Seizure–genotype relationship in Fukuyama-type congenital muscular dystrophy

Abstract

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.

Introduction

Cortical malformations are being increasingly implicated in the etiology of childhood epilepsy. There are genes that are known to cause pediatric epilepsy in association with specific brain malformation. Identifying the disease genes for such disorders not only allows us to develop DNA-based diagnostic tests and provide better genetic counseling, it also helps us understand the basic mechanisms of brain development and epileptogenesis [1], [2].

Fukuyama-type congenital muscular dystrophy (FCMD), the second most common muscular dystrophy in Japan, is an autosomal recessive disorder characterized by brain malformation and dystrophic changes in skeletal muscle, resulting in mental retardation, epilepsy and motor impairment [3], [4]. Previous autopsy studies of FCMD revealed that the major pathologic change in the central nervous system is polymicrogyria of the cerebrum and cerebellum [5], [6]. Its structure is characteristic; unlike the four-layered type, the regulated layer structure is almost lost (unlayered form of polymicrogyria), with marked proliferation of blood vessels and connective tissues, and in some regions, thickened meninges and blood vessels enter the molecular layer irregularly (cobblestone lissencephaly). Studies in affected fetuses demonstrate that the abnormal cytoarchitecture results from gaps in the glial limiting membrane that allow migrating neurons and glia to climb past the true cortical plate onto the brain surface and into the subarachnoid space [7], [8]. Gross pathologic findings seen on computed tomography (CT) or magnetic resonance imaging (MRI) include unlayered polymicrogyria within the cerebral cortex that is primarily in the frontal lobes and pachygyria that is largely temporo-occipital [9], [10]. In the cerebellum, numerous intraparenchymal cysts closely related to the polymicrogyria are seen at the hemispheres [10]. FCMD could be a natural model for studying the epileptogenesis of prenatal cortical lesions.

Recently, Toda et al. identified the gene responsible for FCMD on 9q31,which encodes a novel 461-amino-acid protein termed fukutin [11], [12]. Most FCMD-bearing chromosomes are derived from a single ancestral founder, and a 3 kb retrotransposal insertion into the 3′ untranslated region of this gene was found to be a founder mutation. This insertion is thought to destabilize the transcript. Point mutations in the FCMD gene have been described only in combination with a retrotransposal insertion in compound heterozygotes in Japan, which indicates that a true null mutation is either lethal or very rare. It was reported that the majority of FCMD patients carry two founder insertions (homozygous), while few are compound heterozygous [13]. In addition, combined heterozygotes between a founder mutation and nonsense or deletion mutations generally have a more severe phenotype than individuals homozygous for the founder mutation.

The association of epilepsies and related seizure disorders in FCMD has been reported in more than half of the patients [4], [14], [15]. However, the long-term prognosis of seizure disorders and the relationship between seizures and genotypes have been little studied. Recently, we examined 46 patients with FCMD diagnosed according to the standard criteria described by Fukuyama et al. in 1960 [3] and followed their progress for more than three years (average 13 years), with special reference to long-term prognosis of seizure disorders and the relationship between seizures and neuropathologic abnormalities [16]. We found seizures were observed in 37 patients (80%) with an average age at onset of three years, one month and that later these seizures developed into Lennox–Gastaut syndrome in three patients. After the discovery of FCMD gene fukutin, mutational analysis has usually been performed to diagnose patients suggestive of FCMD according to the standard criteria. Here, we analyzed the relationship between seizures and genotypes in FCMD to predict prognosis of seizures and to consider treatment of epilepsies associated with FCMD.