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|Year : 2015 | Volume
| Issue : 4 | Page : 495-496
Limb girdle muscular dystrophies in India
Satish V Khadilkar
Department of Neurology, Grant Medical College and Sir J J Group of Government Hospitals, Mumbai, Maharashtra, India
|Date of Web Publication||4-Aug-2015|
Satish V Khadilkar
Department of Neurology, Grant Medical College and Sir J J Group of Government Hospitals, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Khadilkar SV. Limb girdle muscular dystrophies in India. Neurol India 2015;63:495-6
The term "limb girdle muscular dystrophy" (LGMD) encompasses myopathies with proximal limb weakness of the pelvic or shoulder girdles. As the clinical boundaries are broad, the basket includes a wide variety of inherited conditions, both autosomal-recessive and dominant. The information on the genetic and molecular aspects of LGMD has been expanding steadily and at this point in time, at least 25 defined conditions are included in this category. At the molecular level, most of these diseases affect the cytoskeleton, weakening the sarcolemma, resulting in a gradual cell damage. Others affect the enzymatic processes, as exemplified by caveolinopathy.
Evaluation of patients with LGMD is challenging. The clinical features are often nondiagnostic, though some clinical clues are known. Early and prominent scapular winging, abdominal herniae, or upper limb onset favors the diagnosis of calpainopathies. Similarly, the brunt of weakness on gastrocnemius and hamstrings is associated with dysferlinopathies, and early prominent foot drop with sparing of quadriceps femoris muscles is seen in patients with GNE myopathy. "Biceps lump" and "diamond on quadriceps"  have been described in patients with dysferlinopathy. Alpha- and gamma-sarcoglycanopathies tend to mimic Duchenne muscular dystrophy, presenting early in life with large calves and severe myopathy. Rippling of muscles is seen in patients with caveolinopathy. However, the clinical features mentioned above are not unique to any disease subtype. For example, scapular winging, common with calpainopathies, is also seen in patients having sarcoglycanopathies, GNE myopathies, etc., The distal posterior weakness phenotype of dysferlinopathies is shared almost entirely by the newer condition, anoctaminopathy. Thus, the clinician has limitations in narrowing down the differential diagnosis.
Same limitations hold true for the widely available laboratory tests in India, such as creatine kinase (CK), electromyography, and the basic histology. Markedly elevated CK levels are seen in dysferlinopathies, sarcoglycanopathies, and calpainopathies, whereas GNE myopathies tend to have low CK levels, often below 1000 IU. Electrophysiology in expert hands may offer hints to the early or severe involvement of groups of muscles to corroborate with clinical evaluation but further leads are difficult to obtain. Histology with basic stains confirms the "final common pathway" showing dystrophic changes in fiber size variation, internalization of nuclei, fiber loss, splitting, degenerating and regenerating fibers, and connective tissue changes. At times, further diagnostic clues may come from conventional histology, e.g., vacuoles, suggesting GNE myopathy and the eosinophilic cellular response in calpainopathy.
Detailed histological and genetic tests are, therefore, necessary for the diagnostic evaluation of patients with LGMDs. These involve qualitative and quantitative testing of various immunostains and sequencing methods performed on DNA. Such tests are available in very few centers in India and as a result, only a small proportion of our LGMD patients have been well evaluated till date. On this background, the paper in this issue of Neurology India, by Nalini et al.,  on immunophenotyping of LGMD 2 assumes importance. In this prospective study, a large number of autosomal-recessive LGMD patients were analyzed. Muscle immunohistochemistry and western blot analysis of the biopsy samples are the highlight of the investigation. The authors confirmed the presence of previously documented LGMDs in India, the calpainopathies, dysferlinopathies, and sarcoglycanopathies. The present investigation found dyferlinopathy to be the most common, followed by alpha-dystroglycanopathies. Sarcoglycanopathies were seen in 14% and calpainopathies were less common, at 10% of the cohort. Importantly, the authors newly document the existence of LGMD 2G, 2H, 2J, 2I, and 2K in a small proportion of cases. The information on alpha-dystroglycanopathies is also new in the Indian context. It needs to be borne in mind, and the authors state in their discussion that there are limitations to the techniques employed and the final diagnosis will have to be achieved by a cohesive addition of the genetic information.
Analysis of information available on the subtypes of LGMDs in various parts of India gives interesting facts and points out the differences in the prevalence of LGMD subtypes in hospital-based data. In a study from North India, Pathak et al.  found calpainopathies to be the most common type, almost accounting for half of the studied samples. In the authors work from the West India, calpainopathies seem to form about one-third of the diagnosed LGMDs. GNE myopathy is common in South India and also in parts of Rajasthan, Gujarat, and Madhya Pradesh. Dysferlinopathies seem less common in a series from West India.  Sharma et al. emphasize the rarity of sarcoglycanopathies in their study material from North India.  Seeing these differences, the authors' proposition in the current investigation that the breakup of subtypes from a single center in South India can serve as a roadmap for the whole country may not be truly applicable.
Given the ethnic diversity of our Indian population, it is not surprising that such differences exist. Hence, the knowledge of the locally prevalent conditions will have to be gradually developed to evolve local paradigms of best-yield investigations to save on costs and efforts. As we know, marriages in blood relatives are common in India. Marriages in communities but not among blood relatives are commonplace as well. Thus, the genetic pools have been segregated over long periods of time in our country. Possibilities of common mutations and founder effects in communities are to be expected and worked upon. In my personal experience, one such investigation in the Agarwals' has had practical benefits.  Agarwals marry within the community. The paternal "gotras" are matched during arranged marriages, but maternal are not, a case of intra-communal exogamy. LGMD patients in this community were studied and were detected to be having calpainopathy. Subsequently, two founder mutations in the calpain 3 gene were identified. Most of the Agarwals with calpainopathy have the same two mutations in combinations. Equipped with this information, it has been possible to give genetic diagnosis to the affected, identify individuals at risk, and provide marriage counseling and antenatal diagnosis for the Agarwal community. In our unique country, such focused attempts, combined with large-scale hospital-based and prevalence data, will hopefully evolve locally applicable strategies to benefit the plethora of Indian LGMD patients.
| » References|| |
Pradhan S. Diamond on quadriceps: A frequent sign in dysferlinopathy. Neurology 2008;70:322.
Nalini A, Singh RJ, Saini J, Prasad C, Mahadevan A. Magnetic resonance neurography identifies involvement of plexuses in leprous neuropathy. Neuro India 2015;63:624-6.
Pathak P, Sharma MC, Sarkar C, Jha P, Suri V, Mohd H, et al.
Limb girdle muscular dystrophy type 2A in India: A study based on semi-quantitative protein analysis, with clinical and histopathological correlation. Neurol India 2010;58:549-54.
Khadilkar SV, Singh RK, Kulkarni KS, Chitale AR. A study of clinical and laboratory features of 14 Indian patients with dysferlinopathy. J Clin Neuromuscul Dis 2004;6:1-8.
Sharma MC, Mannan R, Singh NG, Gulati G, Kalra V, Sarkar C. Sarcoglycanopathy: An enigmatic form of muscular dystrophy: A report of 7 cases. Neurol India 2004;52:446-9.
Ankala A, Kohn JN, Dastur R, Gaitonde P, Khadilkar SV, Hegde MR. Ancestral founder mutations in calpain-3 in the Indian Agarwal community: Historical, clinical, and molecular perspective. Muscle Nerve 2013;47:931-7.
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