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Neurology India, Vol. 58, No. 4, July-August, 2010, pp. 509-511 Editorial Limb-girdle muscular dystrophy type 2A Pradhan Sunil Department of Neurology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow Date of Acceptance: 21-Jul-2010 Code Number: ni10139 PMID: 20739783 DOI: 10.4103/0028-3886.68658 Limb-girdle muscular dystrophy type 2A (LGMD-2A) is an autosomal recessive neuromuscular disorder characterized mainly by symmetrical and selective wasting of the pelvic, scapular and trunk muscles. Face, heart and cognition are typically spared. Abdominal muscles are lax and weak. Unlike sarcoglycanopathy (LGMD 2C-2F), quadriceps femoris muscle is relatively preserved, calf hypertrophy is less frequent and macroglossia is never seen. [1] There is clinical and MRI evidence of more selective weakness of the posterior compartment of thigh. Also, hip adductors are characteristically weak, but this is not specific to LGMD-2A and has been described in relation with sarcoglycanopathy by Khadilkar and Singh as hip-abduction sign. [2] Serum creatine kinase is moderately elevated. Muscle biopsy shows necrotic regeneration pattern. In most cases, symptoms start at 10 to 20 years of age; and with gradual progression, patients become chair-bound 10 to 20 years after the onset of symptoms. Calpains are intracellular calcium-modulated non-lysosomal cysteine proteases which remove portions of protein substrates, thereby irreversibly modifying their function. [3],[4] Members of the calpain protease family are present in different tissues of a variety of organisms. Some calpains are ubiquitously expressed, while others are tissue specific. Calpains are thought to be involved in several physiological events, but their precise functions are only poorly understood. Alterations in two of the calpains have been identified as being responsible for a human disease: (1) calpain-3, causing limb-girdle muscular dystrophy type 2A; and (2) calpain-10, involved in non-insulin-dependent diabetes. [5] The human calpain-3 gene (CAPN3) localizes to chromosome 15q15.1-15.3 and has 24 exons spanning 53 kb of DNA. [3],[4] The gene has a peculiarity of having many small exons, while intron 1 alone with a size of 24.3 kb covers about half of the gene. The calpain-3 gene is predominantly expressed in skeletal muscle tissue as a 3.5-kb RNA transcript that is responsible for the production of gene product CAPN3 protein (a protease). Calpain-3 is a muscle-specific 94-kDa protein. CAPN3 protein has four main domains: (1) inserted sequence 1 (IS1), containing proteolytic domain; (2) IS2, containing connectin-/ titin-binding site; (3) NS, containing domain; and (4) a calcium-binding site with Ca-dependent autocatalytic domain. Ono et al. [6] constructed nine CAPN3 missense mutations found in LGMD-2A and analyzed the functional consequences. [6] All mutants almost completely lost their proteolytic activity but retained their autolytic and connectin-/ titin-binding ability. This led to the initial belief that these latter properties are perhaps not involved in the LGMD-2A phenotype. These results provided strong evidence that LGMD-2A results from the loss of proteolysis of substrates by calpain-3, suggesting that muscular dystrophies may develop from such a novel molecular mechanism as well. [6] However, using Western blot analysis, nearly 20% of LGMD-2A patients had been found to have a normal CAPN3 expression. In these patients, deranged Ca 2+ -dependent autocatalytic activity [7] and alteration in other CAPN3 substrates (titin and filamin C) [8] have been predicted to be responsible for the disease. These and some other studies also suggested CAPN3 to be a muscle cytoskeleton regulator. [9] Mutations in LGMD-2A have been found distributed along the entire length of the CAPN3 gene. A small hot spot is present in exon 21 and exon 11 with excess of missense mutations. Although some mutations are found more frequently, most represent individual variants. Some mutations were found on only one haplotype, suggesting a common ancestry, e.g., metropolitan French families having common ancestry with Turkish and Amish communities; and families from Reunion Island having common ancestry with Basques and among themselves. Thus, a single test may not be good enough in arriving at the proper diagnosis. This is because of the fact that only ~80% of the Western blot-confirmed cases of calpainopathy have abnormality in CAPN3 gene expression, and only ~80% of patients with CAPN3 gene abnormalities have LGMD-2A phenotype. The incidence of LGMD-2A has been found to be the highest (nearly 40%) among all LGMDs in most of the European countries, while it was much less (around 26%) in Japan [10] and still lesser (around 10%) in United States. [11] In this context, the article by Pathak et al.[12] in this issue is perhaps the first of its kind from India which gives idea about the prevalence of LGMD-2A and its clinical features in patients confirmed by Western blot. But due to reasons mentioned above, better picture would emerge with simultaneous genetic study of Western blot-confirmed calpainopathy, Western blot-negative but clinically possible LGMD-2A, all other LGMDs and other unclassified muscular dystrophies. This is evident from one of the Spanish studies in which combination of positive clinical and Western blot studies could correctly diagnose 90% of the LGMD-2A patients; while among those negative for both, 12% still had LGMD-2A. [13] Several variations in the LGMD phenotype have been reported in different ethnic groups. The gluteo-tibial (Leyden-Moebius) variant, which is characterized by the primary affection of muscles of pelvic girdle and shin with early contractures of ankle joints, tip-toe walking, calf enlargement and gradual progression to shoulder girdle muscles, was the most frequent presentation in the Russian population; this was attributed to c.550delA mutation in the CAPN3 gene. [14] Among the genetically confirmed Czech LGMD-2A patients, a few have been found on histopathology to have neurogenic changes in the muscle biopsy. [15] In one of the Japanese studies, pelvic and shoulder girdle muscle involvement was found to be the most prominent feature. [16] The article by Pathak et al.[12] in this issue would be the first authentic report on phenotypic presentation of this Indian LGMD-2A cohort. As shown by other authors, however, the actual phenotype expression of LGMD-2A is expected to be much broader if genetic studies are carried out in addition to the diagnostic workup. [17] Still more accurate assessment of the prevalence of this disease would be possible with the inclusion of the pre-symptomatic patients with hyperCKemia, which has shown a remarkable difference in the approach to this disease [18] - nearly similar to what has been observed in patients with dystrophinopathies. From the point of view of the developing countries where the Western blot technique is not well developed for calpain analysis, some pathologists have shown interest in the observation of lobulated muscle fibers in the diagnosis of LGMD-2A, where these fibers are definitely seen with much higher frequency compared to other muscle diseases even though these fibers would generally suggest chronicity of the muscular dystrophy. [19] More studies are perhaps needed to understand what is the predictive value of these lobulated muscle fibers in the diagnosis of LGMD-2A. References
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