Résumé :
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Limb girdle muscular dystrophies are a heterogeneous group of pathologies characterized by weakness and wasting of the limb girdle muscles, with typical sparing of the face. To date, seven autosomal dominant forms (LGMD1A-G) and thirteen autosomal recessive forms (LGMD2A-M) have been characterised. All of the LGMD are rare diseases and some of them have only been described in a few families or in ethnic groups. We have recruited a group of five living and reviewed the records of five deceased distantly related French-Canadians of Acadian descent affected by a childhood-onset form of recessive LGMD. All cases originate from the small archipelago of the Magdalen Islands isolated in the Gulf of St-Lawrence. Clinical characterization of the disease was performed on all affected individuals. A SNP genome scan was performed on all affected individuals and one parent to uncover the genetic locus of the disease. All cases present with limb girdle weakness on average at the age of 7 years but they lose walking at a wide range of ages. Children have normal motor milestones and intelligence. With time, they develop macroglossia, decreased pulmonary function, hyperlordosis, large calves and mild to moderate contractures. Creatine kinase levels are elevated (663-10,000 U/L) in the first decades, but are back to normal at later stages. Muscle pathology showed non-specific dystrophic changes without any specific histological findings. Homozygosity mapping was used for analysis based on the likely sharing of the same founder mutation. A chromosomal region of 0.6Mb not previously associated with a muscular dystrophy on chromosome 17q21.31 was uncovered (multipoint LOD score 3.1). The sequencing of the two most promising candidate genes uncovered a rare missense polymorphism in a conserved integrin domain of ITGA2B. This study presents the description of a new recessive childhood-onset limb-girdle muscular dystrophy and the mapping of its original chromosomal locus.
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