Limb-girdle muscular dystrophy type 2A
Overview
LGMD2A may be the most common autosomal recessive LGMD, accounting for about 30% of all cases in the Brazilian and other populations. In some areas, including the Basque region of Spain (where a founder mutation is identified), LGMD2A accounts for almost 80% of all cases of LGMD.
Causes
* LGMD2A may be the most common autosomal recessive LGMD, accounting for about 30% of all cases in the Brazilian and other populations. In some areas, including the Basque region of Spain (where a founder mutation is identified), LGMD2A accounts for almost 80% of all cases of LGMD. * About two thirds of patients present at 8-15 years of age, with a range of 2-40 years. * The most typical presentation is of weakness due to scapular-humeral-pelvic weakness that may be similar to the presentation of facioscapulohumeral dystrophy. LGMD2I may also have a similar phenotype. * Hip-girdle weakness is most prominent in the gluteus maximus and hip adductors. Along with abdominal weakness, this leads to a wide-based, lordotic gait. * Atrophy is often prominent. * Progression tends to be slow, and wheelchair use begins 11-28 years after the onset of symptoms. * The clinical course varies widely among and within families. * More than 280 different, mostly private, mutations have been identified throughout the calpain-3 gene. With the exception of founder effects in isolated populations, no predominant mutations exist. All types of mutations have been found including nonsense mutations leading to stop codons, missense mutations often leading to decreased catalytic activity of calpain-3, splice site and frameshift mutations, and large deletions or insertions. * In general, null mutations give rise to phenotypes more severe than those due to missense mutations. * Calpain-3 (p94) is a member of the calpain family of intracellular, soluble cysteine proteases that all have calcium-dependent activation. It is expressed almost exclusively in muscle and is likely anchored by titin. * The mechanisms involved in the pathogenesis of LGMD2A are unknown. Calpain-3 is a protease with many substrates that likely is involved in many physiological processes within muscle. It has been proposed to be involved in apoptosis, muscle cell differentiation, sarcomere formation, muscle remodeling, and regulation of the cytoskeleton. One hypothesis suggests that mutations in the calpain-3 gene lead either directly to loss of proteolytic activity or to secondary loss of activity due to its loss of anchorage with titin. The loss of proteolytic activity may lead to reduced turnover of muscle proteins, and an accumulation of damaged proteins that then accumulate within muscle. This leads to a cell stress response and cell toxicity and ultimately to a dystrophic phenotype. * On muscle biopsy, calpain-3 can be visualized by using Western blots but not muscle immunohistochemistry. Correlation between the degree of deficiency and the clinical phenotype can be total, partial, or (in rare cases) nonexistent. Expression of dystrophin and the sarcoglycans is normal. Expression of dysferlin can be reduced. * Presentation with asymptomatic hyperCKemia has been reported in about 10% of cases. * Facial and cardiac involvement have not been reported.
Diagnosis
Patients have prominent atrophy of the periscapular, biceps, gluteus maximus, thigh adductors, and hamstring muscles, with sparing of the hip abductors. Contractures are common, in which case the disease needs to be differentiated from Emery-Dreifuss muscular dystrophy, Bethlem myopathy, and laminin-alpha2 deficiency
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.