Seizure–genotype relationship in Fukuyama-type congenital muscular dystrophy

Fukuyama-type congenital muscular dystrophy (FCMD) is an autosomal recessive disorder prevalent in Japan, characterized by cobblestone lissencephaly and dystrophic changes in skeletal muscle, resulting in mental retardation, epilepsy and motor impairment. FCMD patients in Japan carry at least one copy of an ancestral founder mutation, a 3 kb insertion in a 3′-untranslated region, that results in a reduction in fukutin mRNA levels. We analyzed 35 patients with FCMD and found 18 patients carried a homozygous founder mutation (homozygotes) and 17 a combined heterozygous between founder mutation and a nonsense or missense mutation (heterozygotes). During an average follow-up of over 10 years, 61% of homozygotes and 82% of heterozygotes developed febrile or afebrile seizures. The ages at onset of febrile and afebrile seizures on average were 5.4 and 4.6 years, respectively, in homozygotes and 3.6 and 3.7 years, respectively, in heterozygotes. Repeated seizures were treated with antiepileptic drugs. While all homozygotes showed good seizure control, four heterozygotes had intractable seizures. Mutations other than the 3 kb insertion were identified in seven of 12 heterozygotes examined. Five patients with a nonsense mutation in exon 3 and one with a missense mutation in exon 5 had a severe phenotype and some showed intractable seizures. On the other hand, one with a nonsense mutation in exon 8 had only one febrile seizure. It was concluded mutational analysis of the FCMD gene could predict seizure prognosis. Heterozygotes usually developed seizures earlier than homozygotes and some heterozygotes showed intractable seizures. Mutational analysis other than of the 3 kb insertion may also help to predict seizure prognosis.