Neuromuscular Disorders
Neurogenetics and genetic and genomic testing
Dec. 09, 2024
Worddefinition
At vero eos et accusamus et iusto odio dignissimos ducimus qui blanditiis praesentium voluptatum deleniti atque corrupti quos dolores et quas.
Distal myopathies …
- Updated 09.18.2024
- Released 12.19.1994
- Expires For CME 09.18.2027
Distal myopathies
Introduction
Overview
The distal myopathies are an expanding group of muscle diseases with the uncharacteristic pattern of predominant weakness in the feet or hands. Rapid advances in our understanding of the underlying gene defects of these myopathies have, to date, separated more than 20 distinct disorders, and many are yet without characterization. In this article, the authors provide an updated classification of distal myopathies and discuss the genetically identified forms along with new genetic mutations that have been associated with distal myopathy.
Key points
|
• Distal myopathies are still frequently confused with Charcot-Marie-Tooth types of neurogenic disorders. | |
|
• Distal myopathies are a group of rare heterogenous disorders that represent 10% of all muscular dystrophies. | |
|
• Muscle imaging is an adjunct diagnostic tool for targeting optimal sites for muscle biopsy and possibly for suggesting diagnostic alternatives. | |
|
• Many genetic forms are late-onset, such that a positive inheritance may be missed. | |
|
• Many underlying gene defects occur as “de novo” mutations with negative family history. |
Historical note and terminology
Distal myopathy as a clinical term is usually credited to Gowers, who in 1902 described distal weakness in a young man, most likely a case of juvenile onset recessive oculopharyngeal distal myopathy (26). However, the term had been used earlier by others, and the first family with a dominant distal myopathy may have been described by the Russian neurologist V Roth in his book on muscular atrophies in 1893. Subsequently, a number of cases were reported as having distal myopathy, but only the family described in 1943 by Milhorat and Wolff was ever confirmed to have a distal myopathy when a mutation in the desmin gene was later identified (85). The disease described by Welander in 1951 was long the prototype of distal myopathy. She described 249 patients from 72 Swedish pedigrees under the title of “myopathia distalis tarda hereditaria” (Welander distal myopathy) with onset in the hands. Between 1974 and 1993, four new entities were clinically defined: (1) late-onset distal myopathy of the lower leg with autosomal-dominant inheritance described by Markesbery and colleagues in 1974 (55); (2) autosomal recessive Miyoshi myopathy with early adult onset in the calf muscles (59); (3) autosomal-recessive distal myopathy with rimmed vacuoles, described by Nonaka and colleagues, with early adult onset in the anterior lower leg muscles (65); and (4) late-onset autosomal-dominant tibial muscular dystrophy (Udd myopathy) with lower-leg anterior compartment involvement (93).
A new era for the distal myopathies began with the progress of molecular genetics in the 1990s. The first disorder linked to a chromosomal locus was that of an Australian family with dominant early-onset distal myopathy (MPD1) (46), and the others soon followed: Miyoshi myopathy (04), distal myopathy with rimmed vacuoles (36), tibial muscular dystrophy (33), and Welander distal myopathy (02). The responsible gene encoding dysferlin was identified for Miyoshi myopathy in 1998 (52), mutations in M-line titin were identified as the cause of tibial muscular dystrophy in 2002 (29), and mutations in GNE were found in distal myopathy with rimmed vacuoles in the same year (63).
Distal muscle weakness and atrophy is frequently the presenting symptom and sign in myopathies otherwise characterized by the histopathological findings of myofibrillar myopathy, including accumulations of desmin and other proteins. This is particularly true for gene defects in ZASP, myotilin, and desmin. In fact, ZASP proved to be the responsible gene in the classic late-onset distal myopathy family reported by Markesbery (27). During the last decade, a number of new entities of distal myopathy have been delineated by molecular genetic definition, making all previous classifications obsolete. However, from a clinical and diagnostic perspective, to narrow the field of gene candidates a broad separation in groups based on genetic transmission and age of onset is still meaningful:
|
(1) Late adult-onset autosomal dominant forms | |||
|
(a) Welander distal myopathy (101) | |||
|
(2) Adult-onset autosomal dominant forms | |||
|
(a) Desminopathy (85) | |||
|
(3) Early-onset autosomal dominant forms | |||
|
(a) Myosinopathy MYH7 (MPD1) (46) | |||
|
(4) Early-onset autosomal recessive forms | |||
|
(a) Distal nebulin myopathy (99) | |||
|
(5) Early adult-onset autosomal recessive forms | |||
|
(a) Dysferlinopathy (59) | |||
|
(6) Adult-onset autosomal recessive form | |||
|
(a) Miyoshi-like non-DYSF/ANO5 (50) | |||
|
(7) X-linked distal myopathy | |||
|
(a) Small muscle protein X (SMPX)-linked distal myopathy (42) | |||
Clinical manifestations
Presentation and course
Clinical manifestations in distal myopathies vary depending on the underlying genetic abnormality. Weakness may start in the hands (Welander myopathy), the posterior compartment of the lower legs (Miyoshi and Miyoshi-like myopathies), or the anterior compartment of the legs (most distal myopathies) with resultant foot drop. As the disease progresses, involvement of the proximal, bulbar, and respiratory muscles may occur, depending on the underlying disorder. MRI may reveal abnormalities beyond what can be detected clinically. Age of onset also varies and ranges from childhood to late adulthood (for example up to 77 years of age in Welander). CK ranges from normal to mildly elevated, but it can be significantly high as in dysferlin myopathy. Electromyography usually shows myopathic changes in the motor units (reduced duration and amplitude and early recruitment), but a mixed picture with neurogenic change in the motor units (increased duration and amplitude) can also be seen with long-standing myopathy.
It is not uncommon for distal myopathies to be misdiagnosed as Charcot-Marie-Tooth neuropathy. Normal sensory examination and normal sensory responses on nerve conduction study, preserved or hypertrophic extensor digitorum brevis, and myopathic changes on electromyogram indicate distal myopathy. Such differentiation may become more difficult in the presence of superimposed acquired neuropathy or radiculopathy.
Welander distal myopathy
Symptoms and signs. Onset of weakness, typically in the index finger and wrist extensors, usually appears in the fifth to sixth decade, followed by atrophy of thenar and intrinsic hand muscles. Finger and wrist flexor weakness may develop after several years of disease progression in 40% of cases. Ankle dorsiflexion weakness occurs in 25% of cases and may be the presenting symptom in 10% (15). Proximal weakness is uncommon. Deep tendon reflexes are preserved in early stages. Patients may complain of cold fingers, but sensory findings by clinical examination are normal (08). The progression is slow, and patients have a normal life expectancy.
Laboratory features. EMG shows small motor unit potentials with early recruitment, fibrillations, and complex repetitive discharges. Nerve conduction velocities are normal. Serum creatine kinase (CK) level is slightly elevated. Muscle biopsy in affected muscles shows degenerated fibers and dystrophic changes. Vacuoles have been reported by some but not all investigators (15). Muscle imaging is informative, with considerable involvement of posterior calf muscles besides fatty degenerative changes in the anterior compartment (01). Because not all calf muscles are involved, ankle plantar flexion weakness is not apparent in early stages.
Molecular genetics. Welander distal myopathy was linked to chromosome 2p13 (02). In Scandinavian patients, a common founder haplotype can be identified over the linked locus, and the founder mutation responsible for the disease was identified in the TIA1 gene (31). The gene is involved in RNA metabolism and stress granule functions, and the mutation alters stress granule dynamics in muscle fibers.
Tibial muscular dystrophy (TMD, Udd myopathy)
Symptoms and signs. Weakness of ankle dorsiflexion usually occurs after 35 to 40 years of age but may start as early as 25 or as late as after 60 years of age. Weakness and tibial anterior atrophy may be asymmetric for years, and progression is slow. Moderate proximal weakness in the lower extremities is present in the eighth decade, and most patients remain ambulant. Typically, extensor digitorum brevis and hand muscles are spared (92). Phenotypic variants are observed in 9% of the patients (94). In Finland, tibial muscular dystrophy is the most common muscle disease, with an estimated prevalence of 20/100,000. Tibial muscular dystrophy patients with Finnish ancestry have been identified in Sweden, Norway, Germany, and Canada. Tibial muscular dystrophy families without Finnish background have been identified in France, Belgium, Spain, and Italy (14; 96; 30; 75).
Laboratory features. Findings on EMG include low-amplitude, short-duration motor unit potentials, fibrillation potentials, and high-frequency or complex repetitive discharges in tibial anterior muscles. Serum CK is normal or slightly elevated. Muscle imaging reveals selective fatty degeneration in lower leg anterior compartment muscles. Later lesions are observed in hamstring and gluteus minimus muscles. Focal lesions may occur in soleus and medial gastrocnemius muscles (93).
Muscle biopsy in mildly affected muscles shows variation of fiber size, thin atrophic fibers, central nuclei, internal structural changes, and endomysial fibrosis. In the tibialis anterior muscle, there are frequently rimmed vacuoles (though this is not a consistent finding) and rare necrotic fibers. Rimmed vacuoles can be seen in other muscles. Changes progress to total fatty replacement in the end-stage muscle. There is secondary calpain 3 protein reduction in the homozygous state (15).
Molecular genetics. Mutations causing this phenotype are located in the C-terminus of the giant sarcomeric protein titin. The Finnish founder mutation (FINmaj) is a complex 11 bp insertion-deletion mutation changing four amino acids (29). Point mutations were identified in unrelated French and Belgian families with tibial muscular dystrophy (14; 96), truncating mutations in the last and second to last exons of titin in Spanish and French families (30), and a point mutation in the last exon in an Italian family with tibial muscular dystrophy (75). Sequencing the last three titin exons is the diagnostic method of choice in new families without Finnish ancestry.
ZASPopathy (Markesbery-Griggs late onset distal myopathy, autosomal dominant)
Symptoms and signs. Most reported families are of Central European descent. Onset of symptoms is after 40 to 50 years of age, with ankle weakness and progressing slowly to involve finger and wrist extensor and causing moderate proximal weakness late in life. Walking ability may be lost after 15 or 20 years of disease duration. Facial, bulbar, and respiratory muscles are not affected. Very late cardiomyopathy with heart block requiring a pacemaker has been described (55); postmortem examination revealed vacuoles in the myocardium.
Laboratory features. EMG shows small amplitude motor-unit potentials with early recruitment in affected muscles. CK levels are normal or mildly elevated. By MRI imaging, the earliest muscle changes can be found in medial gastrocnemius and soleus even before subjective symptoms. Later, all lower leg muscles are involved with moderate changes only in proximal leg muscles. Muscle biopsy shows clear myofibrillar abnormality with rimmed and non-rimmed vacuoles, dark and hyaline structures in the trichrome stain, and myofibrillar disintegration on EM. Cytoplasmic aggregations contain ectopic dystrophin, desmin, myotilin, and alphaB-crystallin (27).
Molecular genetics. The main ZASP (Z-disc alternatively spliced PDZ-domain containing protein, also termed LDB3 gene) mutations identified are two ancient European founder mutations (27). One is the A165V, and the other recurring ZASP mutation, A147T, causes an identical phenotype.
Distal myotilinopathy (autosomal dominant, often sporadic)
Symptoms and signs. Myotilinopathy was originally identified in two families with the dominant limb-girdle phenotype (LGMD1A). Later experience has shown that most patients with myotilinopathy present with late-onset distal myopathy (81). Weakness of ankle plantar- or dorsiflexion begins between 50 and 60 years of age (67). Pains and cramps may also be the first symptoms. Progression can be marked, including upper limbs and proximal leg muscle weakness and loss of ambulation 10 years after onset. Dysphonia or respiratory defects are rare in the distal phenotype (70; 71).
Laboratory features. Myopathic changes with fibrillations and complex repetitive discharges are present in affected muscle groups on EMG. CK levels vary from normal to 2- to 3-fold increased or up to 15-fold. Extensive fatty degenerative changes in calf muscles and milder proximal leg muscle involvement can be shown by muscle imaging. Muscle biopsy findings are indistinguishable from those in ZASPopathy. Myotilin mutations were also shown in the pathologically defined spheroid body myopathy (22).
Molecular genetics. Almost all myotilin mutations are located within the second exon, coding for a serine-rich domain of the Z-disc protein. Rare mutations outside this exon may cause proximal limb-girdle phenotype with no major myofibrillar pathology.
Vocal cord and pharyngeal distal myopathy (VCPDM, MPD2, autosomal dominant)
Symptoms and signs. An autosomal dominant myopathy characterized by distal upper and lower extremity weakness and prominent symptoms of vocal cord and pharyngeal weakness was reported by Feit and colleagues in 1998 (19). Onset varied from 35 to 60 years of age, with weakness starting either in ankle and toe extensors or in finger extensors.
Laboratory features. EMG showed mild slowing of velocities and myopathic potentials. Serum CK levels were normal or up to 8-fold increased. Muscle biopsy showed frequent rimmed vacuolated fibers.
Molecular genetics. The disease in the original family and in one other family is caused by a missense mutation in a protein of the nuclear matrix called Matrin3 (83).
Valosin-containing protein-mutated distal myopathy (autosomal dominant)
Symptoms and signs. Valosin-containing protein mutations have been associated with multisystem disease including inclusion body myopathy, Paget disease, frontotemporal dementia (IBMPFD), and motor neuron disease-like presentation. Muscle weakness usually showed a proximal or scapuloperoneal distribution (45). A valosin-containing protein-mutated family with a late-onset pronounced distal myopathy was indistinguishable on clinical grounds from Welander distal myopathy or tibial muscular dystrophy (68). Paget disease was not part of this distal phenotype, the myopathy was slowly progressive, and frontotemporal dementia occurred very late with a rapidly progressive lethal course.
Of note, similar cases of multisystem proteinopathy with no valosin-containing protein mutations were identified in association with mutations in hnRNPA2B1 and in hnRNPA1 (44).
Sequestosome1 distal myopathy
Symptoms and signs. SQSTM1 mutations are associated with dominantly inherited distal myopathy with rimmed vacuoles. The muscle weakness starts in the leg anterior compartment. CK ranges from normal to mildly elevated. The vacuoles are positive for transactive response DNA binding protein 43 (TDP-43). Similar to velosin-containing protein mutations, SQSTM1 mutations were reported in Paget disease of the bones, amyotrophic lateral sclerosis, and frontotemporal dementia (09). In a genetic study of sporadic inclusion body myositis (sIBM), a candidate gene analysis was conducted using whole-exome sequencing data from 181 sIBM patients, and whole-transcriptome expression analysis was performed in patients with genetic variants of interest (24). This study identified rare missense variants in 4% of sIBM patients, out of which two variants, the SQSTM1 p.G194R and the VCP p.R159C, were significantly overrepresented as compared to controls.
Alpha-B crystallin-mutated distal myopathy (autosomal dominant or autosomal recessive)
Symptoms and signs. A few patients and families with mutated CRYAB have been described previously with distal and proximal muscle weakness, particularly of the legs, combined with cataracts and dilated cardiomyopathy (97). A report describes a distinct late-onset distal myopathy without cardiomyopathy, respiratory dysfunction, or significant cataracts and with rimmed vacuolar myopathology associated with the G154S mutation (77). CK is mildly elevated, and histopathology shows myopathy with desmin accumulation.
TAR DNA binding protein of 43 kDa (TDP-43) distal myopathy
Symptoms and signs. Zibold and colleagues reported two French families with adult-onset progressive distal weakness and atrophy (105). Onset was in the upper extremities in four patients, whereas five patients either had lower extremity onset or their hands and legs were affected simultaneously. Progressive weakness predominantly affected the hand and finger extensors and the anterior and lateral leg muscles without any fasciculation or upper motor neuron signs. It spread slowly to to all four extremities, involving bulbar and respiratory musculature without requiring tube feeding or respiratory support during the day. Asymmetry was reported in six of nine patients.
Laboratory features. EMG showed myopathic changes without neurogenic changes. CK levels ranged from normal to mildly elevated up to 500 IU/l. MRI and CT scans showed distal muscle atrophy, which correlated with the examinations (predominant in the posterior forearm muscles and anterior leg muscles). Muscle biopsies revealed chronic myopathic changes with rimmed vacuoles but no neurogenic changes.
Molecular genetics. Though TARDBP mutations have been associated with an inherited form of amyotrophic lateral sclerosis, these two families with French distal myopathy had a novel c.1127G>T substitution in the TARDBP gene. This gene encodes a mutant TDP-43 protein harboring a G376V variant protein. The variant was not present in a database covering human genome variation. This expands the spectrum of neuromuscular disease associated with the TARDBP gene.
ADULT-ONSET DOMINANT DISTAL MYOPATHIES
Desminopathy (autosomal dominant or autosomal recessive)
Symptoms and signs. The first reported distal myopathy family, later confirmed to be a true myopathy, had desminopathy (58; 35; 85). Juvenile or early adult-onset distal leg weakness with signs of cardiomyopathy or respiratory failure and fairly rapid progression of symptoms should lead the clinician toward the desmin gene. Most primary desminopathies show increased cytoplasmic desmin aggregations together with general myofibrillar myopathy findings and occasional rimmed vacuoles. However, the classic scapuloperoneal syndrome of Kaeser, originally reported to be a neurogenic disease, was found to be caused by desmin mutation. The myofibrillar pathology was very mild, and aberrant cytoplasmic protein aggregation was minimal (100). Pathology may not always be highly myofibrillar myopathic in desminopathy.
Distal upper limb filaminopathy (autosomal dominant)
Symptoms and signs. In ABD filaminopathy, the first symptoms are weakness of handgrip in the early 20s followed by thenar atrophy and calf weakness in the 40s. The progression is very slow, and most patients remain ambulant despite late proximal limb weakness (102; 16). In Bulgarian families with mutations in C-terminal FilaminC the first symptoms, occurring later in the 30s to 50s, were atrophy of first interosseus muscles with more finger extension than flexion weakness followed later by lower limb weakness (28). Respiratory muscle involvement occurs in half of cases.
Laboratory features. EMG is myopathic, and muscle biopsy findings are nonspecific. Rimmed vacuoles are lacking and, in particular, no pathology of myofibrillar myopathy type is present in ABD filaminopathy, whereas an occasional rimmed vacuole and some myofibrillar disorganization can be observed in C-terminal filaminopathy. CK levels are normal or mildly (up to eight times) elevated.
Molecular genetics. The mutated gene is FLNC, encoding muscle-specific filamin C protein. The gene is previously known to cause myofibrillar myopathy with a late-onset proximal and distal phenotype. In that case, the mutations are located in the central or more distal part, whereas in the case of distal ABD filaminopathy the mutations are located in the N-terminal actin-binding domain (ABD) (16); in a case of upper limb C-terminal distal filaminopathy, a truncating nonsense mutation was found in the C-terminus (28).
Oculopharyngeal distal myopathy, OPDM (autosomal dominant or autosomal recessive)
Symptoms and signs. The first symptom is either oculopharyngeal weakness (ptosis, ophthalmoplegia, dysarthria, dysphagia) or limb weakness. The onset is in adulthood in most reported cases, but it could also be earlier in life. There are cases of childhood onset. Cardiac and respiratory involvement have been reported in some cases (17; 40; 13; 66; 80).
Laboratory features. EMG revealed myopathic units in a majority of patients (17; 13), and some patients had myotonic discharges (17). CK ranged from normal to more than 2000 IU/L (17; 13; 66). Muscle MRI showed mild to severe fatty replacement, affecting the distal muscles more than the proximal ones (13). Myopathic changes and rimmed vacuoles were typical findings on muscle biopsy; however, in addition, there were intranuclear inclusions on immunostaining and ultrastructural studies in the muscles or other organs (66; 80). These inclusions were positive for p62 and ubiquitin.
Molecular genetics. Few genetic abnormalities linked to oculopharyngeal distal myopathy have been identified. Expansion of GGC repeat in GIPC1 was found in a few families with oculopharyngeal distal myopathy and multiple sporadic cases (13). Saito and colleagues reported CGG repeat expansion in LRP12 in a father and son with adult-onset oculopharyngeal distal myopathy (80). CGG expansion in NOTCH2NLC was found to be associated with oculopharyngeal distal myopathy with peripheral and central neurologic manifestations (66). Pathological evidence of similar neurologic and systemic involvement was found in an autopsy of a patient with LRP12 CGG expansion (80). Zeng and colleagues reported GGC repeat expansion in RILPL1 as the cause of oculopharyngeal distal myopathy type 4 in two families from central China (103).
DNAJB6b mutations distal-onset myopathy (autosomal dominant)
DNAJ family is a homolog of heat shock protein 40 (HSP40) and regulates molecular chaperone activity by stimulating ATPase activity and associating with HSP70. DNAJB6b mutations are linked to LGMD1D and 1E (proximal weakness), but they have been reported in association with distal onset myopathy of the legs more than the arms with early bulbar involvement in some cases. CK is mildly elevated, and EMG shows myopathic changes. Rimmed vacuoles are a typical finding on muscle biopsy. Mutations causing a complete loss in the G/F domain or affecting distal amino acids (96 and 100) are associated with distal myopathy whereas mutations affecting the proximal part of the G/F domain tend to cause limb-girdle pattern (79).
HSPB8 mutations myopathy (autosomal dominant)
Although DNAJB6b is associated with a chaperone-assisted selective autophagy complex, HSPB8 is a part of the same complex. HSPB8 mutations, which were reported previously with Charcot-Marie-Tooth 2L and distal hereditary motor neuronopathy IIa, were also found in two families associated with early onset autosomal dominant distal myopathy of the anterior legs more than the arms with rimmed vacuoles and myofibrillar pathology (25). CK levels ranged between 250 and 2000 U/L, and EMG demonstrated motor axon loss type neuropathy.
ACTN2 mutations distal myopathy (autosomal dominant)
Symptoms and signs. Chen and colleagues reported three members of a Chinese family with adult-onset distal myopathy; the myopathy was associated with cardiac muscle involvement in two of them (10).
Laboratory features. CK was normal, but EMG showed irritative myopathy. A muscle biopsy was done on one patient and showed several minicores, predominantly in type 1 fibers, in addition to other myopathic changes and fiber type grouping.
Molecular genetics. A novel frameshift pathogenic variant was identified in the ACTN2 gene using whole exome sequencing. This variant prolonged the original stop codon, resulting in a C-terminal extension of the protein.
CASQ1 mutations distal myopathy (autosomal dominant)
Symptoms and signs. Zhang and colleagues reported a 42-year-old female with slowly progressive upper extremity weakness, predominantly distal (104). The patient also had proximal weakness in the upper extremities, mild right scapular winging, and atrophy in the ulnar forearm muscles.
Laboratory features. CK was normal. EMG showed findings consistent with chronic myopathy, with myotonic discharges and complex repetitive discharges. Muscle biopsy showed myopathic changes in addition to empty vacuoles, fine eosinophilic granules, and type 1 fiber predominance.
Molecular genetics. A novel heterozygous mutation in the sixth exon of the Calsequestrin 1 (CASQ1) gene was identified. Calsequestrin 1 is a crucial calcium-binding protein localized in the sarcoplasmic reticulum. Previous reports of mutations in this gene were associated with proximal myopathy.
EARLY-ONSET DOMINANT DISTAL MYOPATHIES
Laing distal myopathy (MPD1, autosomal dominant)
Symptoms and signs. The first symptoms of weakness of ankle dorsiflexion, neck flexors, and a hanging big toe usually appear in early childhood. Weakness of finger extensors, shoulder muscles, scoliosis, and milder proximal weakness may occur. The progression is very slow, and most patients remain ambulant (46).
Laboratory features. EMG is myopathic, and muscle biopsy findings may be compatible with congenital fiber-type disproportion. Rimmed vacuoles are usually not present in most cases. CK levels are normal or mildly elevated. Muscle MRI shows increased signal and atrophy in the tibialis anterior muscle, extensor halluces longus, extensor digitorum longus, sartorius, and medial head of the gastrocnemius with involvement of the extensor digitorum communis only in the upper extremity (56). Using myosin heavy chain (MyHC) immunohistochemistry, fiber types may be abnormally distributed in the affected tibial anterior muscle, showing very atrophic and hybrid type1 fibers expressing also fast MyHC (47). The pathology may also include sarcoplasmic bodies (88).
Molecular genetics. The mutated gene is MYH7 encoding slow beta myosin heavy chain protein, which is the main myosin isoform in type 1 slow muscle fibers and in the heart. Interestingly, cardiopathy is only occasionally part of the phenotype in Laing distal myopathy. All mutations causing this phenotype are located in the tail region of the MYH7 heavy chain dimer, whereas mutations in other parts of the protein may cause cardiomyopathy without skeletal myopathy (57).
Tropomyosin 3 (TPM3) mutated distal myopathy (autosomal dominant)
Symptoms and signs. Two patients with childhood-onset, predominantly distal myopathy were previously identified from a large Australian family with nemaline myopathy secondary to a mutation in TPM3 (37). Chen and colleagues reported a 35-year-old male who developed finger weakness in his early twenties, followed by proximal upper extremity weakness and distal lower extremity weakness in his thirties (11).
Laboratory features. The patient with adult-onset disease had normal CK level and nonirritative myopathy on EMG. His lower body MRI showed fatty infiltration in proximal and distal muscles most prominent in the sartorius and extensor digitorum longus muscles. The muscle biopsy in the childhood-onset cases showed nemaline rods, but in the adult-onset case, it showed nonspecific myopathic changes without rods.
Molecular genetics. The childhood cases were associated with a known mutation in the large Australian family (M9R mutation in TPM3), whereas a novel heterozygous variant of the TPM3 gene was thought to be pathogenic in the adult-onset case.
Kelch-like homologue 9 (KHLH9) mutated distal myopathy (autosomal dominant)
Symptoms and signs. Onset of symptoms in later childhood appeared with weakness of ankle dorsiflexion in the, so far, only known German family. Later patients have atrophy of intrinsic hand muscles, and the progression is very slow in that most patients remain ambulant despite later proximal limb weakness (12).
Laboratory features. EMG is myopathic with no clear findings of neuropathy on electrophysiological studies despite the late clinical finding of mild distally decreased sensation. Muscle biopsy findings are myopathic without rimmed vacuoles. CK levels are mildly to moderately elevated.
Molecular genetics. The mutated gene is KHLH9, encoding a kelch-like homologue protein, and the missense mutation in the only known family was p.L95F (12). The mutation reduces association with Cullin 3 in the Kelch-like homologue 9-Cullin 3-E3 ubiquitin ligase complex, which is involved in ubiquitin-dependent protein degradation.
Distal upper limb POLG1 mutated distal myopathy
Symptoms and signs. Two patients were reported with early onset distal upper limb atrophy, developing also distal lower limb and generalized weakness with cataracts (74).
Laboratory features. EMG is myopathic and muscle biopsy findings reported in one patient showed a few ragged red fibers. CK levels are slightly elevated. Brain MRI was reportedly normal.
Molecular genetics. Multiple deletions of mtDNA were present in the muscle biopsy, leading to a search for genes responsible for mtDNA replication. Two different novel mutations in the polymerase domain of POLG1 were identified.
BICD2 (Bicaudal D, Drosophila, homolog 2) mutated distal myopathy
Symptoms and signs. Early childhood onset of distal lower limb weakness presented in six patients from Germany (five patients were related), with calf atrophy and inability to walk on their toes (95). There was also a case of adult-onset in a Brazilian patient with more predominant anterior compartment involvement (86). The inheritance pattern is autosomal dominant.
Laboratory features. EMG reveals myopathic and neurogenic changes. CK is normal to mildly elevated. Muscle MRI showed changes in the distal muscles (more in the anterior compartment in the Brazilian patient and more in the posterior compartment in the German patients). Proximal muscle changes on MRI were reported in the patients from Germany. Muscle biopsy shows nonspecific myopathic changes, but Unger and colleagues also reported type 1 fiber predominance and neurogenic changes (95).
Molecular genetics. Three different mutations in the BICD2 gene were reported in association with the cases above. Mutations in BICD2 gene were also reported to cause autosomal dominant spinal muscular atrophy with lower extremity predominance 2 (SMALED2) and hereditary spastic paraplegia (95).
Distal myopathy variant secondary to RYR1 mutation
Symptoms and signs. One patient was reported with childhood onset hand stiffness but weakness in the hands in late adulthood involving finger extensors and sparing finger flexors. He also has jaw contracture (48). Subsequently, three families with calf-predominant myopathy were reported to have RYR1 mutations without any episode of malignant hyperthermia or rhabdomyolysis (43). The majority (eight of 10 cases) had evidence of Achilles tendon tightness, and three had additionally mild proximal muscle weakness.
Laboratory features. CK was mildly elevated in the first reported patient, but in the later report, some family members had elevation up to 10 times the upper normal limit. EMG showed irritative myopathic changes in most patients. Muscle biopsy of the first reported patient showed features consistent with centronuclear myopathy and radial distribution of sarcoplasmic strands. In the family members with predominantly calf myopathy, muscle biopsies showed increased central nucleation and core pathology.
Molecular genetics. The first patient was on whole exome sequencing a compound heterozygote for a pathogenic variant in RYR1 and a missense variant of unknown significance in the same gene. Interestingly, the patient’s son, who has elevated CK and diffuse myalgia, carries only the pathogenic variant in RYR1 gene. Two of the three reported families harbored previously unreported RYR1 mutations.
Distal myopathy secondary to collagen XII mutation
Symptoms and signs. Six patients from four independent families were reported (61). The three pediatric patients had proximal and distal weakness. The three adult patients had weakness limited to distal muscles with the anterior leg compartment being more affected than the posterior leg compartment (32). onset of weakness in adult patients was in the fourth decade, but they had mild transient motor delay in childhood that did not affect function in the second or third decades. Five patients had joint hyperlaxity.
Laboratory features. CK was normal in all patients. EMG showed myopathic changes in most patients. Two patients underwent muscle biopsy. One muscle biopsy was normal, and the other one showed type 1 fiber predominance and ring fibers in addition to nonspecific myopathic changes.
Molecular genetics. Three families had dominant glycine missense variants, and one family had a heterozygous, intragenic, in-frame deletion of exon 52 of COL12A1. All pathogenic variants resulted in increased intracellular retention of collagen XII in patient-derived fibroblasts in addition to loss of extracellular, fibrillar collagen XII deposition. In vitro small interfering RNAs targeting the mutant allele containing the exon 52 deletion showed a near-complete correction of collagen XII staining patterns.
EARLY-ONSET RECESSIVE DISTAL MYOPATHIES
Distal nebulin myopathy (autosomal dominant)
Symptoms and signs. Weakness in extensor muscles of the ankles and toes is present already in childhood with later weakness of extensors of fingers and hands. The phenotype is very similar to Laing myopathy, although neck flexor weakness is less marked. The progression is slow, and patients do not have major disability in adult life (99).
Laboratory features. EMG shows myopathic or mixed findings. CK is normal or mildly elevated. Muscle imaging reveals selective fatty degeneration in the anterior tibial muscles. Biopsy of affected distal muscle may show scattered and grouped atrophic fibers mimicking neurogenic changes. Light microscopy does not reveal nemaline rods, but small rod-like structures may be observed on electron microscopy (99).
Molecular genetics. Disruptive recessive mutations in the nebulin gene cause severe and classic nemaline myopathy. Patients with this milder distal phenotype have two missense mutations in the large gene (99).
Allelic variant: distal nemaline myopathy. Recessive childhood onset distal myopathy with nemaline rods on light microscopic muscle pathology and compound heterozygous nonsense or truncating mutations in nebulin has been identified (49).
ADSSL1 mutation myopathy
Park and colleagues reported four patients from two unrelated Korean families who presented with early onset distal weakness and mild facial weakness but no bulbar involvement. Whole exome sequencing showed ADSSL1 mutation, which was found to be pathogenic through in vitro and in vivo assays using myoblast cells and zebrafish models. The patients had more anterior leg compartment involvement clinically, but the MRI showed more fatty replacement in the gastrocnemius muscles. Onset was between 13 and 15 years of age, and CK was mildly elevated. Muscle biopsy revealed rimmed vacuoles in three patients and only chronic myopathic changes in the fourth patient (69).
EARLY ADULT-ONSET DISTAL MYOPATHIES
Distal myopathy with rimmed vacuoles (DRMV, Nonaka myopathy, autosomal recessive)
Symptoms and signs. The first patients were reported from Japan, and later the disease was reported in many other populations. Weakness of ankle dorsiflexors and toe extensors appear in the second or third decade, causing foot drop and a steppage gait. Patients develop proximal weakness with relative sparing of quadriceps muscles and may be wheelchair-dependent 10 to 15 years after onset (65).
Laboratory features. EMG shows small amplitude and brief motor-unit potentials and fibrillation potentials. CK level is increased 3- to 4-fold. Rimmed vacuolar pathology is the most prominent finding on muscle biopsy, but it is not specific and can be present in many other myopathies. Autosomal dominant inheritance, late age of onset, and severe cardiomyopathy favor these other myopathies over distal myopathy with rimmed vacuoles (15). On electron microscopy 15- to 18-nm filamentous inclusions in the nucleus and cytoplasm in addition to the autophagic vacuoles are observed.
Molecular genetics. The mutated gene UDP-N-acetylglucosamine 2 epimerase/N-acetyl mannosamine kinase (GNE) was first identified in patients with quadriceps sparing myopathy in the Middle East (hereditary inclusion body myopathy, h-IBM) (18). Later, the same gene was confirmed in Nonaka DRMV families (63).
Miyoshi myopathy (MM, autosomal recessive)
Symptoms and signs. Onset of symptoms is between 15 to 25 years of age with weakness and atrophy of the calf muscles (59; 60). The anterior lower leg muscles are occasionally affected at onset (38). Proximal muscles in legs and arms are always involved later, and the two phenotypes of dysferlinopathy, Miyoshi myopathy, and LGMD2B eventually merge into one (39). Hamstring muscle groups are usually weaker than the quadriceps, and the deltoid is usually spared even with biceps atrophy (51; 78). About one third of patients can no longer walk within 10 years from onset. Patients with Miyoshi myopathy were first reported from Japan and have later been diagnosed in many populations, with an overall frequency of dysferlinopathies of 1 in 1 million.
Laboratory features. EMG is myopathic with small amplitude motor-unit potentials and spontaneous activity. Motor-unit potentials with increased amplitude and duration and reduced recruitments can be seen in the gastrocnemius muscle due to chronicity and severity of the disease in this muscle. Serum CK levels range from 10 to 150 times the upper normal limit. CK elevation is usually present for years prior to the onset of weakness (03). Muscle MRI shows selective involvement of the posterior compartment muscles and may show the “diamond on quadriceps” sign due to bulging of a portion of the quadriceps femoris toward the anterolateral aspect of the midthigh on contraction (76). Muscle biopsy findings are dystrophic with fiber necrosis and regeneration and without rimmed vacuoles. There is necrosis and degeneration of muscle fibers, and in some mutations, there is marked inflammation that may lead to a misdiagnosis of polymyositis. The diagnosis of Miyoshi myopathy relies on absent dysferlin on immunohistochemical staining of sections or on Western blotting. Partial reduction in dysferlin expression can be secondary to other disorders such as limb-girdle muscular dystrophies (73). True dysferlin abnormality can be confirmed through monocyte testing for dysferlin western blot (23) or through genetic testing that has become more readily available in recent years.
Molecular genetics. Identical mutations in the dysferlin gene on chromosome 2p13 can cause both distal Miyoshi myopathy and proximal onset LGMD2B (52). The patterns of muscle involvement may be distinct at onset even if the phenotypes are indistinguishable at a late stage.
Distal anoctaminopathy (ANO5, autosomal recessive)
Clinical and genetic features. Patients and families with a Miyoshi myopathy-like phenotype but without dysferlin mutations have been identified with mutations in another gene, ANO5, coding for a calcium-activated chloride channel anoctamin-5. The clinical phenotype, including age of onset and initial calf muscle weakness and atrophy, as well as the very high CK levels and nonspecific dystrophic myopathology, can be very similar to dysferlin-mutated Miyoshi myopathy (07). In patients with compatible phenotype (especially if asymmetric involvement is observed) but with negative genetic testing for dysferlin mutation, this gene is a first-choice candidate (72).
Telethonin-mutated distal myopathy
Symptoms and signs. One patient was reported with adult-onset foot drop, which progressed over time and became associated with proximal weakness in the lower extremities. There was no weakness in the upper extremities 25 years after the symptoms’ onset (06). The patient did not have evidence of cardiomyopathy or gastrointestinal involvement, which are reported in association with the more common limb girdle early onset form.
Laboratory features. CK was normal. EMG showed myopathic pattern. Muscle biopsy showed myopathy with frequent rimmed vacuoles and mild type I fiber predominance.
Molecular genetics. The patient had next-generation sequencing, which revealed a homozygous pathogenic variant in the telethonin gene. Western blot using antitelethonin antibody revealed an absence of signal in the patient’s muscle.
Prognosis and complications
In desminopathy, associated cardiomyopathy and respiratory muscle involvement needs monitoring. In the case of valosin-containing protein mutated distal myopathy, Paget disease cannot be excluded even if it was not present in the primary distal myopathy family, and late dementia is a lethal complication.
Clinical vignette
A 28-year-old man was examined because of walking difficulties and occasional calf pain during exercise. He was the youngest of five children. The patient's older brother had high serum creatine kinase values, but neurologic and cardiac examinations revealed no abnormalities.
On clinical examination, all the patient's muscles had normal bulk except the calf muscles, which were atrophic. He could not walk on his toes and was unable to hop on one foot. Tendon reflexes were preserved, and there was no sensory abnormality.
His serum creatine kinase value was 12,000 U/L and did not vary on repeated examinations. The creatine kinase-MB band isoenzyme was within normal range, and ECG showed no abnormality. EMG examination revealed myopathic changes that were more pronounced in the calf muscles but also detectable in other muscles. T1-weighted MR images showed bilateral leg muscle degeneration and fatty replacement in the gastrocnemius muscles. There was no involvement of the thigh muscles. The patient had two muscle biopsies, the first from the vastus lateralis and the second from the gastrocnemius. Only mild myopathic changes (increased number of central nuclei and increased variation of fiber size) were seen in the vastus lateralis muscle, but the gastrocnemius showed almost an end-stage picture, with frequent necrotic fibers and increased fat and connective tissue.
The clinical picture and laboratory findings are compatible with early adult-onset type 2 (Miyoshi) distal myopathy.
X-LINKED DISTAL MYOPATHY
SMPX distal myopathy
Symptoms and signs. Johari and colleagues reported 10 patients from nine families in five different countries with adult-onset distal myopathy with early finger extension and ankle dorsiflexion weakness (42). Some patients had scapular winging. There was no respiratory or cardiac involvement, nor hearing loss.
Laboratory features. CK was mostly mildly elevated, but one patient had a normal level. EMG was myopathic in all patients, and MRI showed early involvement of the anterior compartment of the legs followed by the posterior compartment, then late involvement of the thigh muscles (more in the hamstrings). The muscle biopsies showed general myopathic changes, but in addition, there were rimmed vacuoles and sarcoplasmic inclusions that stained positive with antibodies against SMPX, SQSTM1/p62, SMI-31, ubiquitin, and the SMPX-interacting protein, vinculin.
Molecular genetics. Missense mutations in the small muscle protein X-linked (SMPX) gene were identified as the cause of this distal myopathy. Of note, a missense mutation in the SMPX gene, which is expressed in the hair cells of the inner ear, was identified as the cause of hearing loss without a muscle disease. It was thought that the hearing loss mutation is a loss-of-function mutation whereas the myopathy ones are gain-of-function mutations that result in an accumulation of mutant protein.
Biological basis
Etiology and pathogenesis
Distal myopathies are heterogenous genetic disorders.
Molecular pathomechanisms in distal myopathies. The group is genetically heterogeneous, and many different molecular pathways will be involved. However, it is striking that most genes responsible for distal myopathies known to date code for structural proteins of the sarcomere. The reason for the preferential involvement of distal muscles when these proteins are defective is not understood (90).
Molecular pathomechanisms in late-onset dominant distal myopathies and myofibrillar myopathies. Most late-onset dominant distal myopathies are pathologically characterized by the abundance of rimmed vacuolated fibers. In the myofibrillar myopathies, these rimmed vacuoles are also part of the pathology, suggesting that some of the degenerative pathways may be shared. However, in the myofibrillar myopathies the more prominent changes are the disintegrated myofibrillar structures, disorganized Z-discs, and abnormal accumulation of proteins (81). These lesions include desmin, dystrophin, neural cell adhesion molecule NCAM, gelsolin, and beta-amyloid precursor protein but do not contain myosin, telethonin, actin, or alpha-actinin. Myotilin and alphaB-crystallin reactivity in the aggregations has proved to be a very sensitive histopathological marker. The pathomechanism of protein aggregation is apparently a dominant negative effect of the mutant allele. Overexpression of mutant desmin protein (L385P) in cultured cells formed intracytoplasmic aggregates, and the majority of these cells died within 72 hours by apoptosis, suggesting a direct toxic effect of the aggregation-prone mutant protein (87). Mutations in filamin C and BAG3 were identified in myofibrillar myopathy families (98; 82). Almost half of the myofibrillar myopathy cases are explained by mutations in these genes. Interestingly, the new distal ABD-filaminopathy, with N-terminal mutations decreasing actin binding, does not develop myofibrillar myopathology, and the new C-terminal dominant nonsense mutation is thought to be pathogenic by haploinsufficiency. Mutations in other sarcomeric proteins such as C-terminal titin cause rimmed vacuolar pathology without apparent protein aggregations. Slow myosin heavy chain and nebulin are usually not associated with rimmed vacuolar pathology. The myopathology in a FINmaj-KI mouse model of titinopathy was ameliorated by decreasing calpain-3 expression.
The mutated gene is KHLH9, encoding a kelch-like homologue cytoplasmic protein, which is a partner of cullin 3, and the missense mutation in the only known family was shown to decrease the binding of KHLH9 protein with Cul3 (12).
Molecular pathogenesis of DMRV/HIBM. GNE is the rate-limiting enzyme in the biosynthesis of sialic acid. GNE is a ubiquitous molecule, encoded by a single gene. Sialic acid modification of glycoproteins and glycolipids is crucial for their function in many biological processes, including cell adhesion and signal transduction. Hyposialylation of proteins in affected muscles has been proposed in Nonaka distal myopathy with rimmed vacuoles (64). This was confirmed in a mouse model that showed benefit from treatment with sialic acid metabolites (54), whereas a human study of such replacement was announced to be negative. An NIH-funded study in GNE myopathy is forthcoming.
Molecular pathomechanisms of dysferlinopathy and anoctaminopathy. Dysferlin is implicated in many cellular functions and has been studied in detail for its involvement in membrane repair mechanisms. Calcium-sensitive domains may mediate vesicular membrane formation and fusion to reseal membrane disruptions. ANO5 has not yet been studied in great detail, but a similar mechanism has been proposed (41). The upregulation and activation of dysferlin by corticosteroids is of interest in this pathway (05).
Epidemiology
The overall frequency of distal myopathy is low, but in populations with distinct founder mutations, as with the Finnish population, distal myopathies may even constitute the most frequent single muscle disease in the population. In Finland, the distal titinopathy is estimated to have a prevalence of 20/100,000.
Prevention
No preventive measures are known for any of the distal myopathies.
Differential diagnosis
Many distal myopathies are still misdiagnosed as axonal neuropathies, and other diagnostic errors have been observed, such as sporadic inclusion body myositis, work-related entrapment neuropathy, and radiculopathy instead of tibial muscular dystrophy, as well as polymyositis instead of dysferlinopathy and anoctaminopathy.
Another important point is that many other myopathies may present a pattern of weakness compatible with distal myopathy. This is frequently observed in facioscapulohumeral muscular dystrophy, myotonic dystrophy, sporadic inclusion body myositis, and less frequently with caveolinopathy (89), DNM2-mutated centronuclear myopathy (21), TPM2 mutated rod-core myopathy, metabolic brancher and debrancher glycogenoses, PNPLA2 lipidosis, and nephrotic cystinosis. Clinical overlap also exists with the group of scapuloperoneal syndromes.
Nations and colleagues reported nine of 236 patients with myasthenia gravis (3%) to have distal weakness exceeding proximal weakness (62). Hands muscles, mainly the finger extensors, were more frequently affected than distal leg muscles.
Juvenile onset sporadic/recessive oculopharyngodistal myopathy has been described in a few reports and certainly represents a distinct entity. This is also true for adult-onset dominant oculopharyngeal distal myopathy. A large number of both recessive and dominant families from Turkey have been reported (17). A number of distal myopathies have been reported in single families and have been shown to be distinct from any of the other known entities by molecular genetic linkage at the time of study:
|
• Distal neuromyopathy with pes cavus (OMIM 601846) (84) |
Diagnostic workup
The gold standard for diagnosis is the identification of the final molecular genetic defect. No definite diagnosis can be made on other grounds. In addition to EMG and muscle biopsy, muscle imaging may be helpful in defining the precise pattern of muscle involvement and suggesting a group of disorders. Based on the combination of age at onset, mode of inheritance, pathology, and muscle imaging, known possible gene defects can be tracked down to a minimal number allowing for specific genetic testing. Flow charts of such differential diagnostic workups have been published (91).
Management
Securing the final genetic diagnosis and avoiding unnecessary or hazardous treatments due to erroneous diagnosis is most relevant. Orthoses are commonly used for stabilization of wrists, fingers, ankles, and toes. In cases of early severe foot drop, tibialis posterior tendon transposition has been used in both tibial muscular dystrophy and valosin-containing protein-mutated distal myopathy with good outcomes for many years. For those associated with cardiomyopathy, such as desmin, CRYAB, ZASP, and VCP myopathies, cardiac evaluation and follow-up are part of the management plan.
Media
References
- 01
- Ahlberg G, Jakobsson F, Fransson A, et al. Distribution of muscle degeneration in Welander distal myopathy: a magnetic resonance imaging and muscle biopsy study. Neuromuscul Disord 1994;4:55-62. PMID 8173352
- 02
- Ahlberg G, Tell D, Borg K, et al. Genetic linkage of Welander distal myopathy to chromosome 2p13. Ann Neurol 1999;46:399-404. PMID 10482271
- 03
- Barohn RJ, Miller RG, Griggs RC. Autosomal recessive distal dystrophy. Neurology 1991;41(9):1365-70. PMID 1891082
- 04
- Bejaoui K, Hirabayashi K, Hentati F, et al. Linkage of Miyoshi myopathy (distal autosomal recessive muscular dystrophy) locus to chromosome 2p12-14. Neurology 1995;45:768-72. PMID 7723968
- 05
- Belanto JJ, Diaz-Perez SV, Magyar CE, et al. Dexamethasone induces dysferlin in myoblasts and enhances their myogenic differentiation. Neuromuscul Disord 2010;20(2):111-21. PMID 20080405
- 06
- Blanco-Palmero VA, Hernández-Laίn A, Uriarte-Pérez de Urabayen D, Cantero-Montenegro D, Olive M, Dominguez-Gonzalez C. Late onset distal myopathy: a new telethoninopathy. Neuromusc Dis 2019;29(1):80-3. PMID 30553702
- 07
- Bolduc V, Marlow G, Boycott KM, et al. Recessive mutations in the putative calcium-activated chloride channel anoctamin 5 cause proximal LGMD2L and distal MMD3 muscular dystrophies. Am J Hum Genet 2010;86(2):213-21. PMID 20096397
- 08
- Borg K, Ahlberg G, Anvret M, Edstrom L. Welander distal myopathy: an overview. Neuromuscul Disord 1998;8:115-8. PMID 9608565
- 09
- Bucelli RC, Arhzaouy K, Pestronk A, et al. SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles. Neurology 2015;85(8):665-74. PMID 26208961
- 10
- Chen L, Chen DF, Dong HL, Liu GL, Wu ZY. A novel frameshift ACTN2 variant causes a rare adult-onset distal myopathy with multi-minicores. CNS Neurosci Ther 2021;27(10):1198-205. PMID 34170073
- 11
- Chen Z, Saini M, Koh JS, et al. A novel variant in the tropomyosin 3 gene presenting as an adult-onset distal myopathy – a case report. BMC Neurol 2023;23(1):181. PMID 37147571
- 12
- Cirak S, von Deimling F, Sachdev S, et al. Kelch-like homologue 9 mutation is associated with an early onset autosomal dominant distal myopathy. Brain 2010;133(Pt 7):2123-35. PMID 20554658
- 13
- Deng J, Yu J, Li P, et al. Expansion of GGC repeat in GIPC1 is associated with oculopharyngodistal myopathy. Am J Human Genet 2020;106(6):793-804. PMID 32413282
- 14
- de Seze J, Udd B, Haravuori H, et al. The first European tibial muscular dystrophy family outside the Finnish population. Neurology 1998;51:1746-8. PMID 9855539
- 15
- Dimachkie MM, Barohn RJ. Distal myopathies. Neurol Clin 2014;32(3):817-42. PMID 25037092
- 16
- Duff RM, Tay V, Hackman P, et al. Mutations in the N-terminal Actin-Binding Domain of Filamin C Cause a Distal Myopathy. Am J Hum Genet 2011;88(6):729-40. PMID 21620354
- 17
- Durmus H, Laval SH, Deymeer F, et al. Oculopharyngeal distal myopathy is a distinct entity: clinical and genetic features of 47 patients. Neurology 2011;76(3):227-35. PMID 21242490
- 18
- Eisenberg I, Avidan N, Potikha T, et al. The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy. Nat Genet 2001;29:83-7. PMID 11528398
- 19
- Feit H, Silbergleit A, Schneider L, et al. Vocal cord and pharyngeal weakness with autosomal distal myopathy: clinical description and gene localization to chromosome 5q31. Am J Hum Genet 1998;63:1732-44. PMID 9837826
- 20
- Felice KJ, Meredith C, Binz N, et al. Autosomal dominant distal myopathy not linked to the known distal myopathy loci. Neuromuscul Disord 1999;9:59-65. PMID 10220859
- 21
- Fischer D, Herasse M, Bitoun M, et al. Characterization of the muscle involvement in dynamin 2-related centronuclear myopathy. Brain 2006;129:1463-9. PMID 16585051
- 22
- Foroud T, Pankratz N, Batchman AP, et al. A mutation in myotilin causes spheroid body myopathy. Neurology 2005;65:1936-40. PMID 16380616
- 23
- Gallardo E, de Luna N, Diaz-Manera J, et al. Comparison of dysferlin expression in human skeletal muscle with that in monocytes for the diagnosis of dysferlin myopathy. PLoS One 2011;6(12): e29061. PMID 22194990
- 24
- Gang Q, Bettencourt C, Machado PM, et al. Rare variants of SQSTM1 and VCP genes and risk of sporadic inclusion body myositis. Neurobiol Aging 2016;47:218.e1-9. PMID 27594680
- 25
- Ghaoui R, Palmio J, Brewer J, et al. Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy. Neurology 2016;86(4):391-8. PMID 26718575
- 26
- Gowers WR. Myopathy and a distal form. Br Med J 1902;2:89-92. PMID 20760370
- 27
- Griggs R, Vihola A, Hackman P, et al. Zaspopathy in a large classic late onset distal myopathy family. Brain 2007;130:1477-84. PMID 17337483
- 28
- Guergueltcheva V, Peeters K, Baets J, et al. Distal myopathy with upper limb predominance caused by filamin C haploinsufficiency. Neurology 2011;77(24):2105-14. PMID 22131542
- 29
- Hackman P, Vihola A, Haravuori H, et al. Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. Am J Hum Genet 2002;71:492-500. PMID 12145747
- 30
- Hackman P, Marchand S, Sarparanta J, et al. Truncating mutations in C-terminal titin may cause more severe tibial muscular dystrophy (TMD). Neuromusc Disord 2008;18:922-8. PMID 18948003
- 31
- Hackman P, Sarparanta J, Lehtinen S, et al. Welander distal myopathy is caused by a mutation in the RNA-binding protein TIA1. Ann Neurol 2013;73(4):500-9. PMID 23401021
- 32
- Harada Y, Zuchner SL, Herrmann DN, et al. Clinical reasoning: a case of bilateral foot drop in a 74-year-old man. Neurology 2020;94(9):405-9. PMID 32041727
- 33
- Haravuori H, Makela-Bengs P, Udd B, et al. Assignment of the tibial muscular dystrophy locus to chromosome 2q31. Am J Hum Genet 1998;62(3):620-6. PMID 9497249
- 34
- Haravuori H, Siitonen A, Mahjneh I, et al. Linkage to two separate loci in a family with a novel distal myopathy phenotype (MPD3). Neuromusc Disord 2004;14:183-7. PMID 15036327
- 35
- Horowitz ST, Schmalbruch H. Autosomal dominant distal myopathy with desmin storage: a clinicopathologic and electrophysiologic study of a large kinship. Muscle Nerve 1994;17:151-60. PMID 8114783
- 36
- Ikeuchi T, Asaka T, Saito M, et al. Gene locus for autosomal recessive distal myopathy with rimmed vacuoles maps to chromosome 9. Ann Neurol 1997;41:432-7. PMID 9124799
- 37
- Ilkovski B, Mokbel N, Lewis RA, et al. Disease severity and thin filament regulation in M9R TPM3 nemaline myopathy. J Neuropathol Exp Neurol 2008;67(9):867-77. PMID 18716557
- 38
- Illa I, Serrano-Munuera C, Gallardo E, et al. Distal anterior compartment myopathy: a dysferlin mutation causing a new muscular dystrophy phenotype. Ann Neurol 2001;49:130-4. PMID 11198284
- 39
- Illarioshkin SN, Ivanova-Smolenskaya IA, Greenberg CR, et al. Identical dysferlin mutation in limb-girdle muscular dystrophy type 2B and distal myopathy. Neurology 2000;55:1931-3. PMID 11134403
- 40
- Ishiura H, Shibata S, Yoshimura J, et al. Noncoding CGG repeat expansions in neural intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease. Nat Genet 2019;51(8):1222-32. PMID 31332380
- 41
- Jaiswal JK, Marlow G, Summerill G, et al. Patients with a non-dysferlin Miyoshi myopathy have a novel membrane repair defect. Traffic 2007;8:77-88. PMID 17132147
- 42
- Johari M, Sarparanta J, Vihola A, et al. Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions. Acta Neuropathol 2021;142(2):375-93. PMID 33974137
- 43
- Jokela M, Tasca G, Vihola A, et al. An unusual ryanodine receptor 1 (RYR1) phenotype: Mild calf-predominant myopathy. Neurology 2019;92(14):e1600-9. PMID 30842289
- 44
- Kim HJ, Kim NC, Wang YD, et al. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 2013;495(7442):467-73. PMID 23455423
- 45
- Kimonis V, Mehta S, Fulchiero E, et al. Clinical studies in familial VCP myopathy associated with Paget disease of bone and frontotemporal dementia. Am J Med Genet 2008;146A:745-57. PMID 18260132
- 46
- Laing NG, Laing BA, Meredith C, et al. Autosomal dominant distal myopathy: linkage to chromosome 14. Am J Hum Genet 1995;56:422-7. PMID 7847377
- 47
- Lamont P, Udd B, Mastaglia F, et al. Laing early-onset distal myopathy: slow myosin defect with variable abnormalities on muscle biopsy. J Neurol Neurosurg Psychiatry 2006;77:208-15. PMID 16103042
- 48
- Laughlin RS, Niu Z, Wieben E, Milone M. RYR1 causing distal myopathy. Mol Genet Genomic Med 2017;5(6):800-4. PMID 29178655
- 49
- Lehtokari VL, Pelin K, Herczegfalvi A, et al. Nemaline myopathy caused by mutations in the nebulin gene may present as a distal myopathy. Neuromuscul Disord 2011;21:556-62. PMID 21724397
- 50
- Linssen WH, de Visser M, Notermans NC, et al. Genetic heterogeneity in Miyoshi-type distal muscular dystrophy. Neuromuscul Disord 1998;8:317-20. PMID 9673985
- 51
- Linssen WH, Notermans NC, Van der Graaf Y, et al. Miyoshi-type distal muscular dystrophy. Clinical spectrum in 24 Dutch patients. Brain 1997; 120:1989-96. PMID 9397016
- 52
- Liu J, Aoki M, Illa I, et al. Dysferlin, a novel skeletal muscle gene, is mutation in Miyoshi myopathy and limb girdle muscular dystrophy. Nat Genet 1998;20:31-6. PMID 9731526
- 53
- Mahjneh I, Haravuori H, Paetau A, et al. A distinct phenotype of distal myopathy in a large Finnish family. Neurology 2003;61(1):87-92. PMID 12847162
- 54
- Malicdan MC, Noguchi S, Hayashi YK, et al. Prophylactic treatment with sialic acid metabolites precludes the development of the myopathic phenotype in the DMRV-hIBM mouse model. Nat Med 2009;15:690-5. PMID 19448634
- 55
- Markesbery WR, Griggs RC, Leach RP, Lapham LW. Late onset hereditary distal myopathy. Neurology 1974;23:127-34. PMID 4855680
- 56
- Mastaglia FL, Phillips BA, Cala LA, et al. Early onset chromosome 14-linked distal myopathy (Laing). Neuromusc Disord 2002;12:350-7. PMID 12062252
- 57
- Meredith C, Herrmann R, Parry C, et al. Mutations in the slow skeletal muscle fiber myosin heavy chain gene (MYH7) cause laing early-onset distal myopathy (MPD1). Am J Hum Genet 2004;75(4):703-8. PMID 15322983
- 58
- Milhorat AT, Wolff HG. Studies in diseases of muscle XIII: progressive muscular dystrophy of atrophic distal type; report of a family; report of autopsy. Arch Neurol Psychiatry 1943;49:655-64.
- 59
- Miyoshi K, Iwasa M, Kawai H. Autosomal recessive distal muscular dystrophy: a new variety of distal muscular dystrophy predominantly seen in Japan. Nippon Rinsho (Tokyo) 1977;35:3922-8.
- 60
- Miyoshi K, Kawai H, Iwasa M, Kusaka K, Nishino H. Autosomal recessive distal muscular dystrophy as a new type of progressive muscular dystrophy. Brain 1986;109:31-54. PMID 3942856
- 61
- Mohassel P, Liewluck T, Hu Y, et al. Dominant collagen XII mutations cause a distal myopathy. Ann Clin Trans Neurol 2019;6(10):1980-8. PMID 31509352
- 62
- Nations SP, Wolfe GI, Amato AA, Jackson CE, Bryan WW, Barohn RJ. Distal myasthenia gravis. Neurology 1999; 52(3):632-4. PMID 10025802
- 63
- Nishino I, Noguchi S, Murayama K, et al. Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy. Neurology 2002;59:1689-93. PMID 12473753
- 64
- Nishino I, Malicdan MC, Murayama K, et al. Molecular pathomechanism of distal myopathy with rimmed vacuoles. Acta Myol 2005;24:80-3. PMID 16550921
- 65
- Nonaka I, Sunohara N, Ishiura S, Satoyoshi E. Familial distal myopathy with rimmed vacuole and lamellar (myeloid) body formation. J Neurol Sci 1981;51:141-55. PMID 7252518
- 66
- Ogasawara M, Lida A, Kumutpongpanich T, et al. CGG expansion in NOTCH2NLC is associated with oculopharyngodistal myopathy with neurological manifestations. Acta Neuropathol Commun 2020;8:204. PMID 33239111
- 67
- Olive M, Goldfarb LG, Shatunov A, et al. Myotilinopathy: refining the clinical and myopathological phenotype. Brain 2005;128:2315-26. PMID 15947064
- 68
- Palmio J, Sandell S, Suominen T, et al. Distinct distal myopathy phenotype caused by VCP gene mutation in a Finnish family. Neuromuscul Disord 2011;21(8):551-5. PMID 21684747
- 69
- Park HJ, Hong YB, Choi YC, et al. ADSSL1 mutation relevant to autosomal recessive adolescent onset distal myopathy. Ann Neurol 2016;79(2):231-43. PMID 26506222
- 70
- Penisson-Besnier I, Dumez C, Chateau D, et al. Autosomal dominant late adult onset distal leg myopathy. Neuromuscul Disord 1998;8:459-66. PMID 9829275
- 71
- Penisson-Besnier I, Talvinen K, Dumez C, et al. Myotilinopathy in a family with late onset myopathy. Neuromuscul Disord 2006;16:427-31. PMID 16793270
- 72
- Penttila S, Palmio J, Suominen T, et al. Eight new mutations and the expanding phenotype variability in muscular dystrophy caused by ANO5. Neurology 2012;78(12):897-903. PMID 22402862
- 73
- Piccolo F, Moore SA, Ford GC, et al. Intracellular accumulation and reduced sarcolemmal expression of dysferlin in limb-girdle muscular dystrophies. Ann Neurol 2000;48:902-12. PMID 11117547
- 74
- Pitceathly RD, Tomlinson SE, Hargreaves I, et al. Distal myopathy with cachexia: an unrecognized phenotype caused by dominantly-inherited mitochondrial polymerase γ mutations. J Neurol Neurosurg Psychiatry 2013;84(1):107-10. PMID 22933815
- 75
- Pollazzon M, Suominen T, Penttilä S, et al. The first Italian family with tibial muscular dystrophy (TMD) caused by a novel titin mutation. J Neurol 2010;257:575-9. PMID 19911250
- 76
- Pradhan S. Clinical and magnetic resonance imaging features of ‘diamond on quadriceps’ sign in dysferlinopathy. Neurol India 2009;57(2):172-5. PMID 19439848
- 77
- Reilich P, Schoser B, Schramm N, et al. The p.G154S mutation of the alpha-B crystallin gene (CRYAB) causes late-onset distal myopathy. Neuromuscul Disord 2010;20(4):255-9. PMID 20171888
- 78
- Rosales XQ, Gastier-Foster JM, et al. Novel diagnostic features of dysferlinopathies. Muscle Nerve 2010;42(1):14-21. PMID 20544924
- 79
- Ruggieri A, Brancati F, Zanotti S, et al. Complete loss of the DNAJB6 G/F domain and novel missense mutations cause distal-onset DNAJB6 myopathy. Acta Neuropathol Commun 2015;25:3:44. PMID 26205529
- 80
- Saito R, Shimizu H, Miura T, et al. Oculopharyngodistal myopathy with coexisting histology of systemic neuronal intranuclear inclusion disease: clinicopathologic features of an autopsied patient harboring CGG repeat expansions in LRP12. Acta Neuropathol Commun 2020;8(1):75. PMID 32493488
- 81
- Selcen D, Engel AG. Mutations in myotilin cause myofibrillar myopathy. Neurology 2004;62:1363-71. PMID 15111675
- 82
- Selcen D, Muntoni F, Burton B, et al. Mutation in BAG3 causes severe dominant childhood muscular dystrophy. Ann Neurol 2009;65:83-9. PMID 19085932
- 83
- Senderek J, Garvey SM, Krieger M, et al. Autosomal-dominant distal myopathy associated with a recurrent missense mutation in the gene encoding the nuclear matrix protein, matrin 3. Am J Hum Genet 2009;84:511-8. PMID 19344878
- 84
- Servidei S, Capon F, Spinazzola M, et al. A distinctive autosomal dominant vacuolar neuromyopathy linked to 19p13. Neurology 1999;53:830-7. PMID 10489050
- 85
- Sjoberg G, Saavedra-Matiz C, Rosen D, et al. A missense mutation in the desmin rod domain is associated with autosomal dominant distal myopathy, and exerts a dominant negative effect on filament formation. Hum Mol Genet 1999;8:2191-8. PMID 10545598
- 86
- Souza PVS, Pinto WBVR, Aivazoglou LU, et al. Distal myopathy due to BICD2 mutations. Clin Neuro Neurosurg 2018;165:47-9. PMID 29306765
- 87
- Sugawara M, Kato K, Komatsu M, et al. A novel de novo mutation in the desmin gene causes desmin myopathy with toxic aggregates. Neurology 2000;55:986-90. PMID 11061256
- 88
- Tasca G, Ricci E, Penttilä S, et al. New phenotype and pathology features in MYH7-related distal myopathy. Neuromuscul Disord 2012;22(7):640-7. PMID 22521714
- 89
- Tateyama M, Aoki M, Nishino I, et al. Mutation in the caveolin-3 gene causes a peculiar form of distal myopathy. Neurology 2002;58:323-5. PMID 11805270
- 90
- Udd B. 165th ENMC International Workshop: distal myopathies III. Neuromusc Disord 2009;19:429-38. PMID 19477645
- 91
- Udd B. Distal myopathies. Neuromusc Disord 2012;22(1):5-12. PMID 22197426
- 92
- Udd B, Kaarianen H, Somer H. Muscular dystrophy with separate clinical phenotypes in a large family. Muscle Nerve 1991;14:1050-8. PMID 1745277
- 93
- Udd B, Partanen J, Halonen P, et al. Tibial muscular dystrophy: late adult-onset distal myopathy in 66 Finnish patients. Arch Neurol 1993;50:604-8. PMID 8503797
- 94
- Udd B, Vihola A, Sarparanta J, Richard I, Hackman P. Titinopathies and extension of the M-line mutation phenotype beyond distal myopathy and LGMD2J. Neurology 2005;64(4):636-42. PMID 15728284
- 95
- Unger A, Dekomien G, Güttsches A, et al. Expanding the phenotype of BICD2 mutations toward skeletal muscle involvement. Neurology 2016;87(21):2235-43. PMID 27784775
- 96
- Van den Bergh P, Bouquiaux O, et al. Tibial muscular dystrophy in a Belgian family. Annal Neurol 2003;54:248-51. PMID 12891679
- 97
- Vicart P, Caron A, Guicheney P, et al. A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy. Nat Genet 1998;20:92-5. PMID 9731540
- 98
- Vorgerd M, van der Ven PF, Bruchertseifer V, et al. A mutation in the dimerization domain of filamin c causes a novel type of autosomal dominant myofibrillar myopathy. Am J Hum Genet 2005;77:297-304. PMID 15929027
- 99
- Wallgren-Pettersson C, Lehtokari V-L, Kalimo H, et al. Distal myopathy caused by homozygous missense mutations in the nebulin gene. Brain 2007;130:1465-76. PMID 17525139
- 100
- Walter M, Reichlich P, Hübner A, et al. Identification of a desmin gene mutation in scapuloperoneal syndrome type Kaeser. Neuromusc Disord 2006;16:708-9.
- 101
- Welander L. Myopathia distalis tarda hereditaria. Acta Med Scand 1951;141:1-124.
- 102
- Williams DR, Reardon K, Roberts L, et al. A new dominant distal myopathy affecting posterior leg and anterior upper limb muscles. Neurology 2005;64:1245-54. PMID 15824355
- 103
- Zeng YH, Yang K, Du GQ, et al. GGC repeat expansion of RILPL1 is associated with oculopharyngodistal myopathy. Ann Neurol 2022;92(3):512-26. PMID 35700120
- 104
- Zhang KY, Zhang GJ, Duran HQ, et al. CASQ1-related myopathy: The first report from China and the literature review. Clin Case Rep 2022;10(12):e06689. PMID 36514469
- 105
- Zibold J, Lessard LE, Picard F, et al. The new missense G376V-TDP-43 variant induces late-onset distal myopathy but not amyotrophic lateral sclerosis. Brain 2024;147(5):1768-83. PMID 38079474
Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Authors
-
Duaa Jabari MD
Dr. Jabari of the University of Kansas Medical Center has no relevant financial relationships to disclose.
See Profile -
Mazen M Dimachkie MD
Dr. Dimachkie, Director of the Neuromuscular Disease Division and Executive Vice Chairman for Research Programs, Department of Neurology, The University of Kansas Medical Center received consultant honorariums from Abata/Third Rock, Abcuro, Amicus, ArgenX, Astellas, Cabaletta Bio, Catalyst, CNSA, Covance/LabCorp, CSL Behring, Dianthus, EMD Serono/Merck, Horizon, Ig Society Inc, Ipsen, Janssen, Octapharma, Priovant, Ra Pharma/UCB Biopharma, Sanofi Genzyme, Shire/Takeda, Treat NMD/TACT, and Valenza Bio. Dr. Dimachikie also received research grants from Alexion/Astra Zaneca, Amicus, Astellas, Catalyst, CSL Behring, EMD Serono/Merck, Genentech, Grifols, GSK, Horizon, Janssen, Mitsubishi Tanabe Pharma, MT Pharma, Novartis, Octapharma, Priovant, Ra Pharma/UCB Biopharma, Sanofi Genzyme, Sarepta Therapeutics, Shire/Takeda, and TMA.
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
- Hannu Somer MD
- David S Saperstein MD
- Bjarne Udd MD PhD
Patient Profile
- Age range of presentation
-
- 1 month to 65+ years
- Sex preponderance
-
- male=female
- Heredity
-
- heredity typical
- heredity may be a factor
- autosomal dominant
- autosomal recessive
- Population groups selectively affected
-
- Swedes
- Finns
- Japanese
- Americans
- Tunisians
- Occupation groups selectively affected
-
- none selectively affected
ICD & OMIM codes
- ICD-10
-
- Distal myopathy: G71.08
- ICD-11
-
- Distal myopathies: 8C75
- OMIM
-
- Distal myopathy, Nonaka type: #605820
- Distal myopathy, Swedish type: %604454
- Distal myopathy, with onset in infancy: %160300
- Distal myopathy: #160500
- Miyoshi muscular dystrophy 1: #254130
- Myopathy, centronuclear, autosomal dominant: #160150
- Myopathy, distal 2; MPD2: #606070
- Myopathy, myofibrillar, desmin-related: #601419
- Tibial muscular dystrophy, tardive: #600334
This is an article preview.
Start a Free Account
to access the full version.
-
Nearly 3,000 illustrations, including video clips of neurologic disorders.
-
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
-
Full spectrum of neurology in 1,200 comprehensive articles.
-
Listen to MedLink on the go with Audio versions of each article.
Questions or Comment?
MedLink®, LLC
3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122
Toll Free (U.S. + Canada): 800-452-2400
US Number: +1-619-640-4660
Support: service@medlink.com
Editor: editor@medlink.com
ISSN: 2831-9125
Also in This Category
-
-
Neuromuscular Disorders
Asymptomatic hyperCKemia
Nov. 19, 2024
-
Neuromuscular Disorders
Limb-girdle muscular dystrophies
Nov. 19, 2024
-
Neuromuscular Disorders
Chronic progressive external ophthalmoplegia
Oct. 29, 2024
-
Neuromuscular Disorders
Drug-induced myasthenic syndromes
Oct. 02, 2024
-
Peripheral Neuropathies
Amyotrophic lateral sclerosis
Sep. 04, 2024
-
General Neurology
ALS-like disorders of the Western Pacific
Aug. 14, 2024
-
Neuromuscular Disorders
Paraspinal neuromuscular syndromes
Aug. 11, 2024