MOLECULAR-GENETIC EVIDENCE OF CLINICAL HETEROGENEITY IN FUKUYAMA-TYPECONGENITAL MUSCULAR-DYSTROPHY

Fukuyama-type congenital muscular dystrophy (FCMD) is an autosomal rec essive severe muscular dystrophy associated with brain malformation. T he gene responsible for FCMD was mapped to chromosome 9q31, a region i n which convincing evidence of strong linkage disequilibrium between F CMD and mfd220 (D9S306) was recently found. FCMD is also characterized clinically by a peak motor function which, at best, allows patients t o sit unassisted or slide on the buttocks. However, a small fraction o f patients acquire the capacity to walk unassisted. Whether such ambul ant cases belong to the FCMD spectrum or to a different disease entity has been a topic of considerable debate. We performed linkage analysi s for ten families with ambulant cases using DNA markers flanking the FCMD locus. The mfd220 locus yielded a significant lod score of 3.09 f or ambulant FCMD. We also found evidence for linkage disequilibrium be tween ambulant FCMD and mfd220. We further conducted haplotype analysi s in FCMD siblings with different phenotype, one of whom was ambulant while the other was not. The results indicate that the FCMD siblings s hare exactly the same haplotype at nine marker loci spanning 23.3 cM s urrounding the FCMD locus. On the basis of these results, we conclude that, genetically, ambulant cases are, in fact, part of the FCMD spect rum.