Alternative titles; symbols
SNOMEDCT: 718179003; ICD10CM: G71.033; ORPHA: 268; DO: 0110276;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p13.2 | Muscular dystrophy, limb-girdle, autosomal recessive 2 | 253601 | Autosomal recessive | 3 | DYSF | 603009 |
A number sign (#) is used with this entry because autosomal recessive limb-girdle muscular dystrophy-2 (LGMDR2) is caused by homozygous or compound heterozygous mutation in the DYSF gene (DYSF; 603009), encoding the skeletal muscle protein dysferlin, on chromosome 2p13.
See also Miyoshi myopathy (MDM1; 254130) and distal myopathy with anterior tibial onset (DMAT; 606768), allelic disorders characterized by more distal muscle involvement.
For a general phenotypic description and a discussion of genetic heterogeneity of LGMD, see LGMDR1 (253600).
At the 229th ENMC international workshop, Straub et al. (2018) reviewed, reclassified, and/or renamed forms of LGMD. The proposed naming formula was 'LGMD, inheritance (R or D), order of discovery (number), affected protein.' Under this formula, LGMD2B was renamed LGMDR2.
In a review of the limb-girdle muscular dystrophies, including 8 autosomal dominant and 5 autosomal recessive forms, Bushby (1999) referred to Miyoshi myopathy and LGMD2B as 'dysferlinopathies.'
Bashir et al. (1994) reported 2 unrelated consanguineous families, 1 of Palestinian and 1 of Sicilian origin, with autosomal recessive LGMD. Age at onset ranged from 15 to 25 years with difficulty in climbing stairs, fatigue, weakness, and markedly elevated serum creatine kinase. EMG showed myopathic changes and skeletal muscle biopsies showed severe myopathic changes with variation of fiber size, fiber splitting, increased connective tissue, and some necrotic changes. Disease progression was relatively slow.
Weiler et al. (1996) reported a large, inbred, aboriginal Canadian kindred in which 7 patients presented with limb-girdle muscular dystrophy, whereas 2 manifested predominantly distal wasting and weakness consistent with Miyoshi myopathy. Those with LGMD all developed distal involvement and all but 1 were wheelchair-bound. Those with distal presentation later showed proximal muscle involvement. Age at onset of weakness was in adolescence. Both types of disorder showed increased serum creatine kinase and similar dystrophic changes on muscle biopsy. There was no evidence of cardiac involvement.
Illarioshkin et al. (1996) reported a 6-generation consanguineous family originating from an isolated mountainous village in the Russian province of Daghestan with 2 forms of progressive muscular dystrophy. Seven patients developed classical LGMD with disease onset between 15 and 30 years and loss of ambulation within a 25-year course. The second group included 3 patients with a slowly progressive distal myopathy first manifested in the late teens and confined to the tibial and calf muscles. Each of these phenotypes segregated independently as an autosomal recessive trait and muscle biopsies showed non-specific myopathic changes.
Bashir et al. (1998) reported 8 Libyan Jewish families with LGMD2B. The 25 patients in these families showed onset of the disease between 12 and 39 years of age (mean 19.5 +/- 5 years). All had lower limb involvement on average 9 years before upper limb symptoms. Thirteen patients (52%) presented with distal lower limb muscle weakness, mostly of the gastrocnemius, with some complaining of transient calf enlargement. Intrafamilial variability was seen in the distribution of muscle weakness. Only 6 patients had lost the ability to walk independently; all of these were older than 35 years. Muscle biopsy showed chronic myopathic changes, and creatine kinase was elevated to 10-25 times normal in all affected individuals.
Passos-Bueno et al. (1999) studied 140 patients from 40 Brazilian families with one of 7 autosomal recessive limb-girdle muscular dystrophies (LGMDs). All LGMD2E (LGMDR4; 604286) and LGMD2F (LGMDR6; 601287) patients had a severe phenotype; considerable inter- and intrafamilial variability was observed in all other types of LGMD. Among the sarcoglycanopathies, serum CK levels were highest in the LGMD2D (LGMDR3; 608099) patients. Comparison between 40 LGMD2A (LGMDR1; 253600) patients and 52 LGMD2B patients showed that LGMD2A patients had a more severe course and higher frequency of calf hypertrophy (86% vs 13%), and that LGMD2B patients were more likely to be unable to walk on toes (70% vs 18%).
McNally et al. (2000) reported a large inbred pedigree of Yemenite Jewish descent with LGMD2B. These patients had slowly progressive muscular weakness of the lower limbs, both distal and proximal, beginning in the late second decade of life. Most developed upper limb involvement within 10 years. Three of 6 patients became wheelchair-bound. The patients had markedly elevated serum creatine kinase levels, and 2 of the 4 patients from whom muscle biopsies were available demonstrated an inflammatory process, a finding not previously described in LGMD. Mutation analysis demonstrated a homozygous mutation in the DYSF gene (609003.0008).
Illa et al. (2007) reported a 54-year-old woman who presented with a 3-year history of progressive fatigue while walking and difficulty climbing stairs. She had proximal muscle weakness of the lower limbs, increased serum creatine kinase and evidence of fatty infiltration of the lower limb muscles on MRI; mutation analysis showed that she was a heterozygous mutation carrier (D625Y; 603009.0013). Her brother had a full LGMD2B phenotype and was compound heterozygous the D625Y mutation and a second missense mutation (603009.0014) in the DYSF gene. Although immunostaining and Western blot analysis showed decreased dysferlin levels in the woman's muscle, RT-PCR showed normal levels of DYSF mRNA. The findings indicated that heterozygous DYSF mutation carriers may develop late-onset milder manifestations of the disorder.
Spuler et al. (2008) reported 2 sibs with LGMD2B caused by compound heterozygosity for mutations in the DYSF gene (G299R, 603009.0017; 603009.0020). Skeletal muscle biopsy showed amyloid fibrils on skeletal muscle biopsy. Amyloid was located in the sarcolemma of muscle cells as well as in blood vessel walls and interstitium. Spuler et al. (2008) postulated that the G299R mutation destabilized the protein structure of dysferlin and increased the propensity to form amyloid fibrils.
Clinical Variability
Paradas et al. (2009) reported 2 Spanish sibs, aged 2 and 5 years, with a congenital muscular dystrophy associated with a homozygous truncating mutation in the DYSF gene (2779delG; 603009.0021). Both showed hypotonia in infancy and difficulty walking, running, and climbing stairs. There was neck and pelvic muscle weakness. The older patient developed increased serum creatine kinase after age 3. There were no abnormalities in muscle bulk or facial or bulbar motor functions, and no skeletal abnormalities. MRI of the older patient at age 5 showed myoedema of the hamstrings and medial gastrocnemius; these changes were not observed in the other affected sib at age 2. Muscle biopsy showed mild dystrophic features and absent dysferlin expression. Paradas et al. (2009) emphasized the early onset of the disorder in these sibs, and suggested that they have a novel phenotype not previously associated with DYSF mutations, which may be due to genetic modifiers.
Cacciottolo et al. (2011) found that all of 55 patients with an undetermined LGMD clinical phenotype and 10 patients with a Miyoshi myopathy phenotype who had less than 20% dysferlin on skeletal muscle biopsy determined by Western blot analysis had pathogenic mutations in the DYSF gene. Exhaustive mutation analysis was performed, including genomic DNA sequencing, mRNA analysis, array CGH, and PCR. Sixty-five different mutations were identified throughout the gene and there were no mutation hotspots. Cacciottolo et al. (2011) noted the difficulty of sequencing the DYSF gene because of its larger size, and concluded that protein analysis showing a dysferlin reduction to 20% of normal values in skeletal muscle or in peripheral blood monocytes can be used to identify LGMD2B/MMD1 caused by DYSF mutations with 100% accuracy.
In a study of 11 large Brazilian LGMD families of different racial backgrounds, Passos-Bueno et al. (1993) excluded 6 families from linkage to the LGMD2A locus on 15q. The findings indicated genetic heterogeneity in LGMD.
Bashir et al. (1994) mapped a form of LGMD (LGMD2B) to short tandem repeat polymorphisms D2S134 and D2S136 on chromosome 2p16-p13. The maximum lod score was 3.57 at zero recombination. The phenotype in the 2 families was similar, with onset in the pelvic girdle musculature in the late teens and usually relatively slow progression.
Passos-Bueno et al. (1995) confirmed the assignment to 2p in their Brazilian families with autosomal recessive LGMD. Haplotypes generated from 5 chromosome 2 markers from all of the known large families linked to 2p were reported together with the recombinants which showed the most likely location of the LGMD2B gene to be between D2S292 and D2S286, a region of approximately 4 cM located 9-cM distal to the linked markers originally described.
Bashir et al. (1996) assembled a 6-cM YAC contig spanning the LGMD2B locus and mapped 7 genes and 13 anonymous polymorphic microsatellites to it. Using haplotype analysis in the linked families, they narrowed the region of interest to an interval between D2S2113 and D2S2112/D2S145. By fluorescence in situ hybridization mapping of YACs positive for closely linked markers, they defined the distal and proximal boundaries of the LGMD2B gene to be 2p13.3 and 2p13.1, respectively.
In an aboriginal Canadian family that segregated both LGMD and Miyoshi myopathy, Weiler et al. (1996) found significant linkage to a locus spanning the region of LGMD2B on chromosome 2p (lod scores greater than 3.0). Although the family was highly consanguineous, 2 different core haplotypes were identified. Six patients, including the 2 with MM, were homozygous for a haplotype encompassing a 4-cM region spanned by D2S291-D2S2145-D2S286. The 3 other patients were compound heterozygous for the 4-cM haplotype and an additional haplotype. The findings indicated that there were 2 mutant alleles of independent origin in this kindred. However, since the haplotypes did not distinguish between the LGMD and MM phenotypes, Weiler et al. (1996) concluded that LGMD and MM in this aboriginal Canadian population are caused by the same mutation in LGMD2B and that additional factors, both genetic and nongenetic, must have contributed to the clinical phenotype.
By linkage analysis of a consanguineous family with both proximal and distal AR muscular dystrophy, Illarioshkin et al. (1996) found linkage to a 6-cM region on 2p between D2S292 and D2S286 (maximum lod score of 5.64 at D2S291). The authors also demonstrated homozygosity by descent at the critical chromosomal region in all patients, thus providing evidence for a common genetic basis of the 2 clinical phenotypes. Illarioshkin et al. (1997) reported extended haplotypes generated from 15 microsatellite markers, including 7 new markers, and thereby narrowed the locus on 2p13 to a region between D2S327 and D2S2111.
In affected members of 8 Libyan Jewish families with LGMD2B, Bashir et al. (1998) identified a homozygous mutation in the DYSF gene (603009.0005). In a ninth Libyan Jewish family, with a single affected member, the mutation was detected in single copy; one of the parents, who did not carry the mutation, was of Romanian origin.
In a large Canadian aboriginal kindred reported by Weiler et al. (1996), Weiler et al. (1999) found that both patients with LGMD2B and patients with MM were homozygous for a mutation in the dysferlin gene (P791R; 603009.0007). Four additional patients from 2 previously unpublished families also had this mutation and haplotype analysis suggested a common origin of the mutation in all patients. On Western blots of muscle, LGMD2B and MM patients showed a similar abundance of dysferlin staining of 15% and 11%, respectively. Normal tissue sections showed that dysferlin localizes to the sarcolemma, while tissue sections from MM and LGMD patients showed minimal staining which was indistinguishable between the 2 types.
In a large inbred Russian family with both LGMD2B and Miyoshi myopathy reported by Illarioshkin et al. (1996), Illarioshkin et al. (2000) identified a homozygous mutation in the DYSF gene (V67D; 603009.0009).
In affected members from 5 families from Sueca, Spain, with a dysferlinopathy, Vilchez et al. (2005) identified a homozygous mutation in the DYSF gene (R1905X; 603009.0012). Two families presented with Miyoshi myopathy, 2 presented with distal myopathy with anterior tibial onset, and 1 presented with LGMD2B. Although the same mutation resulted in different phenotypes, affected members of each family expressed the same phenotype. Haplotype analysis indicated a founder effect. Sueca was founded in 1245 by 17 settlers belonging to the Hospital Order, which received land from King James I of Aragon as a reward for help in reconquering Valencia from the Moors.
Guglieri et al. (2008) found that LGMD2B was the second most common form of LGMD after LGMD2A among 155 Italian probands. LGMD2B occurred in 18.7% of probands, whereas LGMD2A occurred in 28.4%. In LGMD2B, there was a correlation between mutation type, age at onset, and protein levels. Patients with truncating mutations in the DYSF gene had an earlier age at onset and an absence of protein on muscle biopsy, whereas patients with missense mutations had some residual protein.
In 6 unrelated Portuguese male patients with LGMD2B, Santos et al. (2010) identified a mutation in the DYSF gene (5492G-A; 603009.0022). A seventh Portuguese patient was compound heterozygous for the 5492G-A mutation and another pathogenic DYSF mutation. The 5492G-A mutation was not found in 240 control alleles, and haplotype analysis supported a founder effect for the mutation. All 7 patients originated or resided in a confined region of the northern interior part of Portugal. Although most patients had a limb-girdle muscular dystrophy, there was some phenotypic variation: 1 patient presented with distal muscle weakness in the lower limbs, and another had cardiac arrhythmia.
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