| #601287 | |||||||||||||||||||||
| MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2F; LGMD2F | |||||||||||||||||||||
| Phenotype Gene Relationships | |||||||||||||||||||||
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| A number sign (#) is used with this entry because of evidence that mutation in the sarcoglycan-delta gene (SGCD; 601411) results in the disease phenotype. For a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy (LGMD), see LGMD2A (253600). | |||||||||||||||||||||
| Clinical Features | |||||||||||||||||||||
| Nigro et al. (1996) reported 8 affected members of 4 Brazilian families with limb-girdle muscular dystrophy type 2F. Muscle biopsy performed on 3 unrelated patients showed a highly degenerated muscle with a myopathic pattern. Immunofluorescence studies on skeletal muscle showed lack of staining for delta-sarcoglycan as well as for the other 3 components of the sarcoglycan complex: alpha (SGCA; 600119), beta (SGCB; 600900), and gamma (SGCG; 608896). Dystrophin (DMD; 300377) was present but reduced in quantity. These findings indicated that the primary delta-sarcoglycan deficiency leads to disruption of the entire complex. Duggan et al. (1997) reported 2 U.S. female patients with LGMD2F. The first girl had been adopted and no information was available on her biologic parents. Neurologic examination at age 9 found facial weakness, mild wasting of proximal muscles in upper and lower extremities, scapular winging, and slight decrease in proximal muscle strength. The patient was wheelchair-dependent at age 14. Immunostaining of muscle fibers showed loss of the sarcoglycan complex. The second girl had frequent falls, toe-walking, large calves, and difficulty with stairs at age 22 months. At age 5 years, she walked with a shuffling gait. Immunostaining of muscle fibers showed loss of the sarcoglycan complex. | |||||||||||||||||||||
| Mapping | |||||||||||||||||||||
| Passos-Bueno et al. (1996) mapped an autosomal recessive form of limb-girdle muscular dystrophy to chromosome 5q33-q34 through linkage analysis in 2 Brazilian kindreds. The maximum lod score was 5.81 at theta = 0.0 with marker D5S470. Passos-Bueno et al. (1996) suggested that the gene may lie in the 9-cM region flanked by the markers D5S470 and D5S820 because of the recombinants observed and because homozygosity was observed in this region. The authors excluded the possibility that LGMD2F and LGMD1A (159000) are caused by mutation in the same gene since the closest marker to LGMD1A maps outside the critical region for LGMD2F. Affected members in these 2 families had a severe clinical phenotype, and muscle biopsy revealed the absence of alpha-sarcoglycan. | |||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||
| In 8 affected members from 4 LGMD2F families from Northern Brazil, Nigro et al. (1996) identified a homozygous 1-bp deletion in the SGCD gene (601411.0001). Following up on the finding of SGCD mutations in Brazilian muscular dystrophy patients, Duggan et al. (1997) studied Duchenne-like and limb-girdle muscular dystrophy patients who were negative for mutations of the dystrophin, SGCA, SGCB, and SGCG genes. They identified 2 American female patients with nonsense mutations of the SGCD gene (601411.0002 and 601411.0003). Microsatellite mapping showed likely consanguinity in the first patient through homozygosity for 13 microsatellite loci covering a 38-cM region of chromosome 5. The second patient was heterozygous. Both girls showed clinical symptoms consistent with Duchenne-like muscular dystrophy. The authors reported the frequency of LGMD2F to be around 4% (2 of 54) in patients with SGCA deficiency by immunostaining. Duggan et al. (1997) concluded that delta-sarcoglycan deficiency occurs in multiple ethnic groups. Furthermore, most or all patients showed a deficiency of the entire sarcoglycan complex, adding support to the hypothesis that these proteins function as a tetrameric unit. Moreira et al. (1998) studied 25 unrelated Duchenne-like muscular dystrophy families, including families originally studied by Nigro et al. (1996). They identified the previously reported frameshift mutation in the SGCD gene (601411.0001) and a novel missense mutation (601411.0004). These 2 mutations caused equally severe phenotypes and were found on distinct haplotypes. Moreira et al. (1998) estimated that the frequency of LGMD2F among their Duchenne-like muscular dystrophy families was at least 13%. Trabelsi et al. (2008) identified a heterozygous mutation in the SGCD gene (601411.0006) in a patient with autosomal recessive LGMD. He was also found to carry a heterozygous partial duplication of exon 1 of the SGCB gene, which is responsible for LGMD2E (604286), although the consequence of the variant on SGCB production was unknown. However, Trabelsi et al. (2008) suggested that this patient had 'double heterozygosity,' or digenic inheritance. The patient showed muscle weakness at age 3 years, complicated by cardiomyopathy at age 13 years. | |||||||||||||||||||||
| Genotype/Phenotype Correlations | |||||||||||||||||||||
| Passos-Bueno et al. (1999) studied 140 patients from 40 Brazilian families with one of 7 autosomal recessive LGMDs. All LGMD2E (604286) and LGMD2F 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 (253600) 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%). | |||||||||||||||||||||
| Animal Model | |||||||||||||||||||||
| The BIO14.6 hamster is a model for sarcoglycan-deficient LGMD with a deletion in the delta-sarcoglycan gene. Holt et al. (1998) investigated the feasibility of sarcoglycan gene transfer for LGMD using a recombinant SGCD adenovirus in the BIO14.6 hamster. They demonstrated extensive long-term expression of delta-sarcoglycan and rescue of the entire sarcoglycan complex, as well as restored stable association of alpha-dystroglycan with the sarcolemma. Importantly, muscle fibers expressing delta-sarcoglycan lacked morphological markers of muscular dystrophy and exhibited restored plasma membrane integrity. Holt et al. (1998) concluded that the sarcoglycan complex is requisite for the maintenance of sarcolemmal integrity, and primary mutations in individual sarcoglycan components can be corrected in vivo. | |||||||||||||||||||||
| REFERENCES | |||||||||||||||||||||
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