LIMB-GIRDLE MUSCULAR-DYSTROPHY AND MIYOSHI MYOPATHY IN AN ABORIGINAL CANADIAN KINDRED MAP TO LGMD2B AND SEGREGATE WITH THE SAME HAPLOTYPE

We report the results of our investigations of a large, inbred, aborig inal Canadian kindred with nine muscular dystrophy patients. The ances try of all but two of the carrier parents could be traced to a founder couple, seven generations back. Seven patients presented with proxima l myopathy consistent with limb girdle-type muscular dystrophy (LGMD), whereas two patients manifested predominantly distal wasting and weak ness consistent with Miyoshi myopathy (distal autosomal recessive musc ular dystrophy) (MM). Age at onset of symptoms, degree of creatine kin ase elevation, and muscle histology were similar in both phenotypes. S egregation of LGMD/MM is consistent with autosomal recessive inheritan ce, and the putative locus is significantly linked (LOD scores >3.0) t o six marker loci that span the region of the LGMD2B locus on chromoso me 2p. Our initial hypothesis that the affected patients would all be homozygous by descent for microsatellite markers surrounding the disea se locus was rejected. Rather, two different core haplotypes, encompas sing a 4-cM region spanned by D2S291-D2S145-D2S286, segregated with th e disease, indicating that there are two mutant alleles of independent origin in this kindred. There was no association, however, between th e two different haplotypes and clinical variability; they do not disti nguish between the LGMD and MM phenotypes. Thus, we conclude that LGMD and MM in our population are caused by the same mutation in LGMD2B an d that additional factors, both genetic and nongenetic, must contribut e to the clinical phenotype.