Molecular genetic evidence of clinical heterogeneity in Fukuyama-type congenital muscular dystrophy

Fukuyama-type congenital muscular dystrophy (FCMD) is an autosomal recessive severe muscular dystrophy associated with brain malformation. The gene responsible for FCMD was mapped to chromosome 9q31, a region in which convincing evidence of strong linkage disequilibrium between FCMD and mfd220 (D9S306) was recently found. FCMD is also characterized clinically by a peak motor function which, at best, allows patients to sit unassisted or slide on the buttocks. However, a small fraction of patients acquire the capacity to walk unassisted. Whether such ambulant cases belong to the FCMD spectrum or to a different disease entity has been a topic of considerable debate. We performed linkage analysis for ten families with ambulant cases using DNA markers flanking the FCMD locus. The mfd220 locus yielded a significant lod score of 3.09 for ambulant FCMD. We also found evidence for linkage disequilibrium between ambulant FCMD and mfd220. We further conducted haplotype analysis in FCMD siblings with different phenotypes, one of whom was ambulant while the other was not. The results indicate that the FCMD siblings share exactly the same haplotype at nine marker loci spanning 23.3 cM surrounding the FCMD locus. On the basis of these results, we conclude that, genetically, ambulant cases are, in fact, part of the FCMD spectrum. Received: 28 June 1996     

Refined Mapping of a Gene Responsible for Fukuyama-Type Congenital Muscular Dystrophy: Evidence for Strong Linkage Disequilibrium

Fukuyama-type congenital muscular dystrophy (FCMD), the second most common form of childhood muscular dystrophy in Japan, is an autosomal recessive severe muscular dystrophy associated with an anomaly of the brain. After our initial mapping of the FCMD locus to chromosome 9q31-33, we further defined the locus within a region of ~5 cM between loci D9S127 and CA246, by homozygosity mapping in patients born to consanguineous marriages and by recombination analyses in other families. We also found evidence for strong linkage disequilibrium between FCMD and a polymorphic microsatellite marker, mfd220, which showed no recombination and a lod score of (Z) 17.49. A “111-bp” allele for the mfd220 locus was observed in 22 (34%) of 64 FCMD chromosomes, but it was present in only 1 of 120 normal chromosomes. This allelic association with FCMD was highly significant (χ² =50.7; P<.0001). Hence, we suspect that the FCMD gene could lie within a few hundred kilobases of the mfd220 locus.