Limb-girdle muscular dystrophy type 2F
Overview
sarcoglycanopathies tend to cause a severe Duchenne-like phenotype, but mild Becker-like phenotypes have been described. Overall, these diseases account for about 20-25% of all LGMDs, but they are overrepresented among severe cases. LGMD2D (alpha-sarcoglycan [adhalin]) accounts for 40% of the sarcoglycanopathies, LGMD2C and 2E (gamma-sarcoglycan and beta-sarcoglycan) each account for about 23% and LGMD2F (delta-sarcoglycan) accounts for 14% of cases in the Brazilian population
Causes
LGMD2C-2F are caused by mutations in the sarcoglycan genes. * LGMD2C is caused by a mutation on chromosome 13 in the gamma-sarcoglycan gene. * LGMD2D is caused by a mutation on chromosome 17 in the alpha-sarcoglycan (adhalin) gene. * LGMD2E is caused by a mutation on chromosome 4 in the beta-sarcoglycan gene. * LGMD2F is caused by a mutation on chromosome 5 in the delta-sarcoglycan gene. * Sarcoglycanopathies have a worldwide distribution. Where no founder effect is present, LGMD2D (alpha-sarcoglycanopathy) is the most common form, accounting for about 50% of cases. Missense and nonsense mutations are the most common for all the sarcoglycanopathies, though with gamma-sarcoglycanopathies (LGMD2C), small or large deletions are also common. * The genotype-phenotype correlation is often unclear. In general, nonsense or truncating mutations tend to increase the severity of disease. Interfamilial and intrafamilial variability with LGMD2C, 2D, and 2E is marked. Most mild cases are due to alpha-sarcoglycan mutations (LGMD2D). Patients with LGMD2E and LGMD2C tend to have severe phenotypes, but mild cases can also occur. Patients with the rare delta-sarcoglycan mutation (LGMD2F) tend to have a severe phenotype. * Sarcoglycan protein complex is a transmembrane complex that is part of the large dystrophin glycoprotein complex. The core of the complex is made up of the beta and delta subunits with weaker binding of the alpha and gamma subunits. This complex likely does not bind directly to dystrophin, but binds to the dystroglycan complex which in turn binds to dystrophin. The sarcoglycan complex also binds strongly to sarcospan as well as to alpha-dystrobrevin and filamin. * The function of the sarcoglycan complex is unknown, but it likely stabilizes the dystrophin glycoprotein complex. In the absence of the sarcoglycan complex, binding of dystrophin to beta-dystroglycan and binding of beta-dystroglycan to alpha-dystroglycan are weakened. * The sarcoglycan complex may also play a role in cell signaling based on the following evidence. It may act as a receptor since it has cysteine bonds, common in other receptors, although no substrate has been identified. ATPase activity occurs in alpha-sarcoglycan. The sarcoglycan complex binds alpha-dystrobrevin, which in turn binds to syntrophin, which binds nNOS and voltage-gated sodium channels. * Muscle biopsy usually shows a dystrophic pattern of muscle-fiber necrosis and regeneration similar to that observed in Duchenne muscular dystrophy. * On immunohistochemistry, dystrophin staining is often slightly reduced, but may be normal (whereas sarcoglycan expression may be mildly reduced in Duchenne-Becker muscular dystrophy). Alpha-sarcoglycan mutations cause absent or reduced alpha-sarcoglycan staining with preservation of staining for gamma-sarcoglycan. Minimal or no staining occurs for beta and delta-sarcoglycan. This is the only mutation for which the amount of residual staining (for alpha-sarcoglycan) and the clinical phenotype are correlated. Gamma-sarcoglycan mutations cause absent or reduced gamma-sarcoglycan staining with trace amounts of alpha, beta, and delta-sarcoglycan staining. Beta- and delta-sarcoglycan mutations usually cause absent staining of the entire sarcoglycan complex.
Diagnosis
Patients may have Duchenne- and/or Becker-like weakness but with additional involvement of the periscapular muscles causing scapular winging. Muscle hypertrophy is common. Mental development is normal. Cardiomyopathy may be present in some.
Prognosis
This depends upon the type. In general slow progression of weakness is to be expected. The affected muscles get worse and it spreads to more muscles. Morbidity and mortality varies between the various types but generally an early onset is associated with a more rapid decline and early mortality.6 In the slow types the patient may still be ambulatory 30 years later. The autosomal dominant forms tend to be less severe than the recessive.