Juvenile limb-girdle muscular dystrophy

Abstract

A series of patients affected by a muscular dystrophy, similar to the original description of a juvenile scapulo-humeral form by Erb in 1884 and fitting with the criteria used to define limb-girdle muscular dystrophies, was discovered in a small community living in the southern part of Reunion Island in the Indian Ocean. A detailed clinical analysis was conducted over 5 years on a cohort of 20 patients. This community presented a high degree of consanguinity as it was segregated from the majority of the island population for more than a century. In previous molecular genetic studies, the disease locus has been mapped to chromosome 15p. Mutations were recently identified in a gene located in this region encoding for muscle-specific calcium activated neutral protease (CANP3). Clinical, pathological, genetic and complete identification of the mutations are presented here, establishing, for the first time, precise clinico-genetic correlations in this form of autosomal recessive, juvenile, limb-girdle muscular dystrophy (LGMD).

Natural history of LGMD2A for delineating outcome measures in clinical trials

“…In terms of clinical presentation, our study confirms and further delineates the picture previously reported in several earlier studies 2, 3, 21, 22, 23, 24, 25, 26. Muscle weakness, which is remarkably symmetrical, is predominant in the axial muscles of the trunk and proximal muscles of the lower limb.…”

“…Indeed, patients carrying two null mutations that result in the premature truncation of protein synthesis are invariably characterized by a higher disease severity than patients with at least one missense mutation 2, 22, 34. Our study is no exception since, for a large number of parameters, the null mutations tend to lead not only to a more severe presentation, but we also observed that the M2 group corresponds to the less severe group (Table 2C).…”

“…Among the previous studies aimed at describing the clinical features of the disease, only the initial publications reported a follow‐up of the progression2, 3, 21, 22 that was roughly evaluated using the Gardner–Medwin and Walton scale 37. The interindividual variability as measured by MMT, QMT, and MFM was significant, both at baseline and over the follow‐up, yielding small to modest SRM in most of the variables used.…”

“…Interestingly, its prevalence is markedly higher in a couple of genetic isolates such as in the Reunion Island, an overseas French territory, in the Basque province of Gipuzkoa, Spain, and in several Amish communities settled in the United States 1, 2, 3…”

Limb-girdle muscular dystrophies in India: A review

“…c.550delA mutation is the most common allele in Caucasian populations. [30] Founder effect for the c.550delA mutation has been demonstrated in the Eastern Mediterranean region (Russia, Croatia, Bulgaria, and Northern Italy)[313233343536373839404142] Other rare mutations which have a founder effect in small populations due to cultural inbreeding associated with historical, demographic, or religious factors have been reported in the population of La Reunion Island in the Indian Ocean (c.946-1G>A),[43] in the Old Order Amish community in Northern Indiana in the USA (c.2306G>A),[4445] in the Guipuzcoa region of the Basque Country of Spain and in Brazil (c.2362_2363delAGinsTCATCT),[464748] Japan (c.1795_1796insA),[495051] the Chioggia village in the Venetian lagoon (p.R490Q),[35] the Mocheni population in the Italian Alps (c.1193 + 6T>A),[52] and the Agarwal community in Northern India (p.D780H and c.2099-1G>T). [53] The last one is relevant to India and hence is discussed further.…”