Haplotype-phenotype correlation in Fukuyama congenital muscular dystrophy

In typical Fukuyama congenital muscular dystrophy (FCMD), peak motor functi on is usually only unassisted sitting or sliding on the buttocks, though a few patients are able to walk at some point. However, a few patients have a severe phenotype and never acquire head control. In addition, it is clinic ally difficult to differentiate this severe FCMD from Walker-Warburg syndro me (WWS) or from muscle-eye-brain disease (MEBD), In order to establish a g enotype-phenotype correlation, we performed haplotype analysis using micros atellite markers closest to the FCMD gene (FCMD) in 56 Japanese FCMD famili es, including 35 families whose children were diagnosed as FCMD with the ty pical phenotype, 12 families with a mild phenotype, and 9 families with a s evere phenotype, Of the 12 propositi with the mild phenotype, 8 could walk and the other 4 could stand with support; 10 cases were homozygous for the ancestral founder (A-F) haplotype whereas the other 2 were heterozygous for the haplotype, In the 9 severe cases, who had never acquired head control or the ability to sit without support, 3 had progressive hydrocephalus, 2 r equired a shunt operation, and 7 had ophthalmological abnormalities. Haplot ype analysis showed that 8 of the 9 cases of the severe phenotype are heter ozygous for the A-F haplotype, and the other one homozygous for the haploty pe, We confirmed that at least one chromosome in each of the 56 FCMD patien ts has the A-F haplotype, The rate of heterozygosity for the A-F haplotypes was significantly higher in severe cases than in typical or mild cases (P < 0,005), Severe FCMD patients appeared to be compound heterozygotes for th e founder mutation and another mutation. Thus, the present study yielded mo lecular genetic evidence of a broad clinical spectrum in FCMD, Am, J, Med. Genet, 92:184-190, 2000, (C) 2000 Wiley-Liss, Inc.