| #604286 | ||||||||||||||||||||||||||||||||||||||||||
| MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2E; LGMD2E | ||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because limb-girdle muscular dystrophy type 2E (LGMD2E) is caused by mutation in the gene encoding beta-sarcoglycan (SGCB; 600900). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy (LGMD), see LGMD2A (253600), which is caused by mutation in the CAPN3 gene on chromosome 15q. | ||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | ||||||||||||||||||||||||||||||||||||||||||
| Jackson and Strehler (1968) reported 5 nuclear Old Amish families from southern Indiana with autosomal recessive limb-girdle muscular dystrophy. The families showed links to an ancestral couple born in the late 1700s (Allamand et al., 1995). In 6 Amish families with LGMD from southern Indiana, Allamand et al. (1995) excluded linkage to the LGMD2A locus on chromosome 15q. Lim et al. (1995) reported the clinical features of 11 Amish patients from southern Indiana with autosomal recessive LGMD. All patients presented with proximal symmetric weakness and atrophy of the limb and trunk muscles. The average age at onset was 7.6 years (range 4 to 12), and loss of walking occurred between 12 and 38 years. Calf hypertrophy was also observed. There was marked intrafamilial variability. Bonnemann et al. (1995) described a young girl with autosomal recessive LGMD. Immunostaining of her muscle biopsy showed specific loss of several components of the sarcoglycan complex: beta-sarcoglycan, alpha-sarcoglycan (SGCA; 600119), and 35-kD sarcoglycan (SGCD; 601411). Thus, secondary destabilization of the sarcoglycan complex is an important pathophysiologic event in autosomal recessive muscular dystrophy. Genetic analysis identified compound heterozygosity for 2 truncating mutations in the SGCB gene (600900.0002, 600900.0003). Barresi et al. (2000) reported 2 unrelated males with LGMD2E who developed fatal dilated cardiomyopathy and died at ages 27 and 18 years, respectively. The affected first-cousin of 1 of the patients did not have cardiomyopathy. Both heart and skeletal muscle biopsies showed reductions in gamma- (SGCG; 608896) and alpha-sarcoglycan, confirming that mutations in 1 sarcoglycan gene can disrupt the whole dystrophin (DMD; 300377)-associated glycoprotein (DAG) complex. Barresi et al. (2000) concluded that cardiac function should be monitored in patients with LGMD and defective sarcoglycan expression. Molecular analysis identified compound heterozygous mutations in the SGCB gene in 1 patient (600900.0003; 600900.0009). | ||||||||||||||||||||||||||||||||||||||||||
| Diagnosis | ||||||||||||||||||||||||||||||||||||||||||
| Prenatal Diagnosis Pegoraro et al. (1999) reported the first prenatal diagnosis of LGMD2E by direct gene mutation detection. | ||||||||||||||||||||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||||||||||||||||||||
| Using pericentromeric markers and an intragenic polymorphic CA repeat on chromosome 4q12, Lim et al. (1995) demonstrated perfect cosegregation with autosomal recessive limb-girdle muscular dystrophy in Amish families from southern Indiana. | ||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||
| In affected members of several Amish families with autosomal recessive LGMD, Lim et al. (1995) identified a homozygous mutation in the SGCB gene (600900.0001). Skeletal muscle biopsy showed a dramatic reduction in SGCB expression in the sarcolemma and a concomitant loss of adhalin (600119) and 35-DAG (SGCD; 601411), which was interpreted as representing a disruption of a functional subcomplex within the dystrophin-glycoprotein complex. Bonnemann et al. (1996) identified novel mutations in the SGCB gene in 2 familial and 2 sporadic cases of severe childhood-onset LGMD. One patient carried a truncating mutation (600900.0004); the other 3 patients had missense mutations in exon 3. Trabelsi et al. (2008) identified biallelic mutations in sarcoglycan genes in 46 (67%) of 69 patients with a clinical diagnosis of autosomal recessive LGMD. Twenty-six (56.5%) patients had SGCA mutations, 8 (17.3%) had SGCB mutations, and 12 (26%) had SGCG mutations. Seven of the 9 SGCB mutations were novel. | ||||||||||||||||||||||||||||||||||||||||||
| Cytogenetics | ||||||||||||||||||||||||||||||||||||||||||
| Kaindl et al. (2005) identified a homozygous 400-kb microdeletion of chromosome 4q11-q12 in 6 members of a consanguineous East Anatolian family with a severe form of LGMD2E with joint hyperlaxity and contractures. The deleted region included both the SGCB and SPATA18 (612814) genes. Other clinical features included onset between birth and 5 years, myopathic facies, and scoliosis. The proband had delayed motor development and lost the ability to walk by age 10 years. She had restrictive respiratory insufficiency, mild diastolic dysfunction of both ventricles, increased serum creatine kinase, type 2 diabetes mellitus, and polycystic ovary syndrome (PCOS; 184700). Three affected family members died of heart failure at ages 20, 30, and 35 years, respectively. Kaindl et al. (2005) commented that the phenotype was similar to that of Duchenne muscular dystrophy (DMD: 310200). | ||||||||||||||||||||||||||||||||||||||||||
| Genotype/Phenotype Correlations | ||||||||||||||||||||||||||||||||||||||||||
| 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 and LGMD2F (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 (608099) patients. Comparison between 40 LGMD2A patients and 52 LGMD2B (253601) 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%). | ||||||||||||||||||||||||||||||||||||||||||
| Population Genetics | ||||||||||||||||||||||||||||||||||||||||||
| Jackson and Carey (1961) reported autosomal recessive limb-girdle muscular dystrophy in 7 nuclear families among the Old Order Amish in northern Indiana. The maternal and paternal lines had common ancestors: 2 brothers married sisters in the early 1800s. These families were later shown to map to chromosome 15q and harbor a common pathogenic mutation in the CAPN3 gene (114240.0001), consistent with LGMD2A (Richard et al., 1995). Allamand et al. (1995) noted that the Amish families from northern and southern Indiana were interrelated by multiple consanguineous links and had a common ancestry that could be traced to the canton of Bern, Switzerland, where limb-girdle muscular dystrophy also has a high frequency (Young et al., 1992). | ||||||||||||||||||||||||||||||||||||||||||
| Animal Model | ||||||||||||||||||||||||||||||||||||||||||
| Araishi et al. (1999) developed a beta-sarcoglycan (BSG)-deficient transgenic mouse by incorporating a vector whose BSG insert lacked exon 2, which encodes the intracellular and transmembrane domains of the protein. The BSG -/- mice exhibited progressive muscular dystrophy, with extensive degeneration and regeneration of myofibers seen histologically. The BSG -/- mice also exhibited muscular hypertrophy characteristic of beta-sarcoglycanopathy in humans. Immunohistochemical and immunoblot analyses of BSG -/- mouse muscle demonstrated that deficiency of beta-sarcoglycan also caused loss of all other sarcoglycans as well as loss of sarcospan (601599) in the sarcolemma, similar to the findings of Bonnemann et al. (1995). On the other hand, laminin-alpha-2 (156225), alpha- and beta-dystroglycan (see 128239), and dystrophin were present in the sarcolemma. In addition, the dystrophin-dystroglycan complex in BSG -/- mice was either unstably assembled or easily dissociable compared to the complex in wildtype mice. The authors concluded that loss of the sarcoglycan complex and sarcospan alone is sufficient to cause muscular dystrophy, that beta-sarcoglycan is an important protein for formation of the sarcoglycan complex associated with sarcospan, and that the role of the sarcoglycan complex and sarcospan may be to strengthen the dystrophin axis connecting the basement membrane with the cytoskeleton. | ||||||||||||||||||||||||||||||||||||||||||
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