-103. PMID 29129153
- 83
- Chan SH, Foley AR, Phadke R, et al. Limb girdle muscular dystrophy due to LAMA2 mutations: diagnostic difficulties due to associated peripheral neuropathy. Neuromusc Dis 2014;24(8):677-83. PMID 24957499
- 84
- Chandra G, Sreetama SC, Mázala DAG, et al. Endoplasmic reticulum maintains ion homeostasis required for plasma membrane repair. J Cell Biol 2021;220(5):e202006035. PMID 33688936
- 85
- Chaouch M, Allal Y, De Sandre-Giovannoli A, et al. The phenotypic manifestations of autosomal recessive axonal Charcot-Marie-Tooth due to a mutation in Lamin A/C gene. Neuromuscul Disord 2003;13(1):60-7. PMID 12467734
- 86
- Chardon JW, Smith AC, Woulfe J, et al. LIMS2 mutations are associated with a novel muscular dystrophy, severe cardiomyopathy and triangular tongues. Clin Genet 2015;88(6):558-64. PMID 25589244
- 87
- Chen CH, Tang SC, Su YN, et al. Cardioembolic stroke related to limb-girdle muscular dystrophy 1B. BMC Res Notes 2013;6:32. PMID 23360689
- 88
- Chen H, Xu G, Lin F, et al. Clinical and genetic characterization of limb girdle muscular dystrophy R7 telethonin-related patients from three unrelated Chinese families. Neuromuscul Disord 2020;30(2):137-43. PMID 32005491
- 89
- Chen J, Zeng W, Han C, Wu J, Zhang H, Tong X. Mutation in the caveolin-3 gene causes asymmetrical distal myopathy. Neuropathology 2016;36(5):485-9. PMID 26947586
- 90
- Chiu W, Hsun YH, Chang KJ, et al. Current genetic survey and potential gene-targeting therapeutics for neuromuscular diseases. Int J Mol Sci 2020;21(24):9589. PMID 33339321
- 91
- Chou FL, Angelini C, Daentl D, et al. Calpain III mutation analysis of a heterogeneous limb girdle muscular dystrophy population. Neurology 1999;52(5):1015-20. PMID 10102422
- 92
- Chutkov JG, Heffner RR, Kramer AA, Edwards JA. Adult-onset autosomal dominant limb-girdle muscular dystrophy. Ann Neurol 1986;20:240-8. PMID 3752967
- 93
- Cirak S, Foley AR, Herrmann R, et al. ISPD gene mutations are a common cause of congenital and limb-girdle muscular dystrophies. Brain 2013;136(Pt 1):269-81. PMID 23288328
- 94
- Clement EM, Godfrey C, Tan J, et al. Mild POMGnT1 mutations underlie a novel limb-girdle muscular dystrophy variant. Arch Neurol 2008;65(1):137-41. PMID 18195152
- 95
- Codding SJ, Marty N, Abdullah N, et al. Dysferlin Binds SNAREs (Soluble N-Ethylmaleimide-sensitive Factor (NSF) Attachment Protein Receptors) and Stimulates Membrane Fusion in a Calcium-sensitive Manner. J Biol Chem 2016;291(28):14575-84. PMID 27226605
- 96
- Coers C, Tellerman-Toppet N. Differential diagnosis of limb-girdle muscular dystrophy and spinal muscular dystrophy. Neurology 1979;29:957-72. PMID 572945
- 97
- Cohn RD, Durbeej M, Moore SA, Coral-Vazquez R, Prouty S, Campbell KP. Prevention of cardiomyopathy in mouse models lacking the smooth muscle sarcoglycan-sarcospan complex. J Clin Invest 2001;107(2):R1-7. PMID 11160141
- 98
- Collier AF, Gumerson J, Lehtimaki K, et al. Effect of ibuprofen on skeletal muscle of dysferlin-null mice. J Pharmacol Exp Ther 2018;364(3):409-19. PMID 29284661
- 99
- Cotta A, Paim JF, da-Cunha-Junior AL, et al. Limb girdle muscular dystrophy type 2G with myopathic-neurogenic motor unit potentials and a novel muscle image pattern. BMC Clinical Pathology 2014;14:41. PMID 25298746
- 100
- Cox D, Henderson M, Straub V, Barresi R. A simple and rapid immunoassay predicts dysferlinopathies in peripheral blood film. Neuromuscul Disord 2019;29(11):874-80. PMID 31668500
- 101
- Crosbie RH, Lim LE, Moore SA, et al. Molecular and genetic characterization of sarcospan: insights into sarcoglycan-sarcospan interactions. Hum Mol Genet 2000;9(13):2019-27. PMID 10942431
- 102
- Currier SC, Lee CK, Chang BS, et al. Mutations in POMT1 are found in a minority of patients With Walker–Warburg Syndrome. Am J Med Genet 2005;133(1):53-7. PMID 15637732
- 103
- D’Amico A, Tessa, A, Bruno C, et al. Expanding the clinical spectrum of POMT1 phenotype. Neurology 2006;66(10):1564-7. PMID 16717220
- 104
- Dabby R, Sadeh M, Hilton-Jones D, et al. Adult onset limb-girdle muscular dystrophy: a recessive titinopathy masquerading as myositis. J Neurol Sci 2015;351(1-2):120-3. PMID 25772186
- 105
- Dai Y, Liang S, Dong X, et al. Whole exome sequencing identified a novel DAG1 mutation in a patient with rare, mild and late age of onset muscular dystrophy‐dystroglycanopathy. J Cell Mol Med 2019;23(2):811-8. PMID 30450679
- 106
- Daimagüler HS, Akpulat U, Özdemir Ö, et al. Clinical and genetic characterization of PYROXD1-related myopathy patients from Turkey. Am J Med Genet A 2021;185(6):1678-90. PMID 33694278
- 107
- Darin N, Kroksmark AK, Ahlander AC, Moslemi AR, Oldfors A, Tulinis M. Inflammation and response to steroid treatment in limb-girdle muscular dystrophy 2I. Eur J Paediatr Neurol 2007;11(6):353-7. PMID 17446099
- 108
- de Morree A, Lutje Hulsik D, Impagliazzo A, et al. Calpain 3 is a rapid-action, unidirectional proteolytic switch central to muscle remodeling. PLoS One 2010;5(8):e11940. PMID 20694146
- 109
- De Paepe B, Velghe E, Salminen L, Toth B, Olivier P, De Bleecker JL. Diagnostic muscle biopsies in the era of genetics: the added value of myopathology in a selection of limb-girdle muscular dystrophy patients. Acta Neurol Belg 2021;121(4):1019-33. PMID 33400223
- 110
- De Sandre-Giovannoli A, Bernard R, Cau P, et al. Lamin a truncation in Hutchinson-Gilford progeria. Science 2003;300(5628):2055. PMID 12702809
- 111
- De Sandre-Giovannoli A, Chaouch M, Kozlov S, et al. Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse. Am J Hum Genet 2002;70(3):726-36. PMID 11799477
- 112
- Demonbreun AR, Wyatt EJ, Fallon KS, et al. A gene-edited mouse model of limb-girdle muscular dystrophy 2C for testing exon skipping. Dis Model Mech 2020;13(2):dmm040832. PMID 31582396
- 113
- DiCapua D, Patwa H. Puerto Rican founder mutation G787A in the SGCG gene: a case report of 2 siblings with LGMD 2C. J Clin Neuromusc Dis 2014;15(3):105-7. PMID 24534832
- 114
- DiFranco M, Kramerova I, Vergara J, et al. Attenuated Ca(2+) release in a mouse model of limb girdle muscular dystrophy 2A. Skelet Muscle 2016;6:11. PMID 26913171
- 115
- DiMauro S, Bonilla E. Mitochondrial encephalomyopathies. In: Engel AG, Franzini-Armstrong C, editors. Myology, 3rd ed, Vol 2. New York, McGraw-Hill, 2004:1623-62.
- 116
- Dincer P, Balci B, Yuva Y, et al. A novel form of recessive limb girdle muscular dystrophy with mental retardation and abnormal expression of alpha-dystroglycan. Neuromuscul Disord 2003;13(10):771-8. PMID 14678799
- 117
- Dincer P, Piccolo F, Leturcq F, Kaplan JC, Jeanpierre M, Topaloglu H. Prenatal diagnosis of limb-girdle muscular dystrophy type 2C. Prenat Diagn 1998;18(12):1300-3. PMID 9885023
- 118
- Ding J, Zhao D, Du R, et al. Clinical and molecular genetic analysis of a family with late-onset LAMA2-related muscular dystrophy. Brain Dev 2016;38(2):242-9. PMID 26304763
- 119
- Dong M, Noguchi S, Endo Y, et al. DAG1 mutations associated with asymptomatic hyperCKemia and hypoglycosylation of a-dystroglycan. Neurology 2015;84(3):273-9. PMID 25503980
- 120
- Dong X, Gao X, Dai Y, et al. Serum exosomes can restore cellular function in vitro and be used for diagnosis in dysferlinopathy. Theranostics 2018;8(5):1243-55. PMID 29507617
- 121
- Donkervoort S, Hu Y, Stojkovic T, et al. Mosaicism for dominant collagen 6 mutations as a cause for intrafamilial phenotypic variability. Hum Mutat 2015;36(1):48-56. PMID 25204870
- 122
- Driss A, Amouri R, Ben Hamida C, et al. A new locus of autosomal recessive limb-girdle muscular dystrophy in a large consanguineous Tunisian family maps to chromosome 19q13.3. Neuromuscul Disord 2000;10:240-6. PMID 10838249
- 123
- Dubowitz V, Roy S. Central core disease of muscle: clinical, histochemical, and electronmicroscopic studies of an affected mother and child. Brain 1970;93:133-420. PMID 5418397
- 124
- Duggan DJ, Gorospe JR, Fanin M, Hoffman EP, Angelini C. Mutations in the sarcoglycan genes in myopathy patients. N Engl J Med 1997a;336:618-24. PMID 9032047
- 125
- Duggan DJ, Manchester D, Stears KP, Mathews DJ, Hart C, Hoffman EP. Mutations in the delta-sarcoglycan gene are a rare cause of autosomal recessive limb-girdle muscular dystrophy (LGMD2). Neurogenetics 1997b;1:49-58. PMID 10735275
- 126
- Duguez S, Bartoli M, Richard I. Calpain 3: a key regulator of the sarcomere. FEBS J 2006;273:3427-36. PMID 16884488
- 127
- Durbeej M, Sawatzki SM, Barresi R, et al. Gene transfer establishes primacy of striated vs. smooth muscle sarcoglycan complex in limb-girdle muscular dystrophy. Proc Natl Acad Sci U S A 2003;100(15):8910-5. PMID 12851463
- 128
- Eisenberg I, Avidan N, Tamara Potikha T, et al. The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy. Nat Genet 2001;29(1):83-7. PMID 11528398
- 129
- El Kerch F, Ratbi I, Sbiti A, Laarabi FZ, Barkat A, Sefiani A. Carrier frequency of the c.525delT mutation in the SGCG gene and estimated prevalence of limb girdle muscular dystrophy type 2C among the Moroccan population. Gen Test Mol Biomarkers 2014;18 (4):253-6. PMID 24552312
- 130
- El-Khoury R, Traboulsi S, Hamad T, Lamaa M, Sawaya R, Ahdab-Barmada M. Divergent features of mitochondrial deficiencies in LGMD2A associated with novel calpain-3 mutations. J Neuropathol Exp Neurol 2019;78(1):88-98. PMID 30500922
- 131
- Emery AE. Abnormalities of the electrocardiogram in female carriers of Duchenne muscular dystrophy. Br Med J 1969;2:418-20. PMID 5781488
- 132
- Emery AE, Dreifuss FE. Unusual type of benign X-linked muscular dystrophy. J Neurol Neurosurg Psychiatry 1966;19:338-42. PMID 5969090
- 133
- Endo Y, Dong M, Noguchi S, et al. Milder forms of muscular dystrophy associated with POMGNT2 mutations. Neurol Genet 2015;1(4):e33. PMID 27066570
- 134
- Engel AG, Gomez MR, Groover RV. Multicore disease: a recently recognized congenital myopathy associated with multifocal degeneration of muscle fibers. Mayo Clin Proc 1971;46:666-81. PMID 5115748
- 135
- Erb W. Dystrophia muscularis progressiva. Klinische und pathologisch-anatomische Studien. Dtsch Z Nervenheit 1891;1:13-94, 173-261.
- 136
- Erb W. Uber die 'juvenile form' der progressiven Muskelatrophie und ihre Beziehungen zur sogenannten Pseudohypertrophie des Muskeln. Dtsch Arch Klin Med 1884;34:467-519.
- 137
- Ermolova N, Kramerova I, Spencer MJ. Autolytic activation of calpain 3 proteinase is facilitated by calmodulin protein. J Biol Chem 2015;290(2):996-1004. PMID 25389288
- 138
- Fan Y, Liu A, Wei C, et al. Genetic and clinical findings in a Chinese cohort of patients with collagen VI-related myopathies. Clin Genet 2018;93(6):1159-71. PMID 29419890
- 139
- Fanin M, Angelini C. Progress and challenges in diagnosis of dysferlinopathy. Muscle Nerve 2016;54(5):821-35.** PMID 27501525
- 140
- Fanin M, Angelini C. Protein and genetic diagnosis of limb girdle muscular dystrophy type 2A: the yield and the pitfalls. Muscle Nerve 2015;52(2):163-73.** PMID 25900067
- 141
- Fanin M, Fulizio L, Nascimbeni AC, et al. Molecular diagnosis in LGMD2A: mutation analysis or protein testing. Hum Mutat 2004;24(1):52-62. PMID 15221789
- 142
- Fanin M, Nascimbeni AC, Angelini C. Muscle atrophy, ubiquitin–proteasome, and autophagic pathways in dysferlinopathy. Muscle Nerve 2014;50(3):340-7. PMID 24395438
- 143
- Fanin M, Nascimbeni AC, Angelini C. Muscle protein analysis in the detection of heterozygotes for recessive limb-girdle muscular dystrophy type 2B and 2E. Neuromuscul Disord 2006;16:792-9. PMID 16934466
- 144
- Fanin M, Nascimbeni AC, Fulizio L, Angelini C. The frequency of limb girdle muscular dystrophy 2A in northeastern Italy. Neuromusc Disord 2005;15(3):218-24. PMID 15725583
- 145
- Fanin M, Nascimbeni AC, Fulizio L, et al. Loss of calpain-3 autocatalytic activity in LGMD2A patients with normal protein expression. Am J Pathol 2003;163(5):1929-36. PMID 14578192
- 146
- Fanin M, Nascimbeni AC, Tasca E, Angelini C. How to tackle the diagnosis of limb-girdle muscular dystrophy 2A. Eur J Hum Genet 2009;17(5):598-603. PMID 18854869
- 147
- Fanin M, Pegoraro E, Matsuda-Asada C, Brown RH, Angelini C. Calpain-3 and dysferlin protein screening in patients with limb-girdle dystrophy and myopathy. Neurology 2001;56:660-5. PMID 11245721
- 148
- Fanin M, Peterle E, Fritegotto C, et al. Incomplete penetrance in limb-girdle muscular dystrophy type 1F. Muscle Nerve 2015;52(2):305-6. PMID 25487718
- 149
- Farag TI, Teebi AS. Duchenne muscular dystrophy in the Arabs [letter]. Am J Med Genet 1990;37:290.
- 150
- Fardeau M, Hillaire D, Mignard C, et al. Juvenile limb-girdle muscular dystrophy: clinical, histopathological, and genetic data on small community living in Reunion Island. C R Acad Sci (Paris) 1996;119(Pt 1):295-308. PMID 8624690
- 151
- Fatkin D, MacRae C, Sasaki T, et al. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J Med 1999;341:1715-24. PMID 10580070
- 152
- Fattahi Z, Kahrizi K, Nafissi S, et al. Report of a patient with limb-girdle muscular dystrophy, ptosis and ophthalmoparesis caused by plectinopathy. Arch Iran Med 2015;18(1):60-4. PMID 25556389
- 153
- Fayssoil A, Drouet T, Luis D, et al. Acute ischemic stroke in gamma-sarcoglycanopathy. Presse Med 2013;42(4 Pt 1):484-6. PMID 16616845
- 154
- Fecarotta S, Gragnaniello V, Della Casa R, et al. Steroid therapy in an alpha-dystroglycanopathy due to GMPPB gene mutations: a case report. Neuromuscul Disord 2018;28(11):956-60. PMID 30126629
- 155
- Fee DB, Harmelink M, Monrad P, et al. Siblings with mutations in TRAPPC11 presenting with limb-girdle muscular dystrophy 2S. J Clin Neuromusc Dis 2017;19(1):27-30. PMID 28827486
- 156
- Findlay AR, Robinson SE, Poelker S, Seiffert M, Bengoechea R, Weihl CC. LGMDD1 natural history and phenotypic spectrum: implications for clinical trials. Ann Clin Transl Neurol 2023;10(2):181-94. PMID 36427278
- 157
- Findley AR, Bengoechea R, Pittman SK, Chou TF, True HL, Weihl CC. Lithium chloride corrects weakness and myopathology in a preclinical model of LGMD1D. Neurol Genet 2019;5(2):e318. PMID 31123706
- 158
- Finsterer J. Phenotypic heterogeneity of POMT2 gene variants. Am J Med Genet 2018;176(3):743-5. PMID 29283213
- 159
- Fiorillo C, Moro F, Astrea G, et al. Novel mutations in the fukutin gene in a boy with asymptomatic hyperCKemia. Neuromusc Dis 2013;23(12):1010-15. PMID 24144914
- 160
- Fischer D, Aurino S, Nigro V, Schroder R. On symptomatic heterozygous alpha-sarcoglycan gene mutation carriers. Ann Neurol 2003;54(5):674-8. PMID 14595658
- 161
- Foltz SJ, Cui YY, Choo HJ, Hartzell HC. ANO5 ensures trafficking of annexins in wounded myofibers. J Cell Biol 2021;220(3):e202007059. PMID 33496727
- 162
- Foroud T, Pankratz N, Batchman AP, et al. A mutation in myotilin causes spheroid body myopathy. Neurology 2005;65(12):1936-40. PMID 16380616
- 163
- Franekova V, Storjord HI, Leivseth G, Nilssen Ø. Protein homeostasis in LGMDR9 (LGMD2I) - the role of ubiquitin-proteasome and autophagy-lysosomal system. Neuropathol Appl Neurobiol 2021;47(4):519-31. PMID 33338270
- 164
- Frosk P, Del Bigio MR, Wrogemann K, Greenberg CR. Hutterite brothers both affected with two forms of limb girdle muscular dystrophy: LGMD2H and LGMD2I. Eur J Hum Genet 2005b;13:978-82. PMID 15886712
- 165
- Frosk P, Greenberg CR, Tennese AA, et al. The most common mutation in FKRP causing limb girdle muscular dystrophy type 2I (LGMD2I) may have occurred only once and is present in Hutterites and other populations. Hum Mutat 2005a;25(1):38-44. PMID 15580560
- 166
- Frosk P, Weiler T, Nylen E, et al. Limb-girdle muscular dystrophy type 2H associated with mutation in TRIM32, a putative E3-ubiquitin-ligase gene. Am J Hum Genet 2002;70(3):663-72. PMID 11822024
- 167
- Fu X, Yang H, Wei C, et al. FKRP mutations, including a founder mutation, cause phenotype variability in Chinese patients with dystroglycanopathies. J Hum Genet 2016;61(12):1013-20. PMID 27439679
- 168
- Fukuyama Y, Kwazura M, Haruna H. A peculiar form of congenital muscular dystrophy. Paediatr Univ Tokyo 1960;4:5-8.
- 169
- Fulizio L, Chiara Nascimbeni A, Fanin M, et al. Molecular and muscle pathology in a series of caveolinopathy patients. Hum Mutat 2005;25(1):82-9. PMID 15580566
- 170
- Furuta M, Sumi-Akamuru H, Takahashi MP, et al. An elderly-onset limb girdle muscular dystrophy type 1B (LGMD1B) with pseudo-hypertrophy of paraspinal muscles. Neuromusc Dis 2016;26(9):593-7. PMID 27220833
- 171
- Gandolla M, Antonietti A, Longatelli V, et al. Test-retest reliability of the Performance of Upper Limb (PUL) module for muscular dystrophy patients. PLoS One 2020;15(9):e0239064. PMID 32986757
- 172
- Garcia-Campos P, Báez-Matus X, Jara-Gutiérrez C, et al. N-acetylcysteine reduces skeletal muscles oxidative stress and improves grip strength in dysferlin-deficient Bla/J mice. Int J Mol Sci 2020;21(12):4293. PMID 32560255
- 173
- Garibaldi M, Fattori F, Bortolotti CA, et al. Core-rod myopathy due to a novel mutation in BTB/POZ domain of KBTBD13 manifesting as late onset LGMD. Acta Neuropathol Commun 2018;6(1):94. PMID 30208948
- 174
- Garvey SM, Liu Y, Miller SE, Hauser MA. Myotilin overexpression enhances myopathology in the LGMD1A mouse model. Muscle Nerve 2008;37(5):663-7. PMID 18335471
- 175
- Garvey SM, Miller SE, Claflin DR, Faulkner JA, Hauser MA. Transgenic mice expressing the myotilin T57I mutation unite the pathology associated with LGMD1A and MFM. Hum Mol Gen 2006;15:2348-62. PMID 16801328
- 176
- Garvey SM, Rajan C, Lerner AP, Frankel WN, Cox GA. The muscular dystrophy with myositis (mdm) mouse mutation disrupts a skeletal muscle-specific domain of titin. Genomics 2002;79(2):146-9. PMID 11829483
- 177
- Gawlik KI, Körner Z, Oliveira BM, Durbeej M. Early skeletal muscle pathology and disease progress in the dy 3K /dy 3K mouse model of congenital muscular dystrophy with laminin α2 chain-deficiency. Sci Rep 2019;9(1):14324. PMID 31586140
- 178
- Geis T, Rödl T, Topaloǧlu H, et al. Clinical long-time course, novel mutations and genotype-phenotype correlation in a cohort of 27 families with POMT1-related disorders. Orphanet J Rare Dis 2019;14(1):179. PMID 31311558
- 179
- Ghaoui R, Benavides T, Lek M, et al. TOR1AIP1 as a cause of cardiac failure and recessive limb-girdle muscular dystrophy. Neuromusc Dis 2016;26(8):500-3. PMID 27342937
- 180
- Ghaoui R, Cooper ST, Lek M, et al. Use of whole-exome sequencing for diagnosis of limb-girdle muscular dystrophy outcomes and lessons learned. JAMA Neurol 2015;72(12):1424-32. PMID 26436962
- 181
- Gibertini S, Ruggieri A, Saredi S, et al. Long term follow-up and further molecular and histopathological studies in the LGMD1F sporadic TNPO3-mutated patient. Acta Neuropathol Commun 2018;6(1):141. PMID 30567601
- 182
- Godfrey C, Escolar D, Brockington M, et al. Fukutin gene mutations in steroid-responsive limb girdle muscular dystrophy. Ann Neurol 2006;60:603-10. PMID 17044012
- 183
- Golla S, Agadi S, Burns DK, et al. Dystrophinopathy in girls with limb girdle muscular dystrophy phenotype. J Clin Neuromuscul Dis 2010;11(4):203-8. PMID 20516809
- 184
- Gomez-Andres D, Diaz J, Munell F, et al. Disease duration and disability in dysfelinopathy can be described by muscle imaging using heatmaps and random forests. Muscle Nerve 2019;59(4):436-44. PMID 30578674
- 185
- Gonzalez Garcia A, Tutmaher MS, Upadhyayula SR, Sanchez Russo R, Verma S. Novel PLEC gene variants causing congenital myasthenic syndrome. Muscle Nerve 2019;60(6):E40-3. PMID 31509265
- 186
- Gonzalez-Mera L, Ravenscroft G, Cabrera-Serrano M, et al. Heterozygous CAPN3 missense variants causing autosomal-dominant calpainopathy in seven unrelated families. Neuropathol Appl Neurobiol 2021;47(2):283-96. PMID 32896923
- 187
- Gonzalez-Quereda L, Gallardo E, Topf A, et al. A new mutation of the SCGA gene is the cause of a late onset mild phenotype limb girdle muscular dystrophy type 2D with axial involvement. Neuromuscul Disord 2018;28(8):633-8. PMID 30007747
- 188
- Gordon ES, Hoffman EP. The ABC’s of limb-girdle muscular dystrophy: alpha-sarcoglycanopathy, Bethlem myopathy, calpainopathy and more. Curr Opin Neurol 2001;14(5):567-73. PMID 11562567
- 189
- Greenberg SA, Salajegheh M, Judge DP, et al. Etiology of limb girdle muscular dystrophy 1D/1E determined by laser capture microdissection proteomics. Ann Neurol 2012;71(1):141-5. PMID 22275259
- 190
- Griffin DA, Johnson RW, Whitlock JM, et al. Defective membrane fusion and repair in Anoctamin5-deficient muscular dystrophy. Hum Mol Gen 2016;25(10):1900-11. PMID 26911675
- 191
- Griffin DA, Pozsgai ER, Heller KN, et al. Preclinical systemic delivery of adeno-associated alpha-sarcoglycan gene transfer for limb-girdle muscular dystrophy. Hum Gene Ther 2021;32(7-8):390-404. PMID 33349138
- 192
- Grose WE, Clark KR, Griffin D, et al. Homologous recombination mediates functional recovery of dysferlin deficiency following AAV5 gene transfer. PLoS One 2012;7(6):e39233. PMID 22720081
- 193
- Guha TK, Pichavant C, Calos MP. Plasmid-mediated gene therapy in mouse models of limb girdle muscular dystrophy. Mol Ther Methods Clin Dev 2019;15:294-304. PMID 31890729
- 194
- Gundesli H, Talim B, Korkusuz P, et al. Mutation in exon 1f of PLEC, leading to disruption of plectin isoform 1f, causes autosomal-recessive limb-girdle muscular dystrophy. Am J Hum Genet 2010;87:834-41. PMID 21109228
- 195
- Gushchina LV, Bhattacharya S, McElhanon KE, et al. Treatment with Recombinant Human MG53 Protein Increases Membrane Integrity in a Mouse Model of Limb Girdle Muscular Dystrophy 2B. Mol Ther 2017;25(10):2360-71. PMID 28750735
- 196
- Gutierrez-Rivas E, Bautista J, Vilchez JJ, et al. Targeted screening for the detection of Pompe disease in patients with unclassified limb-girdle muscular dystrophy or asymptomatic hyperCKemia using dried blood: A Spanish cohort. Neuromusc Dis 2015;25:548-53. PMID 25998610
- 197
- Guyon JR, Kudryashova E, Potts A, et al. Calpain 3 cleaves filamin C and regulates its ability to interact with gamma- and delta-sarcoglycans. Muscle Nerve 2003;28(4):472-83. PMID 14506720
- 198
- Haberlova J, Mitrovic Z, Zarkovic K, et al. Psycho-organic symptoms as early manifestation of adult onset POMT1-related limb girdle muscular dystrophy. Neuromuscul Disord 2014;24(11):990-2. PMID 25088310
- 199
- Hack AA, Ly CT, Jiang F, et al. Gamma-sarcoglycan deficiency leads to muscle membrane defects and apoptosis independent of dystrophin. J Cell Biol 1998;142(5):1279-87. PMID 9732288
- 200
- Hackman P, Juvonen V, Sarparanta J, et al. Enrichment of the R77C-sarcoglycan gene mutation in Finnish LGMD2D Patients. Muscle Nerve 2005;31(2):199–204. PMID 15736300
- 201
- Hackman P, Vihola A, Haravuori H, et al. Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. Am J Hum Genet 2002;71(3):492-500. PMID 12145747
- 202
- Hagedorn JL, Dunn TM, Bhattarai S, et al. Electroretinogram abnormalities in FKRP-related limb-girdle muscular dystrophy (LGMDR9). Doc Ophthalmol 2023;146(1):7-16. PMID 36399172
- 203
- Halmo SM, Singh D, Patel S, et al. Protein O-linked mannose β-1,4-N-acetylglucosaminyltransferase 2 (POMGNT2) is a gatekeeper enzyme for functional glycosylation of α-dystroglycan. J Biol Chem 2017;292(6):2101-9. PMID 27932460
- 204
- Hara Y, Balci-Hayta B, Yoshida-Moriguchi T, et al. A dystroglycan mutation associated with limb-girdle muscular dystrophy. N Eng J Med 2011;364(10):939-46. PMID 21388311
- 205
- Harandi VM, Oliveira BMS, Allamand V, Friberg A, Fontes-Oliveira CC, Durbeej M. Antioxidants reduce muscular dystrophy in the dy2J/dy2J mouse model of laminin α2 chain-deficient muscular dystrophy. Antioxidants (Basel) 2020;9(3):244. PMID 32197453
- 206
- Haravuori H, Vihola A, Straub V, et al. Secondary calpain3 deficiency in 2q-linked muscular dystrophy: titin is the candidate gene. Neurology 2001;56(7):869-77. PMID 11294923
- 207
- Harris E, Bladen C, Mayhew A, et al. The Clinical Outcome Study for dysferlinopathy: an international multicenter study. Neurol Genet 2016;2(4):e89.** PMID 27602406
- 208
- Harris E, McEntagart M, Topf A, et al. Clinical and neuroimaging findings in two brothers with limb girdle muscular dystrophy due to LAMA2 mutations. Neuromusc Dis 2017a;27(2):170-4. PMID 27932089
- 209
- Harris E, Topf A, Barresi R, et al. Exome sequences versus sequential gene testing in the UK highly specialised service for limb girdle muscular dystrophy. Orphanet J Rare Dis 2017b;12(1):151. PMID 28877744
- 210
- Hata S, Doi N, Shinkai-Ouchi F, Ono Y. A muscle-specific calpain, CAPN3, forms a homotrimer. Biochim Biophys Acta Proteins Proteom 2020;1868(7):140411. PMID 32200007
- 211
- Hauerslev S, Sveen ML, Duno M, et al. Calpain 3 is important for muscle regeneration: evidence from patients with limb girdle muscular dystrophies. BMC Musculoskelet Disord 2012;13:43. PMID 22443334
- 212
- Hauser MA, Conde CB, Kowaljow V, et al. Myotilin mutation found in second pedigree with LGMD1A. Am J Hum Genet 2002;71(6):1428-32. PMID 12428213
- 213
- Hauser MA, Horrigan SK, Salmikangas P, et al. Myotilin is mutated in limb girdle muscular dystrophy 1A. Hum Mol Genet 2000;14:2141-7. PMID 10958653
- 214
- Hayward M. Electrodiagnosis of the muscular dystrophies. Br Med Bull 1980;36:127-32. PMID 6266570
- 215
- Henriques SF, Gicquel E, Marsolier J, Richard I. Functional and cellular localization diversity associated with Fukutin-related protein patient genetic variants. Hum Mutat 2019;40(10):1874–85. PMID 31268217
- 216
- Hermanova M, Zapletalova E, Sedlackova J, et al. Analysis of histopathologic and pathologic findings in Czech LGMD2A patients. Muscle Nerve 2006;33:424-32. PMID 16372320
- 217
- Herson S, Hentati F, Rigolet A, et al. A phase I trial of adeno-associated virus serotype 1-γ-sarcoglycan gene therapy for limb girdle muscular dystrophy type 2C. Brain 2012;135(Pt 2):483-92. PMID 22240777
- 218
- Heydemann A. Severe murine limb-girdle muscular dystrophy type 2c pathology is diminished by FTY720 treatment. Muscle Nerve 2017;56(3):486-94. PMID 27935071
- 219
- Heydemann A, Hubera JM, Demonbreuna A, Hadhazy M, McNally EM. Genetic background influences muscular dystrophy. Neuromuscul Disord 2005;15(9-10):601-9. PMID 16084087
- 220
- Hicks D, Sarkozy A, Muelas N, et al. A founder mutation in anoctamin 5 is a major cause of limb-girdle muscular dystrophy. Brain 2011;134 (Pt 1):171-82. PMID 21186264
- 221
- Higuchi I, Shiraishi T, Hashiguchi T. Frameshift mutation in the collagen VI gene causes Ullrich's disease. Ann Neurol 2001;50:261-5. PMID 11506412
- 222
- Hinou H, Kikuchi S, Ochi R, Igarashi K, Takada W, Nishimura SI. Synthetic glycopeptides reveal specific binding pattern and conformational change at O-mannosylated position of α-dystroglycan by POMGnT1 catalyzed GlcNAc modification. Bioorganic Med Chem 2019;27(13):2822-31. PMID 31079966
- 223
- Ho CY, Jaalouk DE, Vartiainen MK, Lammerding J. Lamin A/C and emerin regulate MKL1-SRF activity by modulating actin dynamics. Nature 2013;497(7450):507-11. PMID 23644458
- 224
- Hofhuis J, Bersch K, Bussenschutt R, et al. Dysferlin mediates membrane tubulation and links T-tubule biogenesis to muscular dystrophy. J Cell Sci 2017;130(5):841-52. PMID 28104817
- 225
- Horowitz SH, Schmalbruch H. Autosomal dominant distal myopathy with desmin storage: a clinicopathologic and electrophysiologic study of a large kinship. Muscle Nerve 1994;17:151-60. PMID 8114783
- 226
- Hsu WC, Lin YC, Chuang HH, Yeh KY, Chan WP, Ro LS. A muscle biosignature differentiating between limb-girdle muscular dystrophy and idiopathic inflammatory myopathy on magnetic resonance imaging. Front Neurol 2021;12:783095. PMID 34987467
- 227
- Hu B, Xiong L, Zhou Y, et al. First familial limb-girdle muscular dystrophy 2L in China Clinical, imaging, pathological, and genetic features. Medicine (Baltimore) 2018b;97(38):e12506. PMID 30235762
- 228
- Hu P, Yuan L, Deng H. Molecular genetics of the POMT1-related muscular dystrophy-dystroglycanopathies. Mutat Res 2018a;778:45-50. PMID 30454682
- 229
- Huang Y, de Morrée A, van Remoortere A, et al. Calpain 3 is a modulator of the dysferlin protein complex in skeletal muscle. Hum Mol Genet 2008;17(12):1855-66. PMID 18334579
- 230
- Husebye SA, Rebne CB, Stokland AE, Sanaker PS, Bindoff LA. A hospital based epidemiological study of genetically determined muscle disease in south western Norway. Neuromuscul Disord 2020;30(3):181-5. PMID 32146000
- 231
- Hussein MR, Hamed SA, Mostafa MG, et al. The effects of glucocorticoid therapy on the inflammatory and dendritic cells in muscular dystrophies. Int J Exp Path 2006;87(6):451-61. PMID 17222213
- 232
- Ibrahim RM, Amr Abdel-Monem M, Hamdy HM, et al. Validity of skeletal muscle ultrasound as a screening tool in the assessment of patients with suspected limb-girdle muscular dystrophy. J Clin Neurosci 2022;96:205-11. PMID 34838430
- 233
- Ikenberg E, Karin I, Ertl-Wagner B, et al. Rare diagnosis of telethoninopathy (LGMD2G) in a Turkish patient. Neuromuscul Disord 2017;27(9):856-60. PMID 28666572
- 234
- Illa I, De Luna N, Dominguez-Perles R, et al. Symptomatic dysferlin gene mutation carriers: characterization of two cases. Neurology 2007;68(16):1284-9. PMID 17287450
- 235
- Indrawati LA, Iida A, Tanaka Y, et al. Two Japanese LGMDR25 patients with a biallelic recurrent nonsense variant of BVES. Neuromuscul Disord 2020;30(8):674-9. PMID 32684383
- 236
- Ishiguro K, Nakayama T, Yoshioka M, et al. Characteristic findings of skeletal muscle MRI in caveolinopathies. Neuromuscul Disord 2018;28(10):857-62. PMID 30174172
- 237
- Israeli D, Cosette J, Corre G, et al. An AAV-SGCG dose-response study in a γ-sarcoglycanopathy mouse model in the context of mechanical stress. Mol Ther Methods Clin Dev 2019;13:494-502. PMID 31194043
- 238
- Izumi R, Niihori T, Takahashi T, et al. Genetic profile for suspected dysferlinopathy identified by targeted next-generation sequencing. Neurol Genet 2015;1(4):e36. PMID 27066573
- 239
- Izzedine H, Brocheriou I, Eymard B, et al. Loss of podocyte dysferlin expression is associated with minimal change nephropathy. Am J Kidney Dis 2006;48(1):43-50. PMID 16797397
- 240
- Jackson CE, Strehler DA. Limb-girdle muscular dystrophy: clinical manifestations and determination of preclinical disease. Pediatrics 1968;41:495-502. PMID 5637795
- 241
- Jahnke VE, Peterson JM, Van Der Meulen JH, et al. Mitochondrial dysfunction and consequences in calpain-3-deficient muscle. Skelet Muscle 2020;10(1):37. PMID 33308300
- 242
- Jain MS, Meilleur K, Kim E, et al. Longitudinal changes in clinical outcome measures in COL6-related dystrophies and LAMA2-related dystrophies. Neurology 2019;93(21):e1932-43. PMID 31653707
- 243
- Jalali-Sefid-Dashti M, Nel M, Heckmann JM, Gamieldien J. Exome sequencing identifies novel dysferlin mutation in a family with paucisymptomatic heterozygous carriers. BMC Med Genet 2018;19(1):95. PMID 29879922
- 244
- Jarry J, Rioux MF, Bolduc V, et al. A novel autosomal recessive limb-girdle muscular dystrophy with quadriceps atrophy maps to11p13-p12. Brain 2007;130:368-80. PMID 17008331
- 245
- Jensen BS, Willer T, Saade DN, et al. GMPPB-Associated Dystroglycanopathy: Emerging Common Variants with Phenotype Correlation. Hum Mutat 2015;36(12):1159-63. PMID 26310427
- 246
- Jerusalem F, Sieb JP. The limb-girdle syndromes. In: Rowland LP, DiMauro S, editors. Handbook of Clinical Neurology. Vol. 62 (18). Amsterdam: Elsevier, 1992:179-96.
- 247
- Jobsis GJ, Boers JM, Barth PG, de Visser M. Bethlem myopathy: a slowly progressive congenital muscular dystrophy with contractures. Brain 1999;122:649-55. PMID 10219778
- 248
- Jobsis GJ, Keizers H, Vreijling JP, et al. Collagen VI mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures. Nat Genet 1996;14:113-5. PMID 8782832
- 249
- Johnson A, Subramony SH, Chuquilin M. Delayed diagnosis of DOK7 congenital myasthenic syndrome: case report and literature review. Neurol Clin Pract 2018a;8(6):e40-2. PMID 30588388
- 250
- Johnson K, De Ridder W, Topf A, et al. Extending the clinical and mutational spectrum of TRIM32-related myopathies in a non-Hutterite population. J Neurol Neurosurg Psychiatry 2019;90(4):490-3. PMID 29921608
- 251
- Jokela M, Lehtinen S, Palmio J, et al. A novel COL6A2 mutation causing late-onset limb-girdle muscular dystrophy. J Neurol 2019;266(7):1649-54. PMID 30963254
- 252
- Jonson PH, Palmio J, Johari M, et al. Novel mutations in DNAJB6 cause LGMD1D and distal myopathy in French families. Eur J Neurol 2018;25(5):790-4. PMID 29437287
- 253
- Kadoya M, Ogata K, Suzuki M, et al. A Japanese male with a novel ANO5 mutation with minimal muscle weakness and muscle pain till his late fifties. Neuromusc Dis 2017;27(5):477-80. PMID 28214267
- 254
- Kanagawa M, Kobayashi K, Tajiri M, et al. Identification of a post-translational modification with ribitol-phosphate and its defect in muscular dystrophy. Cell Rep 2016;14(9):2209-23. PMID 26923585
- 255
- Katz JS, Rando TA, Barohn RJ, et al. Late-onset distal muscular dystrophy affecting the posterior calves. Muscle Nerve 2003;28(4):443-8. PMID 14506716
- 256
- Kawahara G, Guyon JR, Nakamura Y, Kunkel LM. Zebrafish models for human FKRP muscular dystrophies. Hum Mol Genet 2010;19(4):623-33. PMID 19955119
- 257
- Kayman-Kurekci G, Talim B, Korkusuz P, et al. Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: a novel gene related to nuclear envelopathies. Neuromusc Dis 2014;24(7):624-33. PMID 24856141
- 258
- Kazakov VM, Bogorodinsky DK, Skorometz AA. The myogenic scapuloperoneal syndrome. Muscular dystrophy in the K kindred: clinical study and genetics. Clin Genet 1976;10:41-50. PMID 949863
- 259
- Kefi M, Amouri R, Driss A, et al. Phenotype and sarcoglycan expression in Tunisian LGMD 2C patients sharing the same del521-T mutation. Neuromuscul Disord 2003;13(10):779-87. PMID 14678800
- 260
- Kemaladewi DU, Bassi PS, Erwood S, et al. A mutation-independent approach for muscular dystrophy via upregulation of a modifier gene. Nature 2019;572(7767):125-30. PMID 31341277
- 261
- Kerr JP, Ziman AP, Mueller AL, et al. Dysferlin stabilizes stress-induced Ca2+ signaling in the transverse tubule membrane. Proc Natl Acad Sci U S A 2013;110(51):20831-6. PMID 24302765
- 262
- Kim DH, Jang DH, Jang JH. Incidental severe fatty degeneration of the erector spinae in a patient with L5-S1 disc extrusion diagnosed with limb-girdle muscular dystrophy R2 dysferin-related. Diagnostics (Basel) 2020;10(8):530. PMID 32751317
- 263
- Kim J, Lana B, Torelli S, et al. A new patient‐derived iPSC model for dystroglycanopathies validates a compound that increases glycosylation of α‐dystroglycan. EMBO Rep 2019;20(11):e47967. PMID 31566294
- 264
- Kim SY, Kim WJ, Kim H, et al. Collagen VI-related myopathy: expanding the clinical and genetic spectrum. Muscle Nerve 2018;58(3):381-8. PMID 29406609
- 265
- Kirschner J, Brune T, Wehnert M, et al. p.S143F Mutation in Lamin A/C: a new phenotype combining myopathy and progeria. Ann Neurol 2005;57(1):148-51. PMID 15622532
- 266
- Kitamura Y, Kondo E, Urano M, Aoki R, Saito K. Target resequencing of neuromuscular disease-related genes using next-generation sequencing for patients with undiagnosed early-onset neuromuscular disorders. J Hum Gen 2016;61:931-42. PMID 27357428
- 267
- Klauck SM, Wilgenbus P, Yates JR, Muller CR, Poustka A. Identification of novel mutations in three families with Emery-Dreifuss muscular dystrophy. Hum Mol Genet 1995;4(10):1853-7. PMID 8595406
- 268
- Klinge L, Dean AF, Kress W, et al. Late onset in dysferlinopathy widens the clinical spectrum. Neuromuscul Disord 2008;18(4):288-90. PMID 18396043
- 269
- Klinge L, Harris J, Sewry C, et al. Dysferlin associates with the developing T-tubule system in rodent and human skeletal muscle. Muscle Nerve 2010;41(2):166-73. PMID 20082313
- 270
- Koehler K, Milev MP, Prematilake K, et al. A novel TRAPPC11 mutation in two Turkish families associated with cerebral atrophy, global retardation, scoliosis, achalasia and alacrima. J Med Genet 2017;54:176-85. PMID 27707803
- 271
- Kojima Y, Noto Y, Takewaki D, et al. Characteristic Posterior-dominant Lower Limb Muscle Involvement in Limb-girdle Muscular Dystrophy due to a DNAJB6 Phe93Leu Mutation. Intern Med 2017;56(17):2347-51. PMID 28794355
- 272
- Kono M, Sawada M, Nakazawa Y, Ogi T, Muro Y, Akiyama M. A Japanese case of galli-galli disease due to a previously unreported POGLUT1 mutation. Acta Derm Venereol 2019;99(4):458. PMID 30653241
- 273
- Krajacic P, Pistilli EE, Tanis JE, Khurana TS, Lamitina ST. FER-1/Dysferlin promotes cholinergic signaling at the neuromuscular junction in C. elegans and mice. Biology Open 2013;2(11):1245-52. PMID 24244862
- 274
- Kramerova I, Marinov M, Owens J, et al. Myostatin inhibition promotes fast fibre hypertrophy but causes loss of AMP-activated protein kinase signalling and poor exercise tolerance in a model of limb-girdle muscular dystrophy R1/2A. J Physiol 2020;598(18):3927-39. PMID 33460149
- 275
- Kudryashova E, Kudryashov, Kramerova I, Spencer MJ. Trim32 is a ubiquitin ligase mutated in limb girdle muscular dystrophy type 2H that binds to skeletal muscle myosin and ubiquitinates actin. J Mol Biol 2005;354(2):413-24. PMID 16243356
- 276
- Kuga A, Ohsawa Y, Okada T, et al. Endoplasmic reticulum stress response in P104L mutant caveolin-3 transgenic mice. Hum Mol Genet 2011;20(15):2975-83. PMID 21610159
- 277
- Kugelberg E, Welander L. Heredofamial juvenile muscular atrophy simulating muscular dystrophy. Arch Neurol Psychiatry 1956;75:500-9. PMID 13312732
- 278
- Kuwabara N, Imae R, Manya H, et al. Crystal structures of fukutin-related protein (FKRP), a ribitol-phosphate transferase related to muscular dystrophy. Nat Commun 2020;11(1):303. PMID 31949166
- 279
- LaBeau-DiMenna EM, Clark KA, Bauman KD, et al. Thin, a Trim32 ortholog, is essential for myofibril stability and is required for the integrity of the costamere in Drosophila. Proc Natl Acad Sci U S A 2012;109(44):17983-8. PMID 23071324
- 280
- Lampe AK, Bushby KMD. Collagen VI related muscle disorders. J Med Genet 2005;42(9):673-85. PMID 16141002
- 281
- Larson AA, Baker PR, Milev MP, et al. TRAPPC11 and GOSR2 mutations associate with hypoglycosylation of α-dystroglycan and muscular dystrophy. Skelet Muscle 2018;8(1):17. PMID 29855340
- 282
- Lazarri E, Meroni G. TRIM32 ubiquitin E3 ligase, one enzyme for several pathologies: from muscular dystrophy to tumours. Int J Biochem Cell Biol 2016;79:469-77. PMID 27458054
- 283
- Lee AJ, Jones KA, Butterfield RJ, et al. Clinical, genetic, and pathologic characterization of FKRP Mexican founder mutation c.1387A>G. Neurol Genet 2019;5(2):e315. PMID 31041397
- 284
- Lee JJA, Maruyama R, Duddy W, et al. Identification of novel antisense-mediated exon skipping targets in DYSF for therapeutic treatment of dysferlinopathy. Mol Ther Nucleic Acids 2018;13:596-604. PMID 30439648
- 285
- Leibovitz Z, Mandel H, Faliz-Zaccai TC, et al. Walker-Warburg syndrome and tectocerebellar dysraphia: a novel association caused by a homozygous DAG1 mutation. Eur J Ped Neurol 2018;22(3):525-31. PMID 29337005
- 286
- Levison H. Dystrophia musculorum progressiva. Clinical and diagnostic criteria, inheritance. Acta Psychiatry Scand Suppl 1951;76:7-176. PMID 14877599
- 287
- Leyden E. Klinik der Rukenmarkskrankheiten. Vol. 2. Berlin: Verlag A. Hirschwald, 1876:525-40.
- 288
- Li Q, Tan C, Chen J, Zhang L. Next-generation sequencing identified a novel DYSF variant in a patient with limb-girdle muscular dystrophy type 2B: a case report. Medicine (Baltimore) 2020;99(41):e22615. PMID 33031319
- 289
- Libell EM, Bowdler NC, Stephan CM, et al. The outcomes and experience of pregnancy in limb girdle muscular dystrophy type R9. Muscle Nerve 2021;63(6):812-7. PMID 33501999
- 290
- Libell EM, Richardson JA, Lutz KL, et al. Cardiomyopathy in limb girdle muscular dystrophy R9, FKRP related. Muscle Nerve 2020;62(5):626-32. PMID 32914449
- 291
- Liewluck T, Goodman BP. Late-onset axial myopathy and camptocormia in a calpainopathy carrier. J Clin Neuromuscul Dis 2012;13(4):209-13. PMID 22622166
- 292
- Liewluck T, Milone M. Untangling the complexity of limb-girdle muscular dystrophies. Muscle Nerve 2018;58(2):166-77.** PMID 29350766
- 293
- Liewluck T, Tracy JA, Sorenson EJ, Engel AG. Scapuloperoneal muscular dystrophy phenotype due to TRIM32-sarcotubular myopathy in South Dakota Hutterite. Neuromuscul Disord 2013a;23(2):133-8. PMID 23142638
- 294
- Liewluck T, Winder TL, Dimberg EL, et al. ANO5-muscular dystrophy: clinical, pathological and molecular findings. Eur J Neurol 2013b;20(10):1383-9. PMID 23663589
- 295
- Lim LE, Duclos F, Broux O, et al. Beta-sarcoglycan: characterization and role in limb-girdle muscular dystrophy linked to 4q12. Nat Genet 1995;11:257-65. PMID 7581448
- 296
- Lin HT, Liu X, Zhang W, et al. Muscle magnetic resonance imaging in patients with various clinical subtypes of LMNA-related muscular dystrophy. Chin Med J 2018;131(12):1472-9. PMID 29893365
- 297
- Little AA, McKeever PE, Gruis KL. Novel mutations in the anoctamin 5 gene (ANO5) associated with limb-girdle muscular dystrophy 2L. Muscle Nerve 2013;47(2):287-91. PMID 23169617
- 298
- Liu J, Campagna J, John V, et al. A small-molecule approach to restore a slow-oxidative phenotype and defective CaMKIIβ signaling in limb girdle muscular dystrophy. Cell Rep Med 2020;1(7):100122. PMID 33205074
- 299
- Ljunggren A, Duggan D, McNally E, et al. Primary adhalin deficiency as a cause of muscular dystrophy in patients with normal dystrophin. Ann Neurol 1995;38(3):367-72. PMID 7668821
- 300
- Locke M, Tinsley CL, Benson MA, Blake DJ. TRIM32 is an E3 ubiquitin ligase for dysbindin. Hum Mol Genet 2009;18(13):2344-58. PMID 19349376
- 301
- Lohmann K, Schlicht F, Svetel M, et al. The role of mutations in COL6A3 in isolated dystonia. J Neurol 2016;263(4):730-4. PMID 26872670
- 302
- Lokken N, Born AP, Duno M, Vissing J. LAMA2-related myopathy: frequency among congenital and limb-girdle muscular dystrophies. Muscle Nerve 2015;52(4):547-53. PMID 25663498
- 303
- Lommel M, Cirak S, Willer T, et al. Correlation of enzyme activity and clinical phenotype in POMT1-associated dystroglycanopathies. Neurology 2010;74(2):157-64. PMID 20065251
- 304
- Louhichi N, Triki C, Quijano-Roy S, et al. New FKRP mutations causing congenital muscular dystrophy associated with mental retardation and central nervous system abnormalities. Identification of a founder mutation in Tunisian families. Neurogenetics 2004;5(1):27-34. PMID 14652796
- 305
- Lukyanenko V, Muriel JM, Bloch RJ. Coupling of excitation to Ca2+ release is modulated by dysferlin. J Physiol 2017;595(15):5191-207. PMID 28568606
- 306
- Luo S, Cai S, Maxwell S, et al. Novel mutations in the C-terminal region of GMPPB causing limb-girdle muscular dystrophy overlapping with congenital myasthenic syndrome. Neuromusc Dis 2017;27(6):557-64. PMID 28433477
- 307
- Lv X, Gao F, Dai T, et al. Distal myopathy due to TCAP variants in four unrelated Chinese patients. Neurogenetics 2021;22(1):1-10. PMID 32761539
- 308
- Ma J, Pichavant C, du Bois H, Bhakta M, Calos MP. DNA-Mediated Gene Therapy in a Mouse Model of Limb Girdle Muscular Dystrophy 2B. Mol Ther Methods Clin Dev 2017;7:123-131. PMID 29159199
- 309
- Madej-Pilarczyk A, Niezgoda A, Janus M, et al. Limb-girdle muscular dystrophy with severe heart failure overlapping with lipodystrophy in a patient with LMNA mutation p.Ser334del. J Appl Genetics 2017;58(1):87-91. PMID 27585670
- 310
- Maggi L, Carboni N, Bernasconi P. Skeletal Muscle Laminopathies: A Review of Clinical and Molecular Features. Cells 2016;5(3):pii.33. PMID 27529282
- 311
- Maggi L, D'Amico A, Pini A, et al. LMNA-associated myopathies The Italian experience in a large cohort of patients. Neurology 2014;83(18):1634-44. PMID 25274841
- 312
- Magri F, Bo RD, D'Angelo MG, et al. Frequency and characterisation of anoctamin 5 mutations in a cohort of Italian limb-girdle muscular dystrophy patients. Neuromuscul Disord 2012;22(11):934-43. PMID 22742934
- 313
- Magri F, Brusa R, Bello L, et al. Limb girdle muscular dystrophy due to LAMA2 gene mutations: new mutations expand the clinical spectrum of a still challenging diagnosis. Acta Myol 2020;39(2):67-82. PMID 32904964
- 314
- Mah JK, Korngut L, Fiest KM, et al. A systematic review and meta-analysis on the epidemiology of the muscular dystrophies. Can J Neurol Sci 2016;43(1):163-77. PMID 26786644
- 315
- Malfatti E, Cassandrini D, Rubegni A, et al. Respiratory muscle involvement in HNRNPDL LGMD D3 muscular dystrophy: an extensive clinical description of the first Italian patient. Acta Myol 2020;39(2):98-100. PMID 32904822
- 316
- Malfatti E, Richard I. Calpainopathies: state of the art and therapeutic perspectives [Article in French]. Med Sci (Paris) 2020;36 Hors série n° 2:17-21. PMID 33427631
- 317
- Mammen AL, Casciola-Rosen L, Christopher-Stine L, Lloyd TE, Wagner KR. Myositis-specific autoantibodies are specific for myositis compared to genetic muscle disease. Neurol Neuroimmunol Neuroinflamm 2015;2(6):e172. PMID 26668818
- 318
- Manya H, Endo T. Glycosylation with ribitol-phosphate in mammals: New insights into the O-mannosyl glycan. Biochem Biophys Acta Gen Subj 2017;1861(10):2462-72. PMID 28711406
- 319
- Marchetti GB, Valenti L, Torrente Y. Clinical determinants of disease progression in patients with beta-sarcoglycan gene mutations. Front Neurol 2021;12:657949. PMID 34276533
- 320
- Margeta M, Connolly AM, Winder TL, Pestronk A, Moore SA. Cardiac pathology exceeds skeletal muscle pathology in two cases of limb-girdle muscular dystrophy type 2I. Muscle Nerve 2009;40(5):883-9. PMID 19705481
- 321
- Martinez HR, Craigen WJ, Ummat M, Adesina AM, Lotze TE, Jefferies JL. Novel cardiovascular findings in association with a POMT2 mutation: three siblings with a-dystroglycanopathy. Eur J Hum Genetics 2014;22(4):486-91. PMID 24002165
- 322
- Martinez-Thompson JM, Moore SA, Liewluck T. A novel CAPN3 mutation in late-onset limb-girdle muscular dystrophy with early respiratory insufficiency. J Clin Neurosci 2018a;53:229-31. PMID 29685414
- 323
- Martinez-Thompson JM, Niu Z, Tracy JA, et al. Autosomal dominant calpainopathy due to heterozygous CAPN3 C.643_663del21. Muscle Nerve 2018b;57(4):679-83. PMID 28881388
- 324
- Massa R, Weller B, Karpati G, Shoubridge E, Carpenter S. Familial inclusion body myositis among Kurdish-Iranian Jews. Arch Neurol 1991;48:519-22. PMID 1850594
- 325
- Mazaleyrat K, Badja C, Broucqsault N, et al. Multilineage differentiation for formation of innervated skeletal muscle fibers from healthy and diseased human pluripotent stem cells. Cells 2020;9(6):1531. PMID 32585982
- 326
- McNally EM, Yoshida M, Mizuno Y, Ozawa E, Kunkel LM. Human adhalin is alternatively spliced and the gene is located on chromosome 17q21. Proc Nat Acad Sci U S A 1994;91(21):9690-4. PMID 7937874
- 327
- Mendell JR, Chicoine LG, Al-Zaidy SA, et al. Gene delivery for limb-girdle muscular dystrophy type 2D by isolated limb infusion. Hum Gene Ther 2019;30(7):794-801. PMID 30838895
- 328
- Mendell JR, Rodino-Klapac LR, Rosales-Quintero X, et al. Limb-girdle muscular dystrophy type 2D gene therapy restores alpha-sarcoglycan and associated proteins. Ann Neurol 2009;66(3):290-7. PMID 19798725
- 329
- Mercuri E, Brown SC, Nihoyannopoulos P, et al. Extreme variability of skeletal and cardiac muscle involvement in patients with mutations in exon 11 of the lamin a/c gene. Muscle Nerve 2005a;31(5):602–9. PMID 15770669
- 330
- Mercuri E, Bushby K, Ricci E, et al. Muscle MRI findings in patients with limb girdle muscular dystrophy with calpain 3 deficiency (LGMD2A) and early contractures. Neuromuscul Disord 2005b;15(2):164-71. PMID 15694138
- 331
- Mercuri E, Lampe A, Allsop J, et al. Muscle MRI in Ullrich congenital muscular dystrophy and Bethlem muscular dystrophy. Neuromuscul Disord 2005c;15(4):303-10. PMID 15792870
- 332
- Merlini L, Carbone I, Capanni C, et al. Familial isolated hyperCKaemia associated with a new mutation in the caveolin-3 (CAV-3) gene. J Neurol Neurosurg Psychiatry 2002;73(1):65-7. PMID 12082049
- 333
- Meryon E. On granular and fatty degeneration of the voluntary muscle. Med Chir Trans 1852;73-85. PMID 20895997
- 334
- Messina DN, Speer MC, Pericak-Vance MA, McNally EM. Linkage of familial dilated cardiomyopathy with conduction defect and muscular dystrophy to chromosome 6q23. Am J Hum Genet 1997;61(4):909-17. PMID 9382102
- 335
- Milev MP, Stanga D, Schänzer A, et al. Characterization of three TRAPPC11 variants suggests a critical role for the extreme carboxy terminus of the protein. Sci Rep 2019;9(1):14036. PMID 31575891
- 336
- Miller G, Musa H, Gautel M, Peckham M. A targeted deletion of the C-terminal end of titin, including the titin kinase domain, impairs myofibrillogenesis. J Cell Sci 2003;116(Pt 23):4811-9. PMID 14600266
- 337
- Milone M, McEvoy KM, Sorenson EJ, Daube JR. Myotonia associated with caveolin-3 mutation. Muscle Nerve 2012;45(6):897-900. PMID 22581547
- 338
- Minetti C, Sotgia F, Bruno C, et al. Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy. Nat Genet 1998;18(4):365-8. PMID 9537420
- 339
- Miyoshi K, Kawai H, Iwasa M, Kusaka K, Nishino H. Autosomal recessive distal muscular dystrophy as a new type of progressive muscular dystrophy. Seventeen cases in eight families including an autopsied case. Brain 1986;109(Pt 1):31-54. PMID 3942856
- 340
- Mobius PJ. Uber die hereditaren nervenkrankheiten. Volkmanns Samml Klin 1879;171:1501-31.
- 341
- Mohamadian M, Rastegar M, Pasamanesh N, Ghadiri A, Ghandil P, Naseri M. Clinical and molecular spectrum of muscular dystrophies (MDs) with intellectual disability (ID): a comprehensive overview. J Mol Neurosci 2022;72(1):9-23. PMID 34727324
- 342
- Mohassel P, Landon-Cardinal O, Foley AR, et al. Anti-HMGCR myopathy may resemble limb-girdle muscular dystrophy. Neurol Neuroimmunol Neuroinflamm 2018;6(1):e523. PMID 30588482
- 343
- Mohire MD, Tandan R, Fries TJ, Little BW, Pendlebury WW, Bradley WG. Early-onset benign autosomal dominant limb-girdle myopathy with contractures [Bethlem myopathy]. Neurology 1988;38:573-80. PMID 3352914
- 344
- Mokhonova EI, Avliyakulov NK, Kramerova I, Kudryashova E, Haykinson MJ, Spencer MJ. The E3 ubiquitin ligase TRIM32 regulates myoblast proliferation by controlling turnover of NDRG2. Hum Mol Gen 2015;24(10):2873-83. PMID 25701873
- 345
- Monies D, Alhindi HN, Almuhaizea MA, et al. A first-line diagnostic assay for limb-girdle muscular dystrophy and other myopathies. Hum Genomics 2016;10(1):32. PMID 27671536
- 346
- Montagnese F, Klupp E, Karampinos DC, et al. Two patients with GMPPB mutation: the overlapping phenotypes of limb-girdle myasthenic syndrome and limb-girdle muscular dystrophy dystroglycanopathy. Muscle Nerve 2017;56(2):334-40. PMID 27874200
- 347
- Moreira ES, Wiltshire TJ, Faulkner G, et al. Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin. Nat Genet 2000;24:163-6. PMID 10655062
- 348
- Mori-Toshimura M, Segawa K, Minami N, et al. Cardiopulmonary dysfunction in patients with limb-girdle muscular dystrophy 2A. Muscle Nerve 2017;55(4):465-9. PMID 27500519
- 349
- Mroczek M, Durmus H, Töpf A, et al. Four individuals with a homozygous mutation in exon 1f of the PLEC gene and associated myasthenic features. Genes (Basel) 2020;11(7):716. PMID 32605089
- 350
- Muchir A, Bonne G, van der Kooi AJ, et al. Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B). Hum Mol Genet 2000;9:1453-9. PMID 10814726
- 351
- Mudau MM, Essop F, Krause A. A novel FKRP-related muscular dystrophy founder mutation in South African Afrikaner patients with a phenotype suggestive of a dystrophinopathy. S Afr Med J 2016;107(1):80-2. PMID 28112097
- 352
- Muller JS, Piko H, Schoser BG, et al. Novel splice site mutation in the caveolin-3 gene leading to autosomal recessive limb girdle muscular dystrophy. Neuromuscul Disord 2006;16:432-6. PMID 16730439
- 353
- Muller KI, Ghelue MV, Lund I, Jonsrud C, Arntzen KA. The prevalence of hereditary neuromuscular disorders in Northern Norway. Brain Behav 2021;11(1):e01948. PMID 33185984
- 354
- Muller T, Krasnianski MR, Witthaut R, Deschauer M, Zierz S. Dilated cardiomyopathy may be an early sign of the C826A Fukutin-related protein mutation. Neuromuscul Disord 2005;15(5):372-6. PMID 15833432
- 355
- Munsat TT, Baloh R, Pearson CM, Fowler W. Serum enzyme alterations in neuromuscular disorders. JAMA 1973;226:1536.
- 356
- Murakami T, Hayashi YK, Noguchi S, et al. Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness. Ann Neurol 2006;60:597-602. PMID 17036286
- 357
- Murphy AP, Morrow J, Dahlqvist JR, et al. Natural history of limb girdle muscular dystrophy R9 over 6 years: searching for trial endpoints. Ann Clin Transl Neurol 2019;6(6):1033-45. PMID 31211167
- 358
- Murphy LB, Schreiber-Katz O, Rafferty K, et al. Global FKRP Registry: observations in more than 300 patients with Limb Girdle Muscular Dystrophy R9. Ann Clin Transl Neurol 2020;7(5):757-66. PMID 32342672
- 359
- Musumeci O, Aguennouz M, Cagliani R, et al. Calpain 3 deficiency in Quail Eater's disease. Ann Neurol 2004;55(1):146-7. PMID 14705129
- 360
- Nallamilli BRR, Chakravorty S, Kesari A, et al. Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients. Ann Clin Transl Neurol 2018;5(12):1574-87. PMID 30564623
- 361
- Narayanaswami P, Weiss M, Selcen D, et al. Evidence-based guideline summary: diagnosis and treatment of limb-girdle and distal dystrophies. Neurology 2014;83(16):1453-63.** PMID 25313375
- 362
- Nevin S. Two cases of muscular degeneration occurring in late adult life, with a review of the recorded cases of late progressive muscular dystrophy (late progressive myopathy). Q J Med 1936;17:51-68.
- 363
- Nicklas S, Otto A, Wu X, et al. TRIM32 regulates skeletal muscle stem cell differentiation and is necessary for normal adult muscle regeneration. PLoS One 2012;7(1):e30445. PMID 22299041
- 364
- Nicolau S, Liewluck T, Shen XM, Selcen D, Engel AG, Milone M. A homozygous mutation in GMPPB leads to centronuclear myopathy with combined pre- and postsynaptic defects of neuromuscular transmission. Neuromuscul Disord 2019;29(8):614-7. PMID 31378432
- 365
- Noguchi S, McNally EM, Ben Othmane K, et al. Mutations in the dystrophin-associated protein gamma-sarcoglycan in chromosome 13 muscular dystrophy. Science 1995;270(5237):819-22. PMID 7481775
- 366
- Norwood FLM, Harling C, Chinnery PF, Eagle M, Bushby K, Straub V. Prevalence of genetic muscle disease in Northern England: in-depth analysis of a muscle clinic population. Brain 2009;132(11):3175-86. PMID 19767415
- 367
- Oates EC, Jones KJ, Donkervoort S, et al. Congenital titinopathy: comprehensive characterization and pathogenic insights. Ann Neurol 2018;83(6):1105-24. PMID 29691892
- 368
- Oestergaard ST, Stojkovic T, Dahlqvist JR, et al. Muscle involvement in limb-girdle muscular dystrophy with GMPPB deficiency (LGMD2T). Neurol Genet 2016;2(6):e112. PMID 27766311
- 369
- Ohlendieck K, Matsumura K, Ionasescu VV, et al. Duchenne muscular dystrophy: deficiency of dystrophin-associated proteins in the sarcolemma. Neurology 1993;43:795-800. PMID 8469343
- 370
- Ohtsuka K, Hata M. Mammalian HSP40/DNAJ homologs: cloning of novel cDNAs and a proposal for their classification and nomenclature. Cell Stress Chaperones 2000;5(2):98-112. PMID 11147971
- 371
- Okazaki T, Matsuura K, Kasagi N, et al. Duchenne muscular dystrophy-like phenotype in an LGMD2I patient with novel FKRP gene variants. Hum Genome Var 2020;7:12. PMID 32351701
- 372
- Olive M, Goldfarb L, Shatunov A, Fischer D, Ferrer I. Myotilinopathy: refining the clinical and myopathological phenotype. Brain 2005;128:2315-26. PMID 15947064
- 373
- Oliveira Santos M, Coelho P, Roque R, Conceição I. Very late-onset limb-girdle muscular dystrophy type 2D: a milder form with a normal muscle biopsy. J Clin Neurosci 2020;72:471-3. PMID 31836381
- 374
- Ono H, Suzuki N, Kanno SI, et al. AMPK complex activation promotes sarcolemmal repair in dysferlinopathy. Mol Ther 2020;28(4):1133-53. PMID 32087766
- 375
- Ono Y, Ojima K, Shinkai-Ouchi F, Hata S, Sorimachi H. An eccentric calpain, CAPN3/p94/calpain-3. Biochimie 2016;122:169-87.** PMID 26363099
- 376
- Ostergaard ST, Johnson K, Stojkovic T, et al. Limb girdle muscular dystrophy due to mutations in POMT2. J Neurol Neurosurg Psychiatry 2018;89(5):506-12.** PMID 29175898
- 377
- Ozawa E, Mizuno Y, Hagiwara Y, Sasaoka T, Yoshida M. Molecular and cell biology of the sarcoglycan complex. Muscle Nerve 2005;32(5):563-76. PMID 15937871
- 378
- Ozyilmaz B, Kirbiyik O, Ozdemir TR, et al. Experiences in the molecular genetic and histopathological evaluation of calpainopathies. Neurogenetics 2022;23(2):103-14. PMID 35157181
- 379
- Paim JF, Cotta A, Vargas AP, et al. Muscle phenotypic variability in limb girdle muscular dystrophy 2 G. J Mol Neurosci 2013;50(2):339-44. PMID 23479141
- 380
- Palmio J, Jonson PH, Inoue M, et al. Mutations in the J domain of DNAJB6 cause dominant distal myopathy. Neuromuscul Disord 2020;30(1):38-46. PMID 31955980
- 381
- Pambianco S, Giovarelli M, Perrotta C, et al. Reversal of Defective Mitochondrial Biogenesis in Limb-Girdle Muscular Dystrophy 2D by Independent Modulation of Histone and PGC-1a Acetylation. Cell Reports 2016;17(11):3010-23. PMID 27974213
- 382
- Panegyres PK, Mastaglia FL, Kakulas BA. Limb-girdle syndromes. Clinical, morphological and electrophysiological studies. J Neurol Sci 1990;95:201-18. PMID 2324771
- 383
- Panicucci C, Fiorillo C, Moro F, et al. Mutations in GMPPB presenting with pseudometabolic myopathy. JIMD Rep 2018;38:23-31. PMID 28456886
- 384
- Panicucci C, Traverso M, Baratto S, et al. Novel TRIM32 mutation in sarcotubular myopathy. Acta Myol 2019;38(1):8-10. PMID 31309175
- 385
- Papadopoulos C, Laforet P, Nectoux J, et al. Hyperckemia and myalgia are common presentations of anoctamin-5-related myopathy in French patients. Muscle Nerve 2017;56(6):1096-100. PMID 28187523
- 386
- Papadopoulos C, Papadimas GK, Kekou K, et al. Caveolinopathies in Greece. Neurologist 2015;20(1):8-12. PMID 26185955
- 387
- Paradas C, Llauger J, Diaz-Manera J, et al. Redefining dysferlinopathy phenotypes based on clinical findings and muscle imaging studies. Neurology 2010;75(4):316-23. PMID 20574037
- 388
- Pashun RA, Azari BM, Achar A, et al. Intramyocardial fat in family with limb-girdle muscular dystrophy type 2E cardiomyopathy and sudden cardiac death. Circ Cardiovasc Imaging 2020;13(7):e010104. PMID 32635746
- 389
- Passos-Bueno MR, Richard I, Vainzof M, et al. Evidence of genetic heterogeneity in the autosomal recessive forms of limb-girdle muscular dystrophy following linkage analysis with 15q probes in Brazilian families. J Med Genet 1993;30:385-7. PMID 8320700
- 390
- Pathak P, Sharma MC, Jha P, et al. Mutational spectrum of CAPN3 with genotype-phenotype correlations in limb girdle muscular dystrophy type 2A/R1 (LGMD2A/LGMDR1) patients in India. J Neuromuscul Dis 2021;8(1):125-36. PMID 33337384
- 391
- Pearson CM. Pathology of human muscular dystrophy. In: Bourne GH, Golarz MN, editors. Muscular Dystrophy in Man and Animals. New York: Hafner, 1963:1-27.
- 392
- Pegoraro V, Angelini C. Circulating miR-206 as a biomarker for patients affected by severe limb girdle muscle dystrophies. Genes (Basel) 2021;12(1):85. PMID 33445560
- 393
- Pena L, Kim K, Charrow J. Episodic myoglobinuria in a primary gamma-sarcoglycanopathy. Neuromuscul Disord 2010;20(5):337-9. PMID 20356742
- 394
- Penisson-Besnier I, Hackman P, Suominen T, et al. Myopathies caused by homozygous titin mutations: limb-girdle muscular dystrophy 2J and variations of phenotype. J Neurol Neurosurg Psychiatry 2010;81(11):1200-2. PMID 20571043
- 395
- Pennington RJ. Clinical biochemistry of muscular dystrophy. Br Med Bull 1980;36:123-6. PMID 7020837
- 396
- Penttila S, Palmio J, Udd B. ANO5-related muscle diseases. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle, 2012.
- 397
- Peric S, Stevanovic J, Johnson K, et al. Phenotypic and genetic spectrum of patients with limb-girdle muscular dystrophy type 2A from Serbia. Acta Myol 2019;38(3):163-71. PMID 31788660
- 398
- Peterle E, Fanin M, Semplicini C, Padilla JJ, Nigro V, Angelini C. Clinical phenotype, muscle MRI and muscle pathology of LGMD1F. J Neurol 2013;260(8):2033-41. PMID 23632945
- 399
- Piccolo F, Roberds SL, Jeanpierre N, et al. Primary adhalinopathy: a common cause of autosomal recessive muscular dystrophy of variable severity. Nat Genet 1995;10:243-5. PMID 7663524
- 400
- Pistoni M, Shiue L, Cline MS, et al. Rbfox1 downregulation and altered calpain 3 splicing by FRG1 in a mouse model of Facioscapulohumeral muscular dystrophy (FSHD). PLoS Genet 2013;9(1):e1003186. PMID 23300487
- 401
- Pizzanelli C, Mancuso M, Galli R, et al. Epilepsy and limb-girdle muscular dystrophy type 2A: double trouble, serendipitous finding, or new phenotype. Neurol Sci 2006;27:134-6. PMID 16816913
- 402
- Politano L, Nigro V, Passamano L, et al. Evaluation of cardiac and respiratory involvement in sarcoglycanopathies. Neuromuscul Disord 2001;11(2):178-85. PMID 11257475
- 403
- Pollitt C, Anderson LV, Pogue R, Davison K, Pyle A, Bushby KM. The phenotype of calpainopathy: diagnosis based on a multidisciplinary approach. Neuromuscul Disord 2001;11(3):287-96. PMID 11297944
- 404
- Poppe M, Bourke J, Eagle M, et al. Cardiac and respiratory failure in limb-girdle muscular dystrophy 2I. Ann Neurol 2004;56(5):738-41. PMID 15505776
- 405
- Poppe M, Cree L, Bourke J, et al. The phenotype of limb-girdle muscular dystrophy type 2I. Neurology 2003;60(8):1246-51. PMID 12707425
- 406
- Potter RA, Griffin DA, Sondergaard PC, et al. Systemic delivery of dysferlin overlap vectors provides long-term gene expression and functional improvement for dysferlinopathy. Hum Gene Ther 2018;29(7):749-62. PMID 28707952
- 407
- Pozsgai ER, Griffin DA, Heller KN, Mendell JR, Rodino-Klapac LR. Beta-sarcoglycan gene transfer decreases fibrosis and restores force in LGMD2E mice. Gene Ther 2016;23(1):57-66. PMID 26214262
- 408
- Pozsgai ER, Griffin DA, Heller KN, Mendell JR, Rodino-Klapac LR. Systemic AAV-mediated B-sarcoglycan delivery targeting cardiac and skeletal muscle ameliorates histological and functional deficits in LGMD2E Mice. Mol Ther 2017;25(4):855-69. PMID 28284983
- 409
- Prahm KP, Feldt-Rasmussen U, Vissing J. Human growth hormone stabilizes walking and improves strength in a patient with dominantly inherited calpainopathy. Neuromuscular Dis 2017;27(4):358-62. PMID 28190647
- 410
- Preisler N, Lukacs Z, Vinge L, et al. Late-onset Pompe disease is prevalent in unclassified limb-girdle muscular dystrophies. Mol Gen Metab 2013;110(3):287-9. PMID 24011652
- 411
- Puckett RL, Moore SA, Winder TL, et al. Further evidence of Fukutin mutations as a cause of childhood onset limb-girdle muscular dystrophy without mental retardation. Neuromuscul Disord 2009;19(5):352-6. PMID 19342235
- 412
- Qiao C, Dai Y, Nikolova VD, et al. Amelioration of muscle and nerve pathology in LAMA2 muscular dystrophy by AAV9-mini-agrin. Mol Ther Methods Clin Dev 2018;9:47-56. PMID 29766020
- 413
- Quattrocelli M, Zelikovich AS, Salamone IM, Fischer JA, McNally EM. Mechanisms and clinical applications of glucocorticoid steroids in muscular dystrophy. J Neuromuscul Dis 2021;8(1):39-52. PMID 33104035
- 414
- Raducu M, Baets J, Fano O, Van Coster R, Cruces J. Promoter alteration causes transcriptional repression of the POMGNT1 gene in limb-girdle muscular dystrophy type 2O. Eur J Hum Genetics 2012;20(9):945-52. PMID 22419172
- 415
- Ralser DJ, Takeuchi H, Fritz G, et al. Altered Notch signaling in Dowling-Degos disease: additional mutations in POGLUT1 and further insights into disease pathogenesis. J Invest Dermatol 2019;139(4):960-4. PMID 30414910
- 416
- Ramos-Fransi A, Martinez-Pineiro A, Almendrote M, et al. Myotilinopathy unmasked by statin treatment: a case report. Muscle Nerve 2018;57(6):E138-40. PMID 29350769
- 417
- Reddy HM, Cho KA, Lek M, et al. The sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States. J Hum Genet 2017;62(2):243-52. PMID 27708273
- 418
- Rekik S, Sakka S, Ben Romdhan S, et al. Novel missense CAPN3 mutation responsible for adult-onset limb girdle muscular dystrophy with calves hypertrophy. J Mol Neurosci 2019;69(4):563-9. PMID 31410652
- 419
- Reyngoudt H, Marty B, Boisserie JM, et al. Global versus individual muscle segmentation to assess quantitative MRI-based fat fraction changes in neuromuscular diseases. Eur Radiol 2021;31(6):4264-76. PMID 33219846
- 420
- Rezniczek GA, Konieczny P, Nikolic B, et al. Plectin 1f scaffolding at the sarcolemma of dystrophic (mdx) muscle fibers through multiple interactions with beta-dystroglycan. J Cell Biol 2007;176:965-77. PMID 17389230
- 421
- Rich KA, Moscarello T, Siskind C, et al. Novel heterozygous truncating titin variants affecting the A-band are associated with cardiomyopathy and myopathy/muscular dystrophy. Mol Genet Genomic Med 2020;8(10):e1460. PMID 32815318
- 422
- Richard I, Broux O, Allamand V, et al. Mutations in the proteolytic enzyme calpain3 cause limb-girdle muscular dystrophy type 2A. Cell 1995;81:27-40. PMID 7720071
- 423
- Riggs JE, Schochet SS Jr, Gutman L, Lerfald SC. Childhood onset inclusion body myositis mimicking limb-girdle muscular dystrophy. J Child Neurol 1989;4:283-5. PMID 2551952
- 424
- Riisager M, Duno M, Hansen FJ, Krag TO, Vissing CR, Vissing J. A new mutation of the fukutin gene causing late-onset limb girdle muscular dystrophy. Neuromusc Dis 2013;23(7):562-7. PMID 23746544
- 425
- Rodino-Klapac LR, Lee JS, Mulligan RC, Clark KR, Mendell JR. Lack of toxicity of alpha-sarcoglycan overexpression supports clinical gene transfer trial in LGMD2D. Neurology 2008;71(4):240-7. PMID 18525034
- 426
- Rohkamm R, Boxler K, Ricker K, Jerusalem F. A dominantly inherited myopathy with excessive tubular aggregates. Neurology 1983;33:331-6. PMID 6681878
- 427
- Rosales XQ, Gastier-Foster JM, Lewis S, et al. Novel diagnostic features of dysferlinopathies. Muscle Nerve 2010;42(1):14-21. PMID 20544924
- 428
- Ruggieri A, Brancati F, Zanotti S, et al. Complete loss of the DNAJB6 G/F domain and novel missense mutations cause distal-onset DNAJB6 myopathy. Acta Neuropathol Commun 2015;3:44. PMID 26205529
- 429
- Ruggieri A, Saredi S, Zanotti S, Pasanisi MB, Maggi L, Mora M. DNAJB6 myopathies: focused review on an emerging and expanding group of myopathies. Front Mol Biosci 2016;3:63.** PMID 27747217
- 430
- Ruggiero L, Fiorillo C, Tessa A, et al. Muscle fiber type disproportion (FTD) in a family with mutations in the LMNA gene. Muscle Nerve 2015;51:604-8. PMID 25256213
- 431
- Saenz A, Leturcq F, Cobo AM et al. LGMD2A: genotype-phenotype correlations based on a large mutational survey on the calpain 3 gene. Brain 2005;128:732-42. PMID 15689361
- 432
- Sahenk Z, Ozes B, Murrey D, et al. Systemic delivery of AAVrh74.tMCK.hCAPN3 rescues the phenotype in a mouse model for LGMD2A/R1. Mol Ther Methods Clin Dev 2021;22:401-14. PMID 34514031
- 433
- Salani S, Lucchiari S, Fortunato F, et al. Developmental and tissue-specific regulation of a novel dysferlin isoform. Muscle Nerve 2004;30(3):366-74. PMID 15318348
- 434
- Salmikangas P, van der Ven PF, Lalowski M, et al. Myotilin, the limb-girdle muscular dystrophy 1A (LGMD1A) protein, cross-links actin filaments and controls sarcomere assembly. Hum Mol Genet 2003;12(2):189-203. PMID 12499399
- 435
- Sanchez F, Weitz C, Gutierrez JM, Mestroni L, Hanneman K, Vargas D. Cardiac MR imaging of muscular dystrophies. Curr Probl Diagn Radiol 2022;51(2):225-34. PMID 33551194
- 436
- Santa T. Fine structure of the human skeletal muscle in myopathy. Arch Neurol 1969;20:479. PMID 5767612
- 437
- Saredi S, Gibertinin S, Matalonga L, et al. Exome sequencing detects compound heterozygous nonsense LAMA 2 mutations in two siblings with atypical phenotype and nearly normal brain MRI. Neuromuscul Disord 2019;29(5):376-80. PMID 31040037
- 438
- Sarkozy A, Deschauer M, Carlier RY, et al. Muscle MRI findings in limb girdle muscular dystrophy type 2L. Neuromuscul Disord 2012;22 Suppl 2:S122-9. PMID 22980763
- 439
- Sarkozy A, Foley AR, Zambon AA, Bonnemann CG, Muntoni F. LAMA2-related dystrophies: clinical phenotypes, disease biomarkers, and clinical trial readiness. Front Mol Neurosci 2020;13:123. PMID 32848593
- 440
- Sarparanta J, Blandin G, Charton K, et al. Interactions with M-band titin and calpain 3 link myospryn (CMYA5) to tibial and limb-girdle muscular dystrophies. J Biol Chem 2010;285(39):30304-15. PMID 20634290
- 441
- Sarparanta J, Jonson PH, Golzio C, et al. Mutations affecting the cytoplasmic function of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy. Nat Genet 2012;44; 450-5. PMID 22366786
- 442
- Sarparanta J, Jonson PH, Kawan S, Udd B. Neuromuscular diseases due to chaperone mutations: a review and some new results. Int J Mol Sci 2020;21(4):1409. PMID 32093037
- 443
- Savarese M, Maggi L, Vihola A, et al. Interpreting genetic variants in titin in patients with muscle disorders. JAMA Neurol 2018;75(5):557-65. PMID 29435569
- 444
- Savarese M, Sarparanta J, Vihola A, Udd B, Hackman P. Increasing role of titin mutations in neuromuscular disorders. J Neuromusc Dis 2016;3(3):293-308.** PMID 27854229
- 445
- Saylam E, Moore SA, Aravindhan A, et al. A novel noncoding FKRP mutation in early onset limb-girdle muscular dystrophy. Neurol Genet 2020;6(1):e388. PMID 32042916
- 446
- Scalco RS, Gardiner AR, Pitceathly RD, et al. CAV3 mutations causing exercise intolerance, myalgia and rhabdomyolysis: expanding the phenotypic spectrum of caveolinopathies. Neuromusc Dis 2016;26(8):504-10. PMID 27312022
- 447
- Schessl J, Kress W, Schoser B. Novel ANO5 mutations causing hyper-CK-emia, limb girdle muscular weakness and Miyoshi type of muscular dystrophy. Muscle Nerve 2012;45:740-2. PMID 22499103
- 448
- Schindler RF, Scotton C, Zhang J, et al. POPDC1 S201F causes muscular dystrophy and arrhythmia by affecting protein trafficking. J Clin Invest 2016;126(1):239-53. PMID 26642364
- 449
- Schneider I, Stoltenburg G, Deschauer M, Winterholler M, Hanisch F. Limb girdle muscular dystrophy type 2L presenting as necrotizing myopathy. Acta Myol 2014;33(1):19-21. PMID 24843231
- 450
- Schoewel V, Marg A, Kunz S, et al. Dysferlin-peptides reallocate mutated dysferlin thereby restoring function. PLoS One 2012;7(11):e49603. PMID 23185377
- 451
- Schottlaender LV, Petzold A, Wood N, et al. Diagnostic clues and manifesting carriers in fukutin-related protein (FKRP) limb-girdle muscular dystrophy. J Neurol Sci 2015;348(1-2):266-8. PMID 25560911
- 452
- Schulte-Mattler WJ, Kley RA, Rotherfuber-Korber E. Immune-mediated rippling muscle disease. Arch Neurol 2005;64(2):364-7. PMID 15668444
- 453
- Schutz PW, Scalco RS, Barresi R, Houlden H, Parton M, Holton JL. Calpainopathy with macrophage-rich, regional inflammatory infiltrates. Neuromuscular Dis 2017;27(8):738-41. PMID 28602176
- 454
- Schwartz M, Hertz JM, Sveen M, Vissing J. LGMD2I presenting with a characteristic Duchenne or Becker muscular dystrophy phenotype. Neurology 2005;64(9):1635-7. PMID 15883334
- 455
- Selcen D, Engel AG. Mutations in myotilin cause myofibrillar myopathy. Neurology 2004;62(8):1363-71. PMID 15111675
- 456
- Selva-O’Callaghan A, Labrador-Horrillo M, Gallardo E, et al. Muscle inflammation, autoimmune Addison’s disease and sarcoidosis in a patient with dysferlin deficiency. Neuromuscul Disord 2006;16:208-9. PMID 16483775
- 457
- Semplicini C, Vissing J, Dahlqvist JR, et al. Clinical and genetic spectrum in limb-girdle muscular dystrophy type 2E. Neurology 2015;84(17):1772-81. PMID 25862795
- 458
- Servian-Morilla E, Cabrera-Serrano M, Johnson K, et al. POGLUT1 biallelic mutations cause myopathy with reduced satellite cells, α-dystroglycan hypoglycosylation and a distinctive radiological pattern. Acta Neuropathol 2020;139(3):565-82. PMID 31897643
- 459
- Servian-Morilla E, Takeuchi H, Lee TV, et al. A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss. EMBO Mol Med 2016;8(11):1289-309. PMID 27807076
- 460
- Shi W, Chen Z, Schottenfeld J, Stahl RC, Kunkel LM, Chan YM. Specific assembly pathway of sarcoglycans is dependent on beta- and delta-sarcoglycan. Muscle Nerve 2004;29(3):409-19. PMID 14981741
- 461
- Shields RW Jr. Limb girdle syndromes. In: Engel AG, Franzini-Armstrong C, editors. Myology. Vol. 2. New York: McGraw-Hill, 1994:1258-74.
- 462
- Shioya A, Takuma H, Takahashi T, Ishii A, Aoki M, Tamaoka A. Radiological findings in siblings with dysferlin mutation with diverse phenotype. J Neurol Sci 2020;409:116579. PMID 31770675
- 463
- Shy GM, Engel AG, Somers JE, Wanko T. Nemaline myopathy: a new congenital myopathy. Brain 1963;86:793-810. PMID 14090530
- 464
- Shy GM, Magee KR. A new congenital nonprogressive myopathy. Brain 1956;79:610-21. PMID 13396066
- 465
- Sinnreich M, Therrien C, Karpati G. Lariat branch point mutation in the dysferlin gene with mild limb-girdle muscular dystrophy, Neurology 2006;66:1114-6. PMID 16606933
- 466
- Smogavec M, Zschuntzsch J, Kress W, et al. Novel fukutin mutations in limb-girdle muscular dystrophy type 2M with childhood onset. Neurol Genet 2017;3(4):e167. PMID 28785732
- 467
- Sondergaard PC, Griffin DA, Pozsgai ER, et al. AAV.dysferlin overlap vectors restore function in dysferlinopathy animal models. Ann Clin Transl Neurol 2015;2(3):256-70. PMID 25815352
- 468
- Sreetama SC, Chandra G, Van der Meulen JH, et al. Membrane stabilization by modified steroid offers a potential therapy for muscular dystrophy due to dysferlin deficit. Mol Ther 2018;26(9):2231-42. PMID 30166241
- 469
- Stanga D, Zhao Q, Milev MP, Saint‐Dic D, Jimenez‐Mallebrera C, Sacher M. TRAPPC11 functions in autophagy by recruiting ATG2B‐WIPI4/WDR45 to preautophagosomal membranes. Traffic 2019;20(5):325-45. PMID 30843302
- 470
- Starling A, Kok F, Passos-Bueno MR, Vainzof M, Zatz M. A new form of autosomal dominant limb-girdle muscular dystrophy (LGMD1G) with progressive fingers and toes flexion limitation maps to chromosome 4p21. Eur J Hum Genet 2004;12(12):1033-40. PMID 15367920
- 471
- Stavusis J, Micule I, Wright NT, et al. Collagen VI-related limb-girdle syndrome caused by frequent mutation in COL6A3 gene with conflicting reports of pathogenicity. Neuromuscul Disord 2020;30(6):483-91. PMID 32448721
- 472
- Stensland E, Lindal S, Jonsrud C, et al. Prevalence, mutation spectrum and phenotypic variability in Norwegian patients with limb girdle muscular dystrophy 2I. Neuromuscul Disord 2011;21(1):41-6. PMID 20961759
- 473
- Stevenson AC. Muscular dystrophy in northern Ireland. I. An account of the condition in fifty-one families. Ann Eugen (London) 1953;18:50-93. PMID 13058272
- 474
- Stevenson AC. Muscular dystrophy in northern Ireland. II. An account of nine additional families. Ann Hum Genet 1955;19:159-64. PMID 14350449
- 475
- Straub V, Carlier PG, Mercuri E. TREAT-NMD workshop: pattern recognition in genetic muscle diseases using muscle MRI: 25-26 February 2011, Rome, Italy. Neuromuscul Disord 2012;22(Suppl 2):S42-53. PMID 22980768
- 476
- Straub V, Ettinger AJ, Durbeej M, et al. Epsilon-sarcoglycan replaces alpha-sarcoglycan in smooth muscle to form a unique dystrophin-glycoprotein complex. J Biol Chem 1999;274(39):27989-96. PMID 10488149
- 477
- Straub V, Murphy A, Udd B, LGMD workshop study group. 229th ENMC international workshop: Limb girdle muscular dystrophies – nomenclature and reformed classification Naarden, the Netherlands, 17–19 March 2017. Neuromuscul Disord 2018;28(8):702-10. PMID 30055862
- 478
- Stubgen JP. Limb-girdle muscular dystrophy: a non-invasive cardiac evaluation. Cardiology 1993;83:324-30. PMID 8111765
- 479
- Stubgen JP, Ras GJ, Schultz CM, Crowther G. Lung and respiratory muscle function in limb-girdle muscular dystrophy. Thorax 1994;83:324-30. PMID 8153942
- 480
- Sun Y, Chen H, Lu Y, et al. Limb girdle muscular dystrophy D3 HNRNPDL related in a Chinese family with distal muscle weakness caused by a mutation in the prion-like domain. J Neurol 2019;266(2):498-506. PMID 30604053
- 481
- Sunohara NK, Nonaka I, Kamei N, Satoyoshi E. Distal myopathy with rimmed vacuole formation: a follow-up study. Brain 1989;112(Pt 1):65-83. PMID 2645018
- 482
- Svahn J, Streichenberger N, Benveniste O, et al. Significant response to immune therapies in a case of subacute necrotizing myopathy and FKRP mutations. Neuromuscular Disord 2015;25(11):865-8. PMID 26363967
- 483
- Sveen ML, Andersen SP, Ingelsrud LH, et al. Resistance training in patients with limb-girdle and Becker muscular dystrophies. Muscle Nerve 2013;47(2):163-9. PMID 23169433
- 484
- Sveen ML, Jeppesen TD, Hauerslev S, Krag TO, Vissing J. Endurance training: an effective and safe treatment for patients with LGMD2I. Neurology 2007;68:59-61. PMID 17200494
- 485
- Sveen ML, Schwartz M, Vissing J. High prevalence and phenotype-genotype correlations of limb girdle muscular dystrophy type 2I in Denmark. Ann Neurol 2006;59(5):808-15. PMID 16634037
- 486
- Tachi N, Tachi M, Sasaki K, Imamura S. Early-onset benign autosomal-dominant limb-girdle myopathy with contractures [Bethlem myopathy]. Pediatr Neurol 1989;5:232-6. PMID 2803379
- 487
- Takahashi K. The effect of prednisone on a patient with dysferlinopathy assessed by maximal voluntary isometric contraction: alternate-day low-dose administration for a 17-year period. Case Rep Neurol 2019;11(1):10-6. PMID 31043956
- 488
- Takahashi T, Aoki M, Imai T, et al. A case of dysferlinopathy presenting choreic movements. Mov Disord 2006;21(9):1513-5. PMID 16817213
- 489
- Takayashi T, Aoki M, Suzuki N, et al. Clinical features and a mutation with late onset of limb girdle muscular dystrophy 2B. J Neurol Neurosurg Psychiatry 2013;84(4):433-40. PMID 23243261
- 490
- Tandan R, Verma A, Mohire M. Adult-onset autosomal recessive neurogenic scapuloperoneal syndrome. J Neurol Sci 1989;94:201-9. PMID 2614468
- 491
- Tasca G, Evila A, Pane M, et al. Isolated semitendinosus involvement in the initial stages of limb-girdle muscular dystrophy 2L. Neuromusc Dis 2014;24(12):1118-19. PMID 25149668
- 492
- Tasca G, Monforte M, Diaz-Manera J, et al. MRI in sarcoglycanopathies: a large international cohort study. J Neurol Neurosurg Psychiatry 2018;89(1):72-7. PMID 28889091
- 493
- Tasca G, Moro F, Aiello C, et al. Limb-girdle muscular dystrophy with a-dystroglycan deficiency and mutations in the ISPD gene. Neurology 2013;80(10):963-5. PMID 23390185
- 494
- Tateyama M, Aoki M, Nishino I, et al. Mutation in the caveolin-3 gene causes a peculiar form of distal myopathy. Neurology 2002;58(2):323-5. PMID 11805270
- 495
- Tedesco FS, Gerli MF, Perani L, et al. Transplantation of genetically corrected human iPSC-derived progenitors in mice with limb-girdle muscular dystrophy. Sci Transl Med 2012;4(140):140ra89. PMID 22745439
- 496
- Ten Dam L, Frankhuizen WS, Linssen WHJP, et al. Autosomal recessive limb‐girdle and Miyoshi muscular dystrophies in the Netherlands: The clinical and molecular spectrum of 244 patients. Clin Genet 2019;96(2):126-33. PMID 30919934
- 497
- ten Dam L, van der Kooi AJ, Rövekamp F, Linssen WH, de Visser M. Comparing clinical data and muscle imaging of DYSF and ANO5 related muscular dystrophies. Neuromusc Dis 2014;24(12):1097-102. PMID 25176504
- 498
- Therrien C, Dodig D, Karpati G, Sinnreich M. Mutation impact on dysferlin inferred from database analysis and computer-based structural predictions. J Neurol Sci 2006;25:71-8. PMID 16996541
- 499
- Tian WT, Zhou HY, Zhan FX, et al. Lysosomal degradation of GMPPB is associated with limb-girdle muscular dystrophy type 2T. Ann Clin Transl Neurol 2019;6(6):1062-71. PMID 31211170
- 500
- Togawa J, Ohi T, Yuan JH, et al. Atypical familial amyotrophic lateral sclerosis with slowly progressing lower extremities-predominant late-onset muscular weakness and atrophy. Intern Med 2019;58(13):1851-8. PMID 31257275
- 501
- Tome FM, Fardeau M, Lebon T, Chevallay M. Inclusion body myositis. Acta Neuropathol (Suppl) 1981;7:287. PMID 6261517
- 502
- Toral-Ojeda I, Aldanondo G, Lasa-Elgarresta J, et al. Calpain 3 deficiency affects SERCA expression and function in the skeletal muscle. Expert Rev Mol Med 2016;18:e7. PMID 27055500
- 503
- Torella A, Fanin M, Mutarelli M, et al. Next-generation sequencing identifies transportin 3 as the causative gene for LGMD1F. PLoS One 2013;8(5):1-7. PMID 23667635
- 504
- Traversa A, Bernardo S, Paiardini A, et al. Prenatal whole exome sequencing detects a new homozygous fukutin (FKTN) mutation in a fetus with an ultrasound suspicion of familial Dandy–Walker malformation. Mol Genet Genomic Med 2020;8(1):e1054. PMID 31756055
- 505
- Tsao CY, Mendell JR. Coexisting muscular dystrophies and epilepsy in children. J Child Neurol 2006;21(2):148-50. PMID 16566880
- 506
- Udd B, Vihola A, Sarparanta J, Richard I, Hackman P. Titinopathies and extension of the M-line mutation phenotype beyond distal myopathy and LGMD2J. Neurology 2005;64(4):596-7. PMID 15728284
- 507
- Ueyama H, Kumamoto T, Nagao S, et al A new dysferlin gene mutation in two Japanese families with limb-girdle muscular dystrophy 2B and Miyoshi myopathy. Neuromuscul Disord 2001;11(2):139-45. PMID 11257469
- 508
- Ujihara Y, Kanagawa M, Mohri S, et al. Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure. Nat Commun 2019;10(1):5754. PMID 31848331
- 509
- Ullah A, Lin Z, Younus M, et al. Homozygous missense variant in POPDC3 causes recessive limb-girdle muscular dystrophy type 26. J Gene Med 2022;24(4):e3412. PMID 35075722
- 510
- Valari M, Theodoraki M, Loukas I, et al. Novel PLEC variant causes mild skin fragility, pyloric atresia, muscular dystrophy and urological manifestations. Acta Derm Venereol 2019;99(13):1309-10. PMID 31513275
- 511
- Vallecillo-Zuniga ML, Rathgeber MF, Poulson PD, et al. Treatment with galectin-1 improves myogenic potential and membrane repair in dysferlin-deficient models. PLoS One 2020;15(9):e0238441. PMID 32881965
- 512
- van der Kooi AJ, ten Dam L, Frankhuizen WS, et al. ANO5 mutations in the Dutch limb girdle muscular dystrophy population. Neuromuscul Disord 2013;23:456-60. PMID 11257469
- 513
- van der Kooi AJ, van Meegen M, Ledderhof TM, et al. Genetic localization of a newly recognized autosomal dominant limb-girdle muscular dystrophy with cardiac involvement. Am J Hum Genet 1997;60:891-5. PMID 9106535
- 514
- van Tintelen JP, Hofstra RM, Katerberg H, et al. High yield of LMNA mutations in patients with dilated cardiomyopathy and/or conduction disease referred to cardiogenetics outpatient clinics. Am Heart J 2007;154(6):1130-9. PMID 18035086
- 515
- Vanegas OC, Bertini E, Zhang RZ. Ullrich scleroatonic muscular dystrophy is caused by recessive mutations in collagen type VI. Proc Natl Acad Sci U S A 2001;98(13):7516-21. PMID 11381124
- 516
- Vannoy CH, Leroy V, Broniowska K, Lu QL. Metabolomics analysis of skeletal muscles from FKRP-deficient mice indicates improvement after gene replacement therapy. Sci Rep 2019;9(1):10070. PMID 31296900
- 517
- Vannoy CH, Leroy V, Lu QL. Replacement therapy on functional rescue and longevity in dystrophic mice. Mol Ther Methods Clin Dev 2018;11:106-20. PMID 30417025
- 518
- Vaughan A, Alvarez-Reyes M, Bridger JM, et al. Both emerin and lamin C depend on lamin A for localization at the nuclear envelope. J Cell Sci 2001;114:2577-90. PMID 11683386
- 519
- Vaz-Pereira S, Dansingani K, Holder GE, Webster AR. Macular dystrophy presenting in one of two siblings with limb-girdle muscular dystrophy type 2L due to mutation of ANO5. Eye (Lond) 2014;28(1):102-4. PMID 24232312
- 520
- Verma A, Bradley WG, Soule N, et al. A quantitative morphometric study of muscle in inflammatory muscle disease. J Neurol Sci 1992a;112:192-8. PMID 1335036
- 521
- Verma A, Sarkar C, Padma MV, Dhir R, Jain S, Maheshwari MC. Dystrophin test in differential diagnosis of childhood muscular dystrophies. J Assoc Physicians India 1992b;40(9):610-3. PMID 1308019
- 522
- Vicente LM, Martí P, Azorín I, Olive M, Muelas N, Vilchez JJ. HNRNPDL-related limb girdle muscular dystrophy in a Spanish family with scapulo-peroneal phenotype, the first family in Europe. J Neurol Sci 2020;414:116875. PMID 32407983
- 523
- Vieira NM, Bueno CR Jr, Brandalise V, et al. SJL dystrophic mice express a significant amount of human muscle proteins following systemic delivery of human adipose-derived stromal cells without immunosuppression. Stem Cells 2008;26(9):2391-8. PMID 18583542
- 524
- Vieira NM, Naslavsky MS, Licinio L, et al. A defect in the RNA-processing protein HNRPDL causes limb-girdle muscular dystrophy 1G (LGMD1G). Hum Mol Gen 2014;23(15):4103-10. PMID 24647604
- 525
- Vilchez JJ, Gallano P, Gallardo E, et al. Identification of a novel founder mutation in the DYSF gene causing clinical variability in the Spanish population. Arch Neurol 2005;62(8):1256-9. PMID 16087766
- 526
- Vinit J, Samson M Jr, Gaultier JB, et al. Dysferlin deficiency treated like refractory polymyositis. Clin Rheumatol 2010;29(1):103-6. PMID 19730931
- 527
- Vissing CR, Preisler N, Husu E, et al. Aerobic training in patients with anoctamin 5 myopathy and hyperckemia. Muscle Nerve 2014;50(1):119-23. PMID 24639367
- 528
- Vissing J, Barresi R, Witting N, et al. A heterozygous 21-bp deletion in CAPN3 causes dominantly inherited limb girdle muscular dystrophy. Brain 2016;139:2154-63. PMID 27259757
- 529
- Vissing J, Dahlqvist JR, Roudaut C, et al. A single c.1715G>C calpain 3 gene variant causes dominant calpainopathy with loss of calpain 3 expression and activity. Hum Mutat 2020;41(9):1507-13. PMID 32557990
- 530
- Vital A, Ferrer X, Goizet C, et al. Peripheral nerve lesions associated with a dominant missense mutation, E33D, of the lamin A/C gene. Neuromuscul Disord 2005;15:618-21. PMID 16084085
- 531
- von der Hagen M, Kaindl AM, Koehler K, et al. Limb girdle muscular dystrophy type 2I caused by a novel missense mutation in the FKRP gene presenting as acute virus-associated myositis in infancy. Eur J Pediatr 2006;165:62-3. PMID 16143867
- 532
- Vrist LTH, Knudsen LF, Handberg C. 'It becomes the new everyday life' - experiences of chronic pain in everyday life of people with limb-girdle muscular dystrophy. Disabil Rehabil 2022:1-8. PMID 36343207
- 533
- Waclawik AJ, Lindal S, Engel AG. Experimental lovastatin myopathy. J Neuropathol Exp Neurol 1993;52:542-9. PMID 8360706
- 534
- Walter MC, Braun C, Vorgerd M, et al. Variable reduction of caveolin-3 in patients with LGMD2B/MM. J Neurol 2003;250(12):1431-8. PMID 14673575
- 535
- Walter MC, Reilich P, Thiele S, et al. Treatment of dysferlinopathy with deflazacort: a double-blind, placebo-controlled clinical trial. Orphanet J Rare Dis 2013;8(1):26. PMID 23406536
- 536
- Walton JN, Nattrass FJ. On the classification, natural history and treatment of the myopathies. Brain 1954;77:170-231. PMID 13190076
- 537
- Wang B, Yang Z, Brisson BK, et al. Membrane blebbing as an assessment of functional rescue of dysferlin-deficient human myotubes via nonsense suppression. J Appl Physiol 2010;109(3):901-5. PMID 20558759
- 538
- Wang C, Wong J, Fung G, et al. Dysferlin deficiency confers increased susceptibility to coxsackievirus-induced cardiomyopathy. Cell Microbiol 2015;17(10):1423-30. PMID 26073173
- 539
- Wang DN, Wang ZQ, Chen YQ, Xu GR, Lin MT, Wang N. Limb-girdle muscular dystrophy type 2I: two Chinese families and a review in Asian patients. Int J Neurosci 2018a;128(3):199-207. PMID 28931339
- 540
- Wang L, Zhang VW, Li S, et al. The clinical spectrum and genetic variability of limb-girdle muscular dystrophy in a cohort of Chinese patients. Orphanet J Rare Dis 2018b;13(1):133. PMID 30107846
- 541
- Wang N, Han X, Hao S, et al. The clinical, myopathological, and molecular characteristics of 26 Chinese patients with dysferlinopathy: a high proportion of misdiagnosis and novel variants. BMC Neurol 2022;22(1):398. PMID 36319958
- 542
- Weiler T, Greenberg CR, Zelinski T, et al. A gene for autosomal recessive limb-girdle muscular dystrophy in Manitoba Hutterites maps to chromosome 19q31-q33: evidence for another limb-girdle muscular dystrophy locus. Am J Hum Genet 1998;63:140-7. PMID 9634523
- 543
- Wein N, Avril A, Bartoli M, et al. Efficient bypass of mutations in dysferlin deficient patient cells by antisense-induced exon skipping. Hum Mutat 2010;31(2):136-42. PMID 19953532
- 544
- Wheeler M, Zarnegar S, McNally EM. Zeta-sarcoglycan, a novel component of the sarcoglycan complex, is reduced in muscular dystrophy. Hum Mol Genet 2002;11(18):2147-54. PMID 12189167
- 545
- Whisnant JP, Espinosa RE, Kierland RR, Lambert EH. Chloroquin neuromyopathy. Proc Staff Meet Mayo Clin 1963;38:501-13. PMID 14090994
- 546
- Willis E, Moore SA, Cox MO, et al. Limb-girdle muscular dystrophy R9 due to a novel complex insertion/duplication variant in FKRP gene. Child Neurol Open 2022;9:2329048X221097518. PMID 35557983
- 547
- Winckler PB, Chwal BC, Dos Santos MAR, et al. Diagnostic yield of multi-gene panel for muscular dystrophies and other hereditary myopathies. Neurol Sci 2022;43(7):4473-81. PMID 35175440
- 548
- Winckler PB, da Silva AMS, Coimbra-Neto AR, et al. Clinicogenetic lessons from 370 patients with autosomal recessive limb-girdle muscular dystrophy. Clin Genet 2019;96(4):341-53. PMID 31268554
- 549
- Winter L, Wiche G. The many faces of plectin and plectinopathies: pathology and mechanisms. Acta Neuropathol 2013;125(1):77-93. PMID 22864774
- 550
- Woodman SE, Sotgia F, Galbiati F, Minetti C, Lisanti MP. Caveolinopathies: mutations in caveolin-3 cause four distinct autosomal dominant muscular diseases. Neurology 2004;62(4):538-43. PMID 14981167
- 551
- Wu B, Drains M, Shah SN, et al. Ribitol dose-dependently enhances matriglycan expression and improves muscle function with prolonged life span in limb girdle muscular dystrophy 2I mouse model. PLoS One 2022;17(12):e0278482. PMID 36454905
- 552
- Wyatt EJ, Demonbreun AR, Kim EY, et al. Efficient exon skipping of SGCG mutations mediated by phosphorodiamidate morpholino oligomers. JCI Insight 2018;3(9):e99357. PMID 29720576
- 553
- Xie Z, Xiao J, Zheng Y, Wang Z, Yuan Y. Magnetic resonance imaging findings in the muscle tissue of patients with limb girdle muscular dystrophy type 2I harboring the founder mutation c.545a>g in the FKRP gene. Biomed Res Int 2018;2018:3710814. PMID 30003095
- 554
- Yabe I, Tanino M, Yaguchi H, et al. Pathology of frontotemporal dementia with limb girdle muscular dystrophy caused by a DNAJB6 mutation. Clin Neurol Neurosurg 2014;127:10-2. PMID 25306414
- 555
- Yang M, Ji S, Xu L, et al. The clinicopathological distinction between immune-mediated necrotizing myopathy and limb-girdle muscular dystrophy R2: key points to prevent misdiagnosis. J Clin Med 2022;11(21):6566. PMID 36362794
- 556
- Yap SM, Farrell M, Cryan J, Smyth S. An Irish case of limb-girdle muscular dystrophy 2I with structural eye involvement. Muscle Nerve 2016;54(3):509-10. PMID 26833294
- 557
- Yoshida M, Ozawa E. Glycoprotein complex anchoring dystrophin to sarcolemma. J Biochem 1990;108:748-52. PMID 2081733
- 558
- Yoshihisa A, Kiko T, Sato T, et al. Urinary N-terminal fragment of titin is a marker to diagnose muscular dystrophy in patients with cardiomyopathy. Clin Chim Acta 2018;484:226-30. PMID 29870683
- 559
- Yu M, Zheng Y, Jin S, et al. Mutational spectrum of Chinese LGMD patients by targeted next-generation sequencing. PLoS ONE 2017;12(4):e0175343. PMID 28403181
- 560
- Yu M, Zhu Y, Xie Z, et al. Novel TTN mutations and muscle imaging characteristics in congenital titinopathy. Ann Clin Transl Neurol 2019;6(7):1311-8. PMID 31353864
- 561
- Zanoteli E, Soares PS, da Silva AMS, et al. Clinical features of collagen VI-related dystrophies: a large Brazilian cohort. Clin Neurol Neurosurg 2020;192:105734. PMID 32065942
- 562
- Zatz M, de Paula F, Starling A, Vainzof M. The 10 autosomal recessive limb-girdle muscular dystrophies. Neuromuscul Disord 2003;13(7-8):532-44. PMID 12921790
- 563
- Zatz M, Passos-Bueno MR, Rappaport D. Estimate of the proportion of Duchenne muscular dystrophy with autosomal recessive inheritance. Am J Med Genet 1989;32:407-10. PMID 2658592
- 564
- Zhang L, Li W, Weng Y, et al. A novel splice site variant in the POPDC3 causes autosomal recessive limb-girdle muscular dystrophy type 26. Clin Genet 2022;102(4):345-9. PMID 35842834
- 565
- Zhong H, Zheng Y, Zhao Z, et al. Molecular landscape of CAPN3 mutations in limb-girdle muscular dystrophy type R1: from a Chinese multicentre analysis to a worldwide perspective. J Med Genet 2021;58(11):729-36. PMID 32994280
- 566
- Zhu X, Hadhazy M, Groh ME, Wheeler MT, Wollmann R, McNally EM. Overexpression of gamma-sarcoglycan induces severe muscular dystrophy. Implications for the regulation of sarcoglycan assembly. J Biol Chem 2001;276:21785-90. PMID 11287429
- 567
- Zima J, Eaton A, Pal E, et al. Intrafamilial variability of limb-girdle muscular dystrophy, LGMD1D type. Eur J Med Gen 2020;63(2):103655. PMID 31034989
Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Authors
-
Miguel Chuquilin MD
Dr. Chuquilin of University of Florida College of Medicine has no relevant financial relationships to disclose.
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Varun Jain MD
Dr. Jain of the University of Florida has no relevant financial relationships to disclose.
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Editor
-
Aravindhan Veerapandiyan MD
Dr. Veerapandiyan of University of Arkansas for Medical Sciences has no relevant financial relationships to disclose.
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Former Authors
- Hsin-Pin Lin MD PhD
- James Wymer MD PhD
- Tiffany Eisenbach MD
- Ashok Verma MD (original author), Tanya A Fatimi MD, and Louis H Weimer MD
Patient Profile
- Age range of presentation
-
- 1 month to 64 years
- Sex preponderance
-
- male=female
- Heredity
-
- heredity typical
- heredity may be a factor
- Population groups selectively affected
-
- Amish
- Brazilians
- Inhabitants of Reunion Island
- Hutterites of Manitoba
- Scottish
- Occupation groups selectively affected
-
- none selectively affected
ICD & OMIM codes
- ICD-9
-
- Limb-girdle muscular dystrophy: 359.1
- ICD-10
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- Limb-girdle muscular dystrophy: G71.0
- OMIM
-
- Limb-girdle muscular dystrophy, type 1A: #159000
- Limb-girdle muscular dystrophy, type 1B: #159001
- Limb-girdle muscular dystrophy, type 1C: #607801
- Limb-girdle muscular dystrophy, type 1E: #603511
- Limb-girdle muscular dystrophy, type 1F: #608423
- Limb-girdle muscular dystrophy, type 1G: #609115
- Limb-girdle muscular dystrophy, type 1H: #613530
- Limb-girdle muscular dystrophy, type 2A: #253600
- Limb-girdle muscular dystrophy, type 2B: #253601
- Limb-girdle muscular dystrophy, type 2C: #253700
- Limb-girdle muscular dystrophy, type 2D: #608099
- Limb-girdle muscular dystrophy, type 2E: #604286
- Limb-girdle muscular dystrophy, type 2F: #601287
- Limb-girdle muscular dystrophy, type 2G: #601954
- Limb-girdle muscular dystrophy, type 2H: #254110
- Limb-girdle muscular dystrophy, type 2I: #607155
- Limb-girdle muscular dystrophy, type 2J: #608807
- Limb-girdle muscular dystrophy, type 2K: #609308
- Limb-girdle muscular dystrophy, type 2L: #611307
- Limb-girdle muscular dystrophy, type 2M: #611588
- Limb-girdle muscular dystrophy, type 2N: #613158
- Limb-girdle muscular dystrophy, type 2O: #613157
- Limb-girdle muscular dystrophy, type 2P: 613818
- Limb-girdle muscular dystrophy, type 2Q: #613723
- Limb-girdle muscular dystrophy, type 2R: #615325
- Limb-girdle muscular dystrophy, type 2S: #615356
- Limb-girdle muscular dystrophy, type 2T: #615352
- Limb-girdle muscular dystrophy, type 2U: #616052
- Limb-girdle muscular dystrophy, type 2V: #232300
- Limb-girdle muscular dystrophy, type 2W: #616827
- Limb-girdle muscular dystrophy, type 2X: #616812
- Limb-girdle muscular dystrophy, type 2Y: #617072
- Limb-girdle muscular dystrophy, type 2Z: #617232
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