Brain, Vol. 119, No. 6, 1895-1909, 1996
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research-article |
Clinical and molecular analysis of a large family with three distinct phenotypes of progressive muscular dystrophy
1Department of Neurology, Brain Research Institute, Niigata University Niigata, Japan 2Department of Neurogenetics Niigata, Japan 3Laboratory of Pathology, Institute of Neurology, Russian Academy of Medical Sciences Niigata, Japan 4Department of Pathomorphology, Institute of Paediatrics and Child Surgery Niigata, Japan 5Department of Molecular Basis of Human Genetics, Institute of Molecular Genetics, Russian Academy of Sciences Niigata, Japan 6N. I. Vavilov Institute of General Genetics, Russian Academy of Sciences Moscow, Russia
Correspondence to:
Correspondence to: Dr Sergei N. Illarioshkin, Department of Neurogenetics, Institute of Neurology, Russian Academy of Medical Sciences, Volokolamskoye Shosse 80, Moscow 123367, Russia
We describe a unique six–generation, highly consanguineous family originating from an isolated mountainous village in the Russian province of Daghestan. Three separate clinical phenotypes of progressive muscular dystrophy were identified in this large family. Seven patients developed a classical limb–girdle variant of muscular dystrophy (LGMD), with disease onset at 15–30 years and loss of ambulation within a 25–year course. The second group included three patients with a slowly progressive distal myopathy first manifested in the late teens and confined to the tibial and calf muscles. Each of these two phenotypes segregated independently as an autosomal recessive trait, and muscle biopsies showed non–specific myopathic changes. Lastly, two male siblings exhibited an atypical variant of Duchenne muscular dystrophy confirmed by detection of a deletion in the dystrophin gene. To clarify the molecular basis of the polymorphic autosomal recessive form of muscular dystrophy in this kindred, we performed molecular genetic studies on 67 family members and obtained significant evidence for linkage to chromosome 2p. A maximum pairwise lod (logarithm of odds) score of 5.64 was achieved at the zero recombination fraction (i.e. at 
= 0.00) for locus D2S291; multipoint linkage analysis confirmed the most likely location of a mutant gene near D2S291. The patients with LGMD and those with the distal muscular dystrophy phenotype share a common affected homozygous haplotype associated with the same founder chromosome; key recombinants defined D2S286 and D2S292 to be the closest loci flanking the mutant gene. Remarkably, two clinically distinct forms of autosomal recessive muscular dystrophy, LGMD type 2B (LGMD2B) and Miyoshi myopathy, were recently mapped to the same locus. We suggest that all three chromosome 2p–linked conditions may represent allelic disorders, i.e. different phenotypic expressions of a single gene.
autosomal recessive muscular dystrophy; clinical phenotypes; molecular genetics; linkage analysis; chromosome 2p
Received May 14, 1996. Revised August 3, 1996. Accepted August 9, 1996.
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