Neuromuscular Disorders
Neurogenetics and genetic and genomic testing
Dec. 09, 2024
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Limb-girdle muscular dystrophies (LGMD) …
- Updated 11.19.2024
- Released 11.06.1995
- Expires For CME 11.19.2027
Limb-girdle muscular dystrophies
Introduction
Overview
The 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 (460). The proposed definition for limb-girdle muscular dystrophy is as follows (460):
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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 two 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.
Key points
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• Limb-girdle muscular dystrophies are genetically inherited in either an autosomal dominant (LGMD D) or autosomal recessive (LGMD R) pattern. | |
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• Onset occurs in childhood through adulthood. | |
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• The prominent clinical feature is progressive proximal weakness. |
Historical note and terminology
The history of limb-girdle muscular dystrophy encompasses the history of primary and secondary muscle diseases as a whole (34; 274; 456; 457; 513; 55; 235; 444). 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 limb-girdle syndromes. Modern techniques of investigation then allowed the recognition and separation of 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 (318). Duchenne mentioned dystrophies with onset at a 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 (346). Clinical descriptions were long ago characterized by the distribution of weakness based on the predominant involvement of the scapulohumeral (138), pelvifemoral (275; 322), 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 (137).
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 (274; 456; 457). 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 (513). 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 (55).
A workshop headed by Bushby reclassified limb-girdle muscular dystrophy based on mode of inheritance and chromosomal localization (66). 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 in the pathogenesis of limb-girdle muscular dystrophies, there has been further exploration into therapeutic targets.
Clinical manifestations
Presentation and course
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• Limb-girdle muscular dystrophy typically presents with slowly progressive proximal weakness of the muscles of the shoulder and hip girdles, although other muscle groups can become affected. | |
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• Limb-girdle muscular dystrophy affects both men and woman and is genetically inherited in either an autosomal dominant (LGMD D) or autosomal recessive (LGMD R) pattern. | |
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• Other systemic manifestations, such as cardiac or respiratory abnormalities, can occur with various subtypes. |
Limb-girdle muscular dystrophies occur in both sexes, with onset often between the second and sixth decade, usually in late childhood or early adulthood, although onset can occur at almost any age. In many cases, weakness begins in the pelvic girdle musculature (Leyden and Mobius type) and then spreads to the pectoral or shoulder musculature. However, in the reverse pattern (Erb type), it is not unusual to see the pectoral or shoulder girdle affected first. In rarer cases, both regions are affected simultaneously. Early facial, distal, or extraocular muscle involvement is not often 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; 326; 468; 236). 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, more muscle groups 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/shoulder 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/shoulder 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). This pattern is also commonly demonstrated in facioscapulohumeral muscular dystrophy (FSHD), and the clinical and genetic distinction should be made. 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 (230; 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. 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. Creatine kinase is variably raised (2x to 350x) in recessive cases and is either normal or only mildly increased (to 6x) in dominant patients (66).
Cardiac involvement, including cardiomyopathy or cardiac conduction abnormalities, can be seen in some subtypes. Certain subtypes may also progress to neuromuscular respiratory involvement, which manifests as a weakened cough, orthopnea, and eventually difficulty taking deep breaths (240). 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 (462).
The clinical course is variable, however, and some patients have a normal lifespan and may remain ambulatory throughout (40; 11; 326; 468; 89; 385).
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 (323).
Chronic pain appears to be a prevalent problem in people with limb-girdle muscular dystrophy, with a negative impact on everyday life (510).
Prognosis and complications
Limb-girdle dystrophies, like all muscular dystrophies, are progressive disorders. The rate of progression, however, varies widely with the different subtypes of limb-girdle muscular dystrophies and between individuals. Autosomal recessive limb-girdle muscular dystrophies that present in childhood generally progress more rapidly, leading to loss of ambulation in late childhood or adolescence and death in early adulthood (36; 539; 151; 14; 240), 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; 326; 468; 236; 240).
Physical disability in limb-girdle muscular dystrophies 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 the onset of symptoms and the inability to walk is highly variable. Muscle contractures may contribute to severe disability in some subtypes and 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. 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 (461) and are generally similar to, but less severe than, Duchenne dystrophy.
Findings indicate that miR-206, a member of the myomiRNA group of miRNAs found to be important for skeletal muscle, 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 (375). 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 (375). However, this marker is not currently used in standard clinical practice.
Biological basis
• The limb-girdle muscular dystrophies are a genetically heterogeneous group of disorders; the biological basis of each subtype is dependent on the gene responsible. | |
• Variants in the same gene may lead to variable phenotypic presentations. |
Etiology and pathogenesis
Classification of limb-girdle muscular dystrophies. In the 1990s, limb-girdle muscular dystrophies were subtyped by genetic mutations and associated protein deficiencies. The autosomal dominant limb-girdle muscular dystrophies were distinguished by the number 1 and the autosomal recessive limb-girdle muscular dystrophies by the number 2. A letter following the numerical designation indicated the subtype (66; 65; 66). However, as the list of newly discovered limb-girdle muscular dystrophies grew, this classification scheme reached the end of the alphabet for the recessive forms, necessitating an update. A reclassification of the limb-girdle muscular dystrophies was proposed by the European Neuromuscular Center LGMD workshop study group in 2017. This new classification follows the following formula: “LGMD, inheritance (R or D, indicating autosomal recessive or dominance inheritance, respectively), order of discovery (number), affected protein” (460). Due to the updated definition of limb-girdle muscular dystrophies noted earlier in this article, some conditions are no longer considered limb-girdle muscular dystrophy. The former limb-girdle muscular dystrophy type 1 is now LGMD D, and the former limb-girdle muscular dystrophy type 2 is now LGMD R. This review describes the limb-girdle muscular dystrophies following the new classification (Table 1). A brief description of the conditions no longer considered in the current limb-girdle muscular dystrophy classification scheme will be included following the detailed summaries of the current types.
Table 1. Classification of LGMD types, affected genes, and associated proteins
New nomenclature | Old Nomenclature | Gene | Protein |
LGMD D1 | LGMD 1D | DNAJB6 | DNAJ homolog, subfamily B, member 6 |
LGMD D2 | LGMD 1F | TNPO3 | Transportin 3 |
LGMD D3 | LGMD 1G | HNRNPDL | Heterogenous nuclear ribonucleoprotein D-like |
LGMD D4 | LGMD 1I | CAPN3 | Calpain-3 |
LGMD D5 | Bethlem myopathy dominant | COL6A1 | Collagen type VI subunits alpha-1, 2, and 3 |
LGMD R1 | LGMD 2A | CAPN3 | Calpain-3 |
LGMD R2 | LGMD 2B | DYSF | Dysferlin |
LGMD R3 | LGMD 2D | SGCA | Alpha-sarcoglycan |
LGMD R4 | LGMD 2E | SGCB | Beta-sarcoglycan |
LGMD R5 | LGMD 2C | SGCG | Gamma-sarcoglycan |
LGMD R6 | LGMD 2F | SGCD | Delta-sarcoglycan |
LGMD R7 | LGMD 2G | TCAP | Telethonin |
LGMD R8 | LGMD 2H | TRIM32 | Tripartite motif-containing protein 32 |
LGMD R9 | LGMD 2I | FKRP | Fukutin-related protein |
LGMD R10 | LGMD 2J | TTN | Titin |
LGMD R11 | LGMD 2K | POMT1 | Protein O-mannosyltransferase 1 |
LGMD R12 | LGMD 2L | ANO5 | Anoctamin 5 |
LGMD R13 | LGMD 2M | FKTN | Fukutin |
LGMD R14 | LGMD 2N | POMT2 | Protein O-mannosyltransferase 2 |
LGMD R15 | LGMD 2O | POMGnT1 | Protein O-mannose beta-1,2-N-acetylglucosaminyltransferase 1 |
LGMD R16 | LGMD 2P | DAG1 | Dystroglycan 1 |
LGMD R17 | LGMD 2Q | PLEC | Plectin |
LGMD R18 | LGMD 2S | TRAPPC11 | Trafficking protein particle complex, subunit 11 |
LGMD R19 | LGMD 2T | GMPPB | GDP-mannose pyrophosphorylase B |
LGMD R20 | LGMD 2U | ISPD | Isoprenoid synthase |
LGMD R21 | LGMD 2Z | POGLUT1 | Protein O-glucosyltransferase 1 |
LGMD R22 | Bethlem myopathy recessive | COL6A1 | Collagen type VI subunits alpha-1, 2, and 3 |
LGMD R23 | Laminin alpha2-related muscular dystrophy | LAMA2 | Laminin alpha-2 |
LGMD R24 | POMGNT2-related muscular dystrophy | POMGnT2 | Protein O-linked mannose beta-1,4-N-acetylglucosaminyl-transferase 2 |
LGMD R25 | BVES | Popeye domain-containing protein 1 | |
LGMD R26 | POPDC3 | Popeye domain-containing protein 3 | |
LGMD R27 | JAG2 | Jagged-2 | |
LGMD R28 | HMGCR | 3-hydroxy-3-methylglutaryl-CoA reductase | |
LGMD R29 | SNUPN | Snurportin-1 |
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.
LGMD D1 DNAJB6-related (previously limb-girdle muscular dystrophy 1D) (7q36) – DNAJ homolog, subfamily B, member 6. DNAJB6 belongs to the DNAJ/HSP40 family of proteins, and it regulates molecular chaperone activity as a cochaperone (355). DNAJB6 is ubiquitously expressed, including in skeletal muscle, though with the 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 (528).
Mutations affecting the glycine/phenylalanine-rich (G/F) domain of DNAJB6 are most commonly reported, but mutations in the J domain can also cause myopathy (426). These mutations likely interfere with the interaction between DNAJB6 and HSP70, resulting in defective antiaggregant properties and altered protein degradation system in cells – in other words, the mutations contribute to aberrant chaperone function (01; 364; 427). 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) (414).
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 (364). 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 (157). 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 (259). Distal predominant weakness is another manifestation of DNAJB6 mutations. Most patients with LGMD demonstrate no cardiac involvement. Dysphagia can be present (242). 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 (413). Some patients are minimally symptomatic even in the seventh decade of life (543).
EMG shows myopathic changes and some patients can display pseudomyotonic or myotonic discharges (242). 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 (413).
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 (158). 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).
LGMD D2 TNPO3-related (previously limb-girdle muscular dystrophy 1F) (7q32) – Transportin 3. Transportin 3 is a nuclear import receptor that transports Ser/Arg-rich (SR) proteins into the nucleus (296). 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 (483; 08). 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 (176).
Penetrance of the mutation is incomplete and increases with age (150). 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. 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, dysphagia, partial ophthalmoparesis, neck extension, and flexor weakness were only occasionally observed (176; 99).
Muscle MRI shows the atrophy is more prominent in lower than in upper extremities, preferentially in the vastus lateralis and posterior leg compartment (381). There can be sparing of the gracilis and rectus femoris muscles (176). Muscle biopsy findings include increased fiber size variability, fiber atrophy, and acid-phosphatase-positive vacuoles, ragged red fibers, cytoplasmic bodies, and enlarged mitochondria with procrystalline inclusions (81; 176; 99).
Poyatos-Garcia and colleagues developed a patient-derived in vitro immortalized myoblast cell line with the c.2771delA TNPO3 mutation (390). They then used CRSIPR-Cas-9-mediated gene editing to correct the mutation, resulting in significant reversion of the pathological phenotype. This study demonstrates that gene editing technology may be a future therapeutic approach for certain TNPO3 mutations.
LGMD D3 HNRNPDL-related (previously limb-girdle muscular dystrophy 1G) (4p21) – Heterogenous nuclear ribonucleoprotein D-like. 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 (503). The disease has been found in at least four families with mutations affecting the same codon (c. G1132C/A, p.D378H/N) in HNRNPDL (454; 503; 38; 463). The mutation may lead to a loss of function, impacting hnRNPDL self-assembly properties, and accelerating protein aggregation in muscle cells (25).
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 (454; 463). Weakness usually starts in the second to fifth decade. Early onset (younger than 50-years-old), cataracts, and diabetes can also be present. In a Spanish family with a scapulo-peroneal phenotype, cognitive impairment was another characteristic (501). 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 (301).
Muscle MRI shows involvement of vastus muscles, with partial sparing of rectus femoris and biceps femoris and complete sparing of adductor longus (463). Muscle biopsy shows a predominantly myopathic histopathological pattern associated with rimmed vacuoles and autophagic vacuoles (38).
LGMD D4 CAPN3-related (previously limb-girdle muscular dystrophy 1I) (15q15) – Calpain-3. Calpain 3 mutations are one of the most common causes of limb-girdle muscular dystrophy. Interestingly, although CAPN3 mutations usually cause autosomal recessive limb-girdle muscular dystrophy (LGMD R1, formerly LGMD 2A), there have been reports of patients heterozygous for the c.643_663del21 mutation who presented with autosomal dominant limb-girdle muscular dystrophy. 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 (507; 309; 343).
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)] (181). Another missense variant is c.1715G>C p.(Arg572Pro) and another deletion mutation of CAPN3 discovered is c.643_663del (508).
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 (343). For more details on CAPN3 function, clinical features, and potential therapeutics.
LGMD D5 COL6A1-, COL6A2-, COL6A3-related (previously Bethlem myopathy dominant) (21q22, 2q37) – Collagen type VI subunits alpha-1, 2, and 3. 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) (237). Collagen VI is a ubiquitously expressed extracellular matrix protein with roles that are not only mechanical in function but also have cytoprotective functions (117).
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. Others reported cases with similar phenotypes, which eventually led to the identification of collagen VI mutations (237; 326; 51).
Onset is earlier than 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 (236). More than two thirds of patients over 50 years of age are wheelchair bound (236; 253). 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 (241).
Similar to other dominant limb-girdle muscular dystrophy syndromes, an allelic recessive disorder was described: Ullrich congenital muscular dystrophy (51). This congenital-onset muscular dystrophy is associated with proximal joint contractures, distal joint hyperextensibility, scoliosis, and normal intelligence (213; 494). Later, autosomal dominant and recessive patterns were observed in both Ullrich and Bethlem phenotypes. Intermediate manifestations are also common, resulting in clinical variability, including intrafamilial variability (125; 253; 73; 537). The recessive form of collagen VI-related dystrophies is designated as LGMD R22.
Muscle MRI in patients with the previously termed Bethlem myopathy shows 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 more diffuse muscle involvement (317; 140).
The use of skin biopsy with COL6 staining is postulated to facilitate diagnosis (83). 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 (268).
Interestingly, mutations in COL6A3 have also been associated with a form of isolated recessive dystonia (DYT27) (286).
A phase 1 clinical trial with safety measurement for the anti-apoptotic compound omigapil was conducted in patients aged 5 to 16 years old diagnosed with LAMA2- and COL6-related dystrophy (162). Patients in this trial had either congenital muscular dystrophy or childhood onset limb-girdle muscular dystrophy (LGMD D5, LGMD R22, or LGMD R33). The study found that omigapil was safe and well tolerated, but no consistent changes were seen in the disease-relevant clinical assessments (162).
LGMD R (previously autosomal recessive [type 2] limb-girdle muscular dystrophies). This category includes a group of autosomal recessive disorders. Proximal muscles are more severely affected. 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 CAPN3-related (previously limb-girdle muscular dystrophy 2A) (15q15) – Calpain-3. LGMD R1 was the first muscular dystrophy shown to be caused by an enzymatic abnormality rather than a structural muscle protein defect. The 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 (407; 130; 204). 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 and works as a structural protein rather than a protease (139; 359). 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 (191). 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 (425). The protein may also play a role as a switch in muscle remodeling (110). 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 (220).
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 (116). Calmodulin is a positive regulator of CAPN3 activity. Calpain-3 deficient myotubes show increased degradation of sarco/endoplasmic reticulum Ca2+ ATPases (SERCA) proteins (482). 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 (398). Calpain-3 also appears to be important for muscle regeneration, comparing LGMD R1 patient samples from others with LGMD R9 and Becker muscular dystrophy (205). In LGMD R1, frizzled related protein (FRZB) is upregulated and there appears to be a reciprocal relationship between FRZB and CAPN3 (77).
First reported in 37 affected members of two large Amish kindreds, this form of muscular dystrophy was later reported in families from the French Reunion Island near Madagascar and in Brazilian families (230; 30; 372; 152). 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 (146). Several different mutations in the CAPN3 gene have been reported in affected members of these genetically unrelated families. Although nearly 500 distinct mutations have been identified, a small number of mutations underlie the majority of cases (183; 143) (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 (89; 149). Some particularly common mutations include the c.2120A>G mutation in the Chinese population and the c.550del in European populations (541). LGMD R1 is the most common form in France, with 10 to 70 cases per million people (300).
Age at onset ranges from 2 to 45 years; loss of ambulation can occur about 10 to 30 years after onset of weakness. There is no correlation between age of onset and time of wheelchair confinement (415). 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 (385; 67). 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 (332). Respiratory failure usually occurs in advanced disease, although one case with marked respiratory muscle weakness in a still-ambulatory patient has been described (308).
Pizzanelli and colleagues reported a young girl with LGMDR1 and coexistent generalized epilepsy (383). Tsao and Mendell describe a boy with absence seizures, a normal brain MRI, and partial calpain deficiency (485). There is one report of late-onset foot drop as a presenting sign (64). 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.
There is considerable variation in disease severity, including some with isolated hyperCKemia and others with predominantly distal myopathy (149). A feature in some cases of LGMD R1 may be eosinophilic myositis, which has been documented patients with increased creatine kinase (CK) levels and peripheral blood hypereosinophilia (353; 401). Some patients with LGMD R1 may present with a pseudometabolic myopathy, with asthenia, myalgia, exercise intolerance, proximal muscle weakness, and excessive lactate production. Asymptomatic hyperCKemia (five 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 (142). 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 (385; 146; 17; 208; 350; 402; 517; 03; 380; 403; 477; 523; 221). 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 (373).
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 (316). 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 LGMD R1 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 (435). Mitochondrial abnormalities with COX-negative muscles fibers, ragged red fibers and mitochondrial depletion have also been described (133).
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 (143). Whereas some calpain-3 mutations alter the level of protein expression, others alter the autocatalytic enzyme activity without affecting protein expression (147). Fanin and colleagues screened 148 muscle biopsy specimens with normal calpain-3 levels and found that 11% of samples had abnormal autolytic function (145). 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 LGMD 2A patients, carrying 66 different mutations (six 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 (148). 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 (150). 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 (342).
Regarding potential therapeutic options for calpainopathies (LGMD D4 and LGMD R1), myostatin inhibition therapy was attempted for patients with LGMD R1 and resulted in muscle hypertrophy, creating a loss of oxidative capacity and, unfortunately, no increase in muscle function or exercise tolerance (262). In one patient with dominantly inherited calpainopathy (c.643_663del21 mutation), an open-label treatment with low-dose recombinant human growth hormone (somatropin) over 4.5 years improved muscle strength measure with dynamometer and stabilized walking ability (measured by 6-minute walk test) (394). This study suggests a possible role of human growth hormone in limb-girdle muscular dystrophy treatment. Recombinant AAV-mediated calpain 3 transfer has demonstrated improvement in animal studies, but gene therapy clinical trials have yet to occur (300). 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 (416). 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 (311).
LGMD R2 DSYF-related (previously limb-girdle muscular dystrophy 2B) (2p13) – 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 (24), 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 (23). 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 (257; 215). 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 (292). Dysferlin is also thought to have a role in myogenesis, angiogenesis, microtubule dynamics, cytokine secretion, lysosome exocytosis, acid sphingomyelinase secretion, and phagocytosis (94). In mice, dysferlin deficiency confers increased susceptibility to coxsackievirus-induced cardiomyopathy (515). Dysferlin also may play a role in cholinergic signaling in the neuromuscular junction (261). There is also activation of the ubiquitin proteasome system (UPS) and autophagy programs in dysferlinopathy partly due to regeneration and an inflammatory reaction (144). 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 (418).
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 (321). 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) (418). 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 (504). Other clinical presentations in patients with dysferlin mutations include proximodistal weakness, 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 (471). 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 (201).
A wide variety of phenotypes have been observed in the series of DYSF mutations characterized to date (70). 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 (487). Late-onset muscular dystrophy linked to dysferlin mutations has also been reported in a 73-year-old man with proximal muscle weakness (256) and another elderly patient with isolated calf weakness and atrophy and markedly elevated creatine kinase (245). The phenotype does not appear to affect progression or prognosis (370).
Rarely, a rigid spine phenotype can develop. A case report from Japan describes a patient with LGMDR2 and chorea (470). An LGMDR2 patient was reported with coexisting sarcoidosis and autoimmune Addison disease, suggesting a possible link between LGMDR2 and autoimmunity (438). Another report describes a patient with LGMDR2 and minimal change nephropathy with absent dysferlin in the renal glomeruli (229). Rosales and colleagues noted some characteristic features in a cohort of 21 patients (412). 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 (505).
Different phenotypes can occur within families, but affected siblings typically have the same disorder (449; 445). 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 (149). 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 (145).
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 (179). A case report demonstrated some unusual fatty degeneration in the lumbar paraspinalis in an LGMD R2 patient, detected on MRI (251).
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 (400).
In addition, clinically affected heterozygotes have been reported in two Spanish mutations (224). 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 (232).
There are over 250 different gene defects reported (Leiden muscular dystrophy database). 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 (277). Absence of the protein is diagnostic for LGMDR2 (09). However, there are patients with reduced but not absent protein, or dysfunctional dysferlin and some with increased dysferlin expression in Western Blot due to a pathological retention of mutated polypeptide in the cytoplasms (479). 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 (141). A nonquantitative immunoassay that may be used at centers with limited resources for detection of dysferlinopathies from peripheral blood samples has been developed (101).
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 (228).
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 (502). 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 (514). 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 (519). This strategy may prove to be useful in other exons (272). 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 (433). 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 (190). 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 (358). 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 (492).
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 (512). 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 (452). Ibuprofen was detrimental to muscle function in dysferlin-deficient mice (97).
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 (261). 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 (250). However, an improved study protocol did not find diltiazem to have any effect on contraction-induced muscle damage in dysferlin-deficient mice (31). In dysferlin-deficient mice, N-acetylcysteine supplementation reduced oxidative damage to muscles and improved the animals’ grip strength, indicating that this antioxidant could be of benefit to patients with LGMD R2 (170).
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 (186). Additionally, dual AAV vectors to package the DYSF cDNA have shown promise in in vitro and in vivo studies (290; 529). The Sarepta investigational gene therapy program utilizing SRP-6004 uses the dual vector approach and is currently in clinical trials (NCT05906251). This approach was previously successful in dysferlin-deficient mice (451; 388).
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 (124). Another approach has been the injection of plasmids encoding dysferlin to hindlimbs of dysferlin-knockout mice (295; 187).
LGMD R3, 4, 5, and 6 SGCA-, SGCB-, SGCG-, SGCD-related (previously limb-girdle muscular dystrophy 2C-F) (17q21, 4q12, 13q12, 5q33) – Sarcoglycan alpha, beta, gamma, and delta. 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 (361). 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 (459). Mutations in any of the four main subunits often disrupt the sarcoglycan complex, leading to decreased biochemical function, typically loss of staining on biopsy samples, and impairment of cytoskeletal-sarcolemmal integrity (29). In fact, the disease in affected individuals is related to the level of residual function of the glycoprotein complex (07). 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 (193). 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 (102). 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 (443).
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 (354) 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 with type alpha sarcoglycanopathy occurring most commonly (89).
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 (96). 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 (131).
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 (474).
LGMD R3 SGCA-related (previously limb-girdle muscular dystrophy 2D) (17q21) – 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 (312). Adhalin (alpha-sarcoglycan) is an integral component of the dystrophin-associated glycoprotein complex (533). 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 (128).
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 (194). 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 rare 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 seven of 12 heterozygote carriers (161). Missense mutations cause relatively milder phenotypes and variable residual adhalin (alpha-sarcoglycan) expression (382). Severity may be as mild as asymptomatic hyperCKemia and patients may also present with very late-onset cases (357). A case presenting with myoglobinuria has also been described (82).
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 (72).
Muscle MRI shows severe involvement of proximal lower extremity muscles and relative sparing of leg muscles until late stages (72). Paraspinal, pelvic, and glutei muscles can be preferentially affected in mild cases (182).
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 (409). They found that sustained, nontoxic levels of alpha sarcoglycan were produced under muscle creatine kinase promoters (409). Additionally, Griffin and colleagues demonstrated effective delivery and increased protein expression of alpha-sarcoglycan from an AAV vector containing codon-optimized full-length human SGCA transgene in a sgca-nul mouse model (185). 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 (315). 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 (315).
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 (313). 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 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. 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 (185).
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 (365).
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 (476).
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 (74). For the sarcoglycanopathies (LGMD R3, 4, 5, 6), CFTR correctors successfully removed defective sarcoglycans complexes in vitro when the mutations were missense (75).
LGMD R4 SGCB-related (previously limb-girdle muscular dystrophy 2E) (4q12) – 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 (230). Families from northern Indiana were shown to carry calpain-3 mutations discussed above (407). The Amish families from southern Indiana were found to have mutations in the gene coding for beta sarcoglycan (282). Clinical features of beta-sarcoglycan-related limb-girdle muscular dystrophy resemble those of calpain-3-associated limb-girdle muscular dystrophy (LGMD R1). Both LGMD 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 (06).
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 four 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 creatine kinase values is seen with disease progression as there is loss of muscle mass (305). 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 (nine) with both. The entire sarcoglycan complex was absent in nine of 10 severe cases and reduced in seven of seven mild cases. The residual amount of sarcoglycan in muscle was a predictor of age at loss of ambulation (439).
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 (371). Routine surveillance of these patients with early cardiac monitoring 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 (371).
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 (392; 393).
Mendell and colleagues developed the first-in-human gene therapy approach to restore beta-sacroglycan in patients with LGMD R4 (314). Bidridistrogene xeboparvovec is an adeno-associated viral vector with a codon-optimized, full-length human SGCB transgene that was given as part of an open-label, nonrandomized phase 1/2 trial (NCT05876780). Interim results show robust beta-sarcoglycan expression and preliminary motor improvements, with the most frequent adverse events being vomiting and gamma-glutamyl transferase increase that were managed with standard treatments.
LGMD R5 SGCG-related (previously limb-girdle muscular dystrophy 2C) (13q12) – Gamma-sarcoglycan. Early works failed to distinguish this severe childhood autosomal recessive form of muscular dystrophy (SCARMD) from Duchenne dystrophy (274; 456; 513). 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 (349). LGMD R5 is the most frequent limb-girdle muscular dystrophy in North African populations as a result of the founder mutation c.525delT (132). The G787A mutation has been described in unrelated children of Puerto Rican ancestry, suggesting a founder effect (115).
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 (384). 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 (248). A case with episodic myoglobinuria is also reported, a pattern more common in metabolic myopathies or occasionally dystrophinopathies (376). A case of embolic stroke secondary to dilated cardiomyopathy has been described (154). 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 (211).
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 (542). Prominent eosinophilic infiltration, mimicking eosinophilic myositis was described in one patient (27). 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 (120).
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 (209). 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 (227). In a SGCG knockout mouse model, Seo and colleagues utilized an AAV vector containing codon-optimized human SGCG transgene and were able to achieve widespread transgene expression in skeletal and cardiac muscle and well as improved muscle histopathology (440).
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 (88).
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 (210). 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 (526). 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 SGCD-related (previously limb-girdle muscular dystrophy 2F) (5q33) – 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, 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 (129; 538). This is a very severe and quickly progressive disease characterized by generalized muscle weakness (04). Hypermobility of the interphalangeal, metacarpophalangeal, and elbow joints and delayed language development can also be present (517). Distal muscle weakness can be present early in the disease (04). Cardiac and respiratory involvement have also been seen in patients with LGMD R6 (04). In a delta sarcoglycan null mouse, prednisolone, hypothesized to improve cardiac function, actually caused further cardiac damage in animals with cardiomyopathy (26).
LGMD R7 TCAP-related (previously limb-girdle muscular dystrophy 2G) (17q12) – Telethonin. This form of limb-girdle muscular dystrophy was localized to the TCAP gene on 17q11-12 coding for telethonin, a sarcomeric protein (331). 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 patients 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 (62). 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 (100). 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 (538).
Muscle biopsy may show rimmed vacuoles or nemaline rods (363). 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 (223; 87). 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) (67; 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 (294).
LGMD R8 TRIM 32-related (previously limb-girdle muscular dystrophy 2H) (9q33) – Tripartite motif-containing protein 32. 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 (263). It was suggested that TRIM32 is involved in the ubiquitin proteosome pathway, a specialized pathway for post-translational regulation of protein levels (167; 270). 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 (285). Immunostainings for desmin and myotilin, substrates of the TRIM32 E3 ligase, were seen increased in the muscle fibers of patients with LGMD R8 (368). Thin, a Drosophila protein highly analogous to TRIM32, is critical to myofibril stability. Fly mutations in this gene produce muscular degeneration (266). In particular, costameric integrin and sarcoglycan protein levels are altered in a Drosophila model for LGMD R8 (28). TRIM32 also regulates skeletal muscle stem cell differentiation and is necessary for normal adult muscle regeneration and myogenic cell proliferation and differentiation (347; 327). 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 (518). 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).
Frosk and colleagues also describe a Hutterite family with two brothers homozygous for both mutations in TRIM32 and FKRP (165). The mother, father, and five sons were homozygous for a TRIM32 mutation and two of five sons were also homozygous for L276I mutations in FKRP. The double homozygous sons exhibited mild decreases in stamina with normal strength. The homozygous LGMD R8 (TRIM32)/heterozygous LGMD R9 (FKRP) family members were virtually asymptomatic (165). 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, and demyelinating neuropathy was also seen in some affected family members (52). A patient with a scapuloperoneal phenotype has also been identified (280).
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 (239).
LGMD R9 FKRP-related (previously limb-girdle muscular dystrophy 2I) (19q13) – 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 LGMD R9. 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) (244). 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 (207; 265). There is also some evidence of metabolic impairments in FKRP-deficient skeletal muscles (495). 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 (246). 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 (58). 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. There was also an increased expression of endoplasmic reticulum stress markers (164).
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 (60).
(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 (436). 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 (436). 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*) (356).
(3) Individuals with a milder form of LGMD R9 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 (341).
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 (455). The modifiers are unknown. Mouse models of FKRP mutations also show a wide range of disease phenotypes (45).
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 (291; 166; 168; 335; 271).
LGMD R9 was originally described in a large consanguineous Tunisian family and linked to 19q (126). Poppe and colleagues described the clinical features of LGMD 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 (387). Over half had cardiac abnormalities, and half of these developed heart failure (386). 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 (337).
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 (166). 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 (467).
A different mutation in FKRP, A455D, was identified in Tunisian patients with a severe MDC1C phenotype and mental retardation, microcephaly, and cerebellar abnormalities (291). Another phenotype presents as an acute myositis, mimicking viral myositis in infants (509). Of clinical importance, diaphragmatic involvement may cause respiratory insufficiency in patients who remain ambulant (67). Two patients with severe congestive heart failure (severe enough to require cardiac transplantation) but mild muscular findings have been described (306).
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 (47). 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 (434). Myalgias are also common. A case of LGMD R9 and unilateral cataracts (531) and metacarpophalangeal joint hypermobility have been described (516).
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 (430). 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 (521).
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 (517; 527). Cases with only mild adductor magnus fatty infiltration also exist (517). 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 (340).
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 (466).
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 (196). 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 (108). Another patient with necrotizing myopathy in muscle biopsy showed response to steroids, azathioprine, and intravenous immunoglobulin (464). A single-dose treatment of AAV9-FKRP in FKRP P448L 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 (496). Lam and colleagues used a dual FKRP/FST gene therapy construct packed into an AAV vector to treat FKRP P448L mice, with improvement in muscle mass (267). 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 (80).
In a mouse model of LGMD R9, long-term ribitol treatment showed improved muscle pathology and function and increased lifespan without serious side effects (525). ISPD overexpression alone and in combination with ribitol has also been shown to improve dystrophic phenotype in a FKRP mutant mouse model (79). 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 (252). 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 dystroglycan glycosylation to mice who were FKRP deficient, mimicking the LGMD R9 state (15).
LGMD R10 TTN-related (previously limb-girdle muscular dystrophy 2J) (2q24) –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 (195). Titin, the biggest single protein 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 (195). 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 (200), 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 (172). 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 (320).
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 (486). 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 (429). 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 (351; 536).
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 (200). The homozygous phenotype was adopted as autosomal recessive LGMD R10 (538). 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 TTN mutation affects the A band, cardiac problems may occur first or may overlap with or follow skeletal muscle weakness (406). 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 (377). 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 (105).
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 (534).
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 (428). 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.) (428).
LGMD R11 POMT1-related (previously limb-girdle muscular dystrophy 2K) (9q34) – Protein O-mannosyltransferase 1. POMT1 along with POMT2 gene products act to transfer O-mannosyl glycan chains onto alpha-dystroglycan (303).
An autosomal recessive limb-girdle muscular dystrophy with mental retardation was reported in six Turkish families (119). 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 (119), 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; 103) 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 (192).
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 (104). 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 (288).
To date, more than 76 disease-associated POMT1 mutations have been reported in the literature (219). 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 a 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 (174).
LGMD R12 ANO5-related (previously limb-girdle muscular dystrophy 2L) (11p14) – Anoctamin 5. ANO5 is a putative calcium-activated chloride channel and is involved in muscle membrane function and repair (184), but its function is not completely understood (283). ANO5 mutations have been discovered to cause defective annexin coordination during cellular repair (163). Mouse models have also demonstrated that ANO5 mutations cause cytosolic calcium overload with plasma membrane injury, which compromises muscle fiber repair (85). 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 other limb-girdle muscular dystrophies. 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 (212; 297). A Finnish group found eight different mutations in 25% of a varied cohort that included 75% Finnish and varied other origin patients (379). 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. LGMD R2 is relatively rare among Asians. No recurrent mutation has been identified in Asian populations so far (71).
Anoctamin 5 (ANO5) mutations can present as LGMD R12 (LGMD2L) (48), Miyoshi-like distal myopathy type 3, asymptomatic hyperCKemia, and myoglobinuria after exercise (369).
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 LGMD R12. Some patients have calf hypertrophy (218). 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 (281), although early onset of weakness was reported in a woman who did heavy exercise training, which may have caused more sarcolemmal membrane injury (44). Jarry and colleagues described 14 patients from eight different families with asymmetric quadriceps femoris atrophy that evolved into a limb-girdle muscular dystrophy phenotype (233). 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 (243). Some patients are also asymptomatic despite elevated CK levels (431). 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 (493). 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 (498).
Muscle MRI may show asymmetric muscle involvement, but the pattern was not found to distinguish this phenotype from others such as Bethlem myopathy (423). 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 (478). A reported patient had isolated semitendinosus involvement in MRI (473). EMG can show electrical fibrillations, positive sharp waves, myopathic motor units, and electrical myotonia without clinical myotonia (281). 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 (432). ANO5 mutation-related myopathy is the second most common cause of amyloid myopathy after immunoglobulin light-chain amyloidosis (279). 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 (05).
In six patients with LGMD R12, home-based, pulse-watch monitored moderate-intensity exercise on a cycle ergometer for 30 minutes, three 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 (506).
LGMD R13 FKTN-related (previously limb-girdle muscular dystrophy 2M) (9q13) – Fukutin. 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 FKTN gene, the same gene that causes Fukuyama congenital muscular dystrophy (177). 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 (244). 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 (488; 484).
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 (408). The CK values decreased with steroid treatment in one patient (450).
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 (169). Another allelic variant presents as dilated cardiomyopathy with little or no muscle involvement (339). Defects in this gene are a recognized cause of childhood-onset muscular dystrophy without mental retardation (395) and can also present with asymptomatic hyperCKemia (160).
LGMD R14 POMT2-related (previously limb-girdle muscular dystrophy 2N) (14q24) – 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 (42).
A case series of 12 patients provides a better description of LGMD R14 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 another 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 (360).
In 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 (307). 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 (159).
Muscle biopsy shows dystrophic changes with selective reduction of alpha-dystroglycan immunostaining (61).
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 (304; 214). 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 (93).
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 (397).
LGMD R16 DAG1-related (previously limb-girdle muscular dystrophy 2P) (3p21) – 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 (119; 198).
A mild, late-onset limb-girdle muscular dystrophy presentation is also possible (106). A boy with DAG1 mutations and asymptomatic hyperCKemia, calf pseudohypertrophy, and mild dystrophic changes in muscles has also been described (123).
DAG1 mutations are also associated to congenital muscular dystrophy (dystroglycanopathy) with Walker-Warburg syndrome with tectocerebellar dysraphia (273).
LGMD R17 PLEC-related (previously limb-girdle muscular dystrophy 2Q (8q24) – Plectin. Plectin is a large intermediate filament-binding protein that helps maintain cytoskeleton stability and neuromuscular junction integrity (524). PLEC mutations can cause LGMD R17, different types of epidermolysis bullosa simplex, and congenital myasthenic syndrome (524; 180). 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 (405).
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 (189). 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 (153). 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; 491).
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 (480).
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 with dystrophic changes, ptosis, facial weakness, fatiguability, and muscle cramps (333). They had clinical improvement with pyridostigmine and salbutamol and also had a common 3.8 Mb haplotype (333).
LGMD R18 TRAPPC11-related (previously limb-girdle muscular dystrophy 2S) (4q35) – Trafficking protein particle complex, subunit 11. 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 (319; 453). TRAPPC11 mutations are associated with congenital muscular dystrophy with fatty liver and infantile-onset cataracts and also myopathy and intellectual disability, including cerebral atrophy, scoliosis, achalasia, and alacrima (a form of triple A syndrome) (258).
LGMD presentation was described in eight Syrian and Hutterite patients with progressive weakness that started at 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 cataracts, 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 (269).
Brain MRI showed mild cerebral atrophy in two patients (46; 156) and multifocal diffusion abnormalities in other cases (269). Muscle MRI shows preferential involvement of the posterior leg compartment (269).
LGMD R19 GMPPB-related (previously limb-girdle muscular dystrophy 2T) (3p21) – 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 and, therefore, result in secondary dystroglycanopathy (76; 90). GMPPB-related disorders are autosomal recessive and cause a variety of clinical syndromes with variable severities, including congenital muscular dystrophy with brain and eye abnormalities, limb-girdle muscular dystrophy, and exercise intolerance with rhabdomyolysis (90). Mutations in GMPPB can also alter the glycosylation of subunits of the acetylcholine receptor resulting in defective neuromuscular junction transmission, thereby causing congenital myasthenic syndrome (33; 293; 329; 90). More than 50 pathogenic mutations have been reported for GMPPB-related disorders, with missense mutations being the most common (90). LGMD R19 (previously LGMD 2T) is the most common clinical disorder associated with GMPPB mutations and can manifest in childhood or adulthood.
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 (76).
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 patterns. Episodic rhabdomyolysis as the only symptom was also reported (69). Asymptomatic hyperCKemia and pseudometabolic myopathy or exercise intolerance have also been described (234; 367). 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 muscle biopsy as well as other myopathic changes and reduced alpha-dystroglycan expression (76; 69; 90). Combined pre- and post-synaptic defects of neuromuscular transmission with low-frequency repetitive nerve stimulation can be seen in proximal muscles but spares the facial muscles (348; 90). Muscle MRI in patients with LGMD R19 shows consistent findings of a preferential affection of paraspinal and hamstring muscles (352).
In patients with GMPPB-related disorders who have evidence of defective neuromuscular junction transmission, treatment with acetylcholinesterase inhibitors, such as pyridostigmine, 3,4-aminopyridine, or salbutamol, may be beneficial and result in some improvement in strength and endurance (410). 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 a decrease in CK value (155).
LGMD R20 ISPD-related (previously limb-girdle muscular dystrophy 2U) (7p21) – Isoprenoid synthase. 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 (92; 475).
LGMD R21 POGLUT1-related (previously limb-girdle muscular dystrophy 2Z) (3q13) – Protein O-glucosyltransferase 1. POGLUT1, 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 one. 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 (442). Later, Servian-Morilla and colleagues reported a cohort of 15 patients with LGMD R21, from nine unrelated families coming from different countries (441). Age of onset varied from congenital and infantile onset to adult-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 (441).
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 (399). Galli-Galli disease, an acantholytic variant of Dowling-Degos disease, has also been reported with POGLUT1 mutations (260).
LGMD R22 Collagen6-related (previously Bethlem myopathy recessive) (21q, 2q) – collagen type VI subunits alpha-1, 2, and 3.
LGMD R22 COL6A1-, COL6A2-, COL6A3-related (previously Bethlem myopathy recessive) (21q22, 2q37) – Collagen type VI subunits alpha-1, 2, and 3. As discussed in the LGMD D5 section, collagen VI, formed from three different subunits encoded by the genes for COL6A1, COL6A2, and COL6A3, is an abundant protein of the extracellular matrix that is involved in multiple cellular processes of tissues including muscle (117). Autosomal dominant and recessive muscular dystrophies result from mutations in the genes for collagen VI and compromise varied phenotypes, with the commonality of a limb-girdle pattern of weakness often associated with joint laxity that is often distal, as well as predominantly proximal contractures (51). Musculoskeletal manifestations, including foot and ankle deformities, scoliosis, and acetabular dysplasia, can occur (448).
LGMD R23 LAMA2-related (6q22) – Laminin alpha-2. 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.
Similar to other limb-girdle muscular dystrophies, there is variability in the severity and age of onset of autosomal recessive muscular dystrophies attributed to LAMA2 mutations. Severe congenital muscular dystrophy type 1A (MDC1A) results from complete merosin deficiency, whereas a milder late-onset limb-girdle phenotype is often associated with partial merosin deficiency (424). LAMA2-related muscular dystrophies can affect both the central and peripheral nervous systems (424). Common clinical features of LAMA2-related muscular dystrophies include axial and proximal weakness, joint contractures, spinal rigidity, scoliosis, and neuromuscular respiratory insufficiency (424; 54). Patients can also have mild mental retardation; white matter changes in brain MRI; dilated cardiomyopathy; peripheral neuropathy, usually demyelinating; and decreased bone mineral density (84; 287; 121; 202; 54). Migraines and epilepsy are other common presentations (298). Onset of symptoms in limb-girdle muscular dystrophy ranges from childhood to adulthood and some patients have independent ambulation and only mild symptoms (121).
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 areas more affected than the center (in mild cases) (458; 84). The sartorius and gracilis muscles were spared. With muscle ultrasound, Bouman and colleagues found the sternocleidomastoid and the biceps brachii muscles to be the most severely affected and the soleus muscle to be the least affected muscle (54). Besides muscle tissue, skin biopsy may show absence or reduced laminin alpha-2 at the dermal-epidermal junction (202). Brain MRI may show diffuse white matter changes similar in appearance to a leukodystrophy even independent of clinical symptoms attributable to the central nervous system (424). Symmetric high signal in the bilateral globus pallidus has also been described (202). 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 (422).
Gene replacement using AAV9 vectors carrying the mini-agrin, which is a 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 (396). Much research has been concentrated on MDC1A, but some results are likely applicable to LGMD R23 as well (173; 231; 249; 02; 199). A phase 1 trial of the anti-apoptotic compound omigapil was conducted in children aged 5 to 16 years old with LAMA2-related dystrophy and showed that the compound was safe and well tolerated, but no consistent changes were seen in the disease-relevant clinical assessments (162).
LGMD R24 POMGNT2-related (3p22) – Protein O-linked mannose beta-1,4-N-acetylglucosaminyl-transferase 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 (197). Patients with POMGNT2 mutations can have proximal weakness consistent with a limb-girdle muscular dystrophy phenotype or hyperCKemia and often have mild intellectual disability without brain malformation (135). However, a case report of a young Moroccan girl identified a novel homozygous missense mutation in POMGNT2 (c.511 G> A, p.Asp171Asn) associated with brainstem dysplasia and agenesis of the pellucid septum in association with dysmorphic facial features, as well as delayed motor development indicating a more severe phenotype from POMGNT2 mutations similar to Walker-Warburg syndrome or muscle-eye-brain disease (78).
LGMD R25 BVES-related (6q21) – Popeye domain-containing protein 1 (encoded by the BVES gene). The Popeye domain-containing proteins (POPDC) are transmembrane proteins that are highly expressed in skeletal and cardiac muscle as well as smooth muscle tissues (57). The BVES gene encodes for the Popeye domain-containing protein 1 (POPDC1), which is a negative regulator of adenylyl cyclase 9 (ADCY9)-medicated cAMP signaling and involved in maintaining muscle homeostasis (276). 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 (225). Additional studies show that homozygous loss-of-function and missense variants in BVES result in various myopathy presentations (exercise intolerance, myalgias, hyperCKemia, and proximal weakness) in addition to cardiac conduction defects (114).
LGMD R26 POPDC3-related – POPDC3 (6q21) – Popeye domain-containing protein 3. This muscular dystrophy is related to the dysfunction of Popeye domain-containing protein 3, which modulates membrane trafficking of interacting proteins (57). Patients will have mildly elevated creatine kinase and can present with proximal weakness in the upper and lower extremities or with exercise intolerance and myalgias (489; 540; 113). Cardiac dysfunction is not usually seen.
LGMD R27 JAG2 related (14q32) – Jagged-2. Notch signaling is essential for regulation of multiple developmental and tissue homeostasis processes, and mutations in genes encoding Notch receptors or ligands lead to a variety of disorders (310). JAG2 is one of five Notch ligands involved in the Notch signaling pathway. Homozygous or compound heterozygous JAG2 variants have been identified in several families with a limb-girdle myopathy phenotype. Onset of weakness can occur in infancy through young adulthood with prominent lower extremity and axial involvement leading to significant gait abnormalities and loss of ambulation (98; 122). Lower extremity MRI of the proximal muscles, particularly the quadriceps, typically shows fatty transformation that progresses from the periphery inwards revealing small central areas of less affected muscle (98; 122).
LGMD R28 HMGCR-related (5q13) – 3-hydroxy-3-methylglutaryl-CoA reductase. HMGCR is important in the cholesterol synthesis pathway and is the rate-limiting enzyme that converts 3-hydroxy-2methylglutaryl coenzyme A (HMG-CoA) to mevalonate. As such, HMGCR inhibition is the target of statin medications to lower cholesterol. Previously, two acquired myopathies, statin-associated myopathy (SAM) and autoimmune anti-HMGCR myopathy, were associated with HMGCR. Bi-allelic variants in HMGCR have been attributed to a recessively inherited limb-girdle muscular dystrophy (330; 532). Using in vitro Hmgcr knockdown mouse skeletal myoblast and a Drosophila model lacking Hmgcr, Gunasekaran and colleagues demonstrated that Hmgcr deficiency led to impaired myotube fusion, decreased proliferation, and increased apoptosis (188). Additionally, protein activity studies of HMGCR variants from affected individuals demonstrated decreased enzyme activity and reduced protein stability (330).
Individuals affected by LGMD R28 can present in early childhood with progressive proximal weakness, hypotonia, delayed motor milestones, or onset of symptoms in later adulthood with myalgias and fatigue followed by proximal weakness (330; 532). The proximal weakness is most prominent in the deltoids and hip flexors and hip adductors as well as the neck flexors and extensors, with relative sparing of the biceps, triceps, and wrist flexors and extensors (330; 532). One patient had facial and bulbar weakness with dysphagia (330). Rate of progression varied but could be rapid in some individuals, leading to loss of ambulation. Respiratory insufficiency was common, but cardiac involvement has not been reported (330; 532). Muscle biopsy demonstrated nonspecific dystrophic changes (330).
Yogev and colleagues synthesized and purified an oral formulation of mevalonolactone, the lactone form of mevalonate, the downstream metabolite of HMGCR (532). After completing toxicology studies in wild-type mice, they obtained approval from the Israeli Ministry of Health to treat a single patient under expanded use/compassion treatment. The patient had both subjective and objective improvement in muscle strength as well as respiratory measures, with minimal adverse effects. The authors indicate further clinical trials of mevalonolactone will take place in the future.
LGMD R29 SNUPN-related (12q24) – Snurportin-1. SNUPN is a nuclear transport protein of small nuclear ribonucleoproteins (snRNPs), essential to the spliceosome. Defects lead to splicing and mRNA dysregulation (226; 345). Patients develop symptoms of proximal weakness in infancy to childhood with elevated creatine kinase and progress to gait abnormalities. Most patients develop contractures and spinal abnormalities, such as scoliosis or rigid spine. Respiratory insufficiency is common and progresses to severe respiratory failure in some patients. Facial muscles are unaffected, and cardiac abnormalities are rare. Congenital bilateral cataracts are present in several patients, along with some central nervous system findings, including cerebellar atrophy and thinning of the corpus callosum on imaging (345). Muscle biopsies show endomysial fibrosis, variability in fiber size with internalized nuclei, reduced oxidative activity, rimmed vacuoles, cytoplasmic abnormalities, and some features similar to myofibrillar myopathy.
LGMD R (number pending) – PYROXD1-related (12p12) – Pyridine nucleotide-disulfide oxidoreductase domain 1. The PYROXD1 gene has been attributed to congenital muscular dystrophies as well as myofibrillar myopathy. However, there have been several case reports of patients with a limb-girdle phenotype presenting in childhood or even adulthood (289; 417; 107; 109). Therefore, this disorder may be added to the limb-girdle muscular dystrophies in the future.
Reclassified conditions (no longer considered in the current limb-girdle muscular dystrophy classification)
When the European Neuromuscular Center LGMD workshop study group met to discuss the nomenclature and classification of limb-girdle muscular dystrophy subtypes in 2017, some prior subtypes were removed from the classification scheme because they did not respect the criteria (460). These disorders are briefly mentioned here. Of note, the ClinGene Muscular Dystrophies and Myopathies gene curation expert panel (MDM GCEP, formerly Limb Girdle Muscular Dystrophy GCEP) published their evaluation of the strength of evidence supporting gene-disease relationships regarding limb-girdle muscular dystrophy classified subtypes. They reported POMGNT1 and DAG1 are related to myopathy disorders but currently have insufficient evidence to support a specific limb-girdle muscular dystrophy relationship (324). Therefore, the current classified subtypes are likely to evolve based on additional evidence and expert review.
The updated limb-girdle muscular dystrophy subtypes removed the following disorders (460; 53).
MYOT-related (previously LGMD 1A) – 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 (419). Mutations in myotilin have also been documented in cases of myofibrillar myopathy, cardiomyopathy, peripheral neuropathy, and distal myopathy (437). This disorder was removed because the predominant phenotype is distal weakness.
LMNA-related (previously LGMD 1B) – 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 (497). This disorder was removed due to its high risk of cardiac arrhythmias and the Emery-Dreifuss muscular dystrophy phenotype.
CAV3-related (previously LGMD 1C) – Caveolin-3. 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 (490). CAV3 mutations are associated with rippling muscle disease, hyperCKemia, and myalgias.
DES-related (previously LGMD 1E and LGMD 2R) – Desmin. Desmin plays a role in sarcomere connections allowing for the formation of myofibrils (53). DES variants are often associated with cardiomyopathy and distal weakness, hence, its removal from the limb-girdle muscular dystrophy classification.
Chromosome 3p23-p25-related (previously LGMD 1H). The associated gene/protein has not been identified; hence, it was removed from the limb-girdle muscular dystrophy classification.
GAA-related (previously LGMD 2V) – Alpha-1-4-glucosidase. GAA encodes the lysosomal enzyme acid alpha-glucosidase, and mutations are the cause of Pompe disease, which is considered a separate myopathy from the limb-girdle muscular dystrophies.
LIMS2-related (previously LGMD 2W) – Lim and senescent cell antigen-like domains 2 protein. 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 (86). At the time of the classification, this disorder was reported in only one family and did not fulfill the criteria.
TOR1A1P1-related (previously LGMD 2Y) – Torsin 1A-interacting protein 1. During cell division, the TOR1A1P1 protein functions as a link between the nuclear membrane and lamina (53). At the time of the classification, this disorder was reported in only one family and did not fulfill the criteria.
Epidemiology
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• Most limb-girdle muscular dystrophies are inherited as autosomal recessive traits. | |
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• Autosomal dominant limb-girdle muscular dystrophies are relatively uncommon. | |
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• 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 to 5.75 per 100,000) after dystrophinopathies, myotonic dystrophies, and facioscapulohumeral muscular dystrophy (299). |
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 to 5.75 per 100,000) after dystrophinopathies, myotonic dystrophies, and fascioscapulohumeral muscular dystrophy (299).
Autosomal dominant limb-girdle muscular dystrophy is relatively rare and has been reported primarily in isolated families (346; 456; 40; 11; 91; 326; 468; 366). 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 (66).
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%) (343). Calpainopathy (LGMD R1, CAPN3 mutation) is the most common limb-girdle muscular dystrophy in American and European countries except Denmark, where LGMD R9 (FKRP mutation) is 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 (336).
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 (49; 500; 284). 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 (178).
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 (134). This dystrophy is caused by alterations in the emerin gene mapped to the chromosome Xq-locus (43; 255). 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 (50; 334).
Facioscapulohumeral muscular 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. 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 (247). In familial neurogenic scapuloperoneal syndrome, EMG and muscle biopsy typically show a neurogenic process (472).
Myotonic dystrophy is usually evident based on 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 (447; 56), nemaline rod myopathy (446), central core disease (127), multicore disease (136), congenital fiber-type disproportion (59), desmin myopathy (216), and myopathy with tubular aggregates (411) 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 to mutations in KBTBD13 starting at age 50 has also been described (171). Careful histochemical studies of muscle specimens will help clarify the diagnosis of congenital myopathies along with genetic testing.
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 (238). 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 (118).
The mitochondrial myopathies represent a large and heterogeneous group of disorders that may have various morphological and biochemical characteristics (118). 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 (264). The presence of fasciculations, relatively diffuse weakness, 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 (362). 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 (217). MRI, particularly of the adductor magnus, in all patients with limb-girdle muscular dystrophy showed fatty replacement with no edema (217). 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 (530). Once a limb-girdle muscular dystrophy syndrome is suspected, a combination of muscle biopsy analysis, analysis of protein components of muscle (immunohistochemistry or 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 and some acquired myopathies. 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 autoimmune inflammatory myositis, dermatomyositis, and anti-synthetase syndrome. 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 autoimmune myositis lack a few or many characteristic clinical and laboratory features and can mimic limb-girdle muscular dystrophy. A high index of suspicion, close clinical monitoring, and adequate clinical trial of immunosuppression therapy in suspected cases of autoimmune myositis are important discriminators. The presence of myositis specific antibodies is highly specific for an acquired autoimmune myositis and not for genetic disease (302).
Immune-mediated necrotizing myopathy associated with anti-HMGCR (3-hydroxy-3-methylglutarylcoenzyme A reductase) antibodies or anti-SRP (signal recognition protein) can mimic limb-girdle muscular dystrophy or present with hyperCKemia. Testing for anti-HMGCR and anti-SRP antibodies should be considered in patients with limb-girdle muscular dystrophy or hyperCKemia, and negative genetic testing as immunotherapy is associated with clinical improvement (325).
Dysferlinopathy (LGMD R2) is probably most likely to masquerade as 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.
Inclusion-body myositis is an inflammatory myopathy that may be confused with limb-girdle muscular dystrophy. Inclusion-body myositis is differentiated from limb-girdle muscular dystrophy by pattern of weakness (typically weakness in the distal finger flexors and quadriceps) and characteristic histopathological changes including rimmed vacuoles with beta-amyloid inclusions (481; 499).
Various endocrine and toxic myopathies are other treatable disorders that must be differentiated from limb-girdle muscular dystrophy (55; 444). Myopathies due to treatment with chloroquine (520) and cholesterol-lowering agents (511) are examples of toxic myopathies, but these compounds are not usually taken at the most common ages of onset for limb-girdle muscular dystrophy.
Associated or underlying disorders
Common associated conditions, such as respiratory insufficiency and cardiac abnormalities, were discussed in the detailed limb-girdle muscular dystrophy subtype sections.
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 an elevation in the serum concentration of various muscle enzymes (338; 378). 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. 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, and they tend to decrease with age and with disease duration. Overall creatine kinase is raised roughly 2x to 350x in recessive cases and is normal to increased 6x in dominant patients (66).
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, polyphasic, low-amplitude motor unit potentials with early recruitment. 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 (206). 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 inexpensive 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 (222). 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 (222).
Muscle MRI. Muscle MRI can be used to identify patterns of muscle involvement, muscle sparing, and peculiar characteristics of different muscular dystrophies. Muscle MRI 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 (404).
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 (63). Muscle biopsy samples in general are characterized by several nonspecific pathological changes similar to those observed in other dystrophies (374). 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 other muscular dystrophies (374; 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 (LGMD R2), 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 (111).
Histochemical studies disclose nonspecific changes typical of primary muscle disease (95). 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 (374; 421). 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 (183; 143). 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 (175). This approach increases diagnostic yield and leads to discovery of new genes and phenotypes (254; 328; 429; 203; 402; 535). It is worth mentioning that repeat disorders, such as facioscapulohumeral muscular dystrophy or myotonic dystrophy, should be excluded if the phenotype is more suggestive of these disorders. 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 (522). 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 the 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. Therefore, supportive care is the principal management strategy. Patients with limb-girdle 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 genetic counseling) 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.
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 patients with limb-girdle muscular dystrophy. Patients should be assessed for assistive devices, such as appropriate orthoses, walking aids, or wheelchairs. In LGMD R9 and LGMD R1, low-intensity training resulted in an increase in endurance and strength in a small study (465). 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 (32).
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 who have a subtype of limb-girdle muscular dystrophy associated with cardiac abnormalities or if a patient has an abnormal EKG, syncope, near-syncope, or palpitations (344). A study suggested surveillance with cardiac MR for limb-girdle muscular dystrophy patients, as MR can detect cardiac involvement earlier than echocardiogram or EKG, especially because patients with limb-girdle muscular dystrophy whose cardiac function is affected may manifest with preserved left ventricular volume and left ventricular ejection fraction despite dilated cardiomyopathy (420).
Regarding swallowing function, patients with dysphagia, frequent aspiration, or weight loss should be referred for swallowing evaluation and speech/swallow therapy 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). When dysphagia or risk of aspiration is severe, it is important 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.
Patients with limb-girdle muscular dystrophy and severely impaired mobility may be at risk for osteopenia or osteoporosis; therefore, calcium and vitamin D supplementation should be considered. Serial dual-energy x-ray absorptiometry (DEXA) scan to assess bone health may be indicated, and an endocrinology referral should be considered for management if osteopenia or osteoporosis is diagnosed.
In the last 2 decades, significant research has been underway to develop molecular and genetic therapies to target not only limb-girdle muscular dystrophies but many other neuromuscular disorders as well. Multiple approaches, such as using antisense oligonucleotides to skip exons or alter splicing, developing small interfering RNA to knock down mutant allele mRNA, utilizing viral vectors for gene delivery, or employing gene editing technology, are being studied in several different limb-girdle muscular dystrophy subtypes. Several excellent reviews summarize these advances in therapeutic development (469; 391; 53; 389). Potential or upcoming experimental treatments were discussed in each section for the specific limb-girdle muscular dystrophy subtypes.
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 (278). 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.
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Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
Stacy Dixon MD PhD
Dr. Dixon of UCHealth Neurosciences Center received honorariums from Argenx for service on a scientific advisory board.
See Profile
Editor
-
Aravindhan Veerapandiyan MD
Dr. Veerapandiyan of University of Arkansas for Medical Sciences has no relevant financial relationships to disclose.
See Profile
Former Authors
- Ashok Verma MD DM
- Tanya A Fatimi MD
- Louis H Weimer MD
- James Wymer MD PhD
- Hsin-Pin Lin MD PhD
- Tiffany Eisenbach MD
- Varun Jain MD
- Miguel Chuquilin 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-10
-
- Muscular dystrophy: G71.0
- Limb-girdle muscular dystrophy (LGMD): G71.03
- Autosomal dominant LGMD: G71.031
- Autosomal recessive LGMD due to calpain-3 dysfunction: G71.032
- LGMD due to dysferlin dysfunction: G71.033
- LGMD due to sarcoglycan dysfunction, unspecified: G71.0340
- LGMD due to alpha sarcoglycan dysfunction: G71.0341
- LGMD due to beta sarcoglycan dysfunction: G71.0342
- LGMD due to other sarcoglycan dysfunction: G71.0349
- LGMD due to anoctamin-5 dysfunction: G71.035
- Other LGMD: G71.038
- LGMD, unspecified: G71.039
- ICD-11
-
- Limb-girdle muscular dystrophy: 8C70.4
- Dominant limb-girdle muscular dystrophy: 8C70.40
- Recessive limb-girdle muscular dystrophy: 8C70.41
- Other specified limb-girdle muscular dystrophy: 8C70.4Y
- Limb-girdle muscular dystrophy, unspecified: 8C70.4Z
- OMIM
-
- LGMD D1: 603511
- LGMD D2: 608423
- LGMD D3: 609115
- LGMD D4: 618129
- LGMD D5: 158810 (listed under Bethlem myopathy 1A)
- LGMD R1: 253600
- LGMD R2: 253601
- LGMD R3: 608099
- LGMD R4: 604286
- LGMD R5: 253700
- LGMD R6: 601287
- LGMD R7: 601954
- LGMD R8: 254110
- LGMD R9: 607155
- LGMD R10: 608807
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