Elsevier

Pediatric Neurology

Volume 38, Issue 1, January 2008, Pages 50-52
Pediatric Neurology

Case report
Novel Deletion Mutation in GFAP Gene in an Infantile Form of Alexander Disease

https://doi.org/10.1016/j.pediatrneurol.2007.08.017Get rights and content

Alexander disease is a rare, fatal neurologic disorder characterized by white-matter degeneration and cytoplasmic inclusions in astrocytes known as Rosenthal fibers, which are immunohistochemically positive to glial fibrillary acidic protein. Mutations in the glial fibrillary acidic protein gene were reported in patients with Alexander disease who had clinical and pathologic characteristics of the disease. All reported cases manifest heterozygous missense mutations, except for some insertions or deletions with no frame shift. Our patient had a heterozygous deletion of genomic sequence 1247-1249GGG>GG in exon 8 of the glial fibrillary acidic protein gene, which leads to a frame shift changing 16 amino acids and inducing a stop codon at codon 431 of 432 codons. The deletion mutation induces a structural conformation change in glial fibrillary acidic protein and their abnormal aggregation in astrocytes. This is the first report of a novel deletion mutation in the glial fibrillary acidic protein gene with a frame shift associated with Alexander disease.

Introduction

Alexander disease is a rare, autosomal-dominant, demyelinating disorder, usually with de novo mutations that mainly affect children. The disease is divided into three forms, according to age at onset: infantile, juvenile, and adult. Of these three, the infantile form is the most common. The infantile form presents clinically with megalencephaly, psychomotor retardation and seizures [1]. Cerebral white-matter abnormalities, predominantly in the frontal lobes by computed tomography and magnetic resonance imaging of the brain, are strongly suggestive of the disease [2], but a definitive diagnosis is based on the pathologic analysis of brain histology, especially to confirm white-matter abnormalities with Rosenthal-fiber formation.

Recently, mutations in the glial fibrillary acidic protein (GFAP) gene were reported in patients with Alexander disease who had the characteristic pathology [3]. Mutations in the GFAP gene were subsequently found in many patients with the disease [4], and mutation analysis has become a useful diagnostic tool. Here we present a Japanese boy with the infantile form, with a novel deletion mutation in the GFAP gene.

Section snippets

Case Report

A Japanese boy, aged 1 year and 1 month, was referred to our hospital because of developmental delay. His parents were not related. There was no family history of neuromuscular disorder.

He was born at 39 weeks of gestation after an uneventful delivery. At birth his body height, weight, and head circumstance were 49.0 cm (−0.3 SD), 3058 g (−0.4 SD), and 34.5 cm (+0.7 SD), respectively. He smiled at age 3 months, and gained head control at 4 months of age. He rolled over at age 6 months, but

Discussion

Alexander disease is classified into three forms: infantile, juvenile, and adult, based on age of onset. The infantile form is the most common, and is characterized clinically by megalencephaly, psychomotor retardation, spastic quadriparesis, and seizures, which appear between birth and 2 years of age [1]. Brain computed tomography and magnetic resonance imaging findings of preferential frontal white-matter involvement are strongly suggestive of the disease, except for patients with atypical

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    Although most of these mutations are missense and located within the highly conserved rod domain of GFAP, some insertional and frame-shift mutations have also been identified. These include an in-frame deletion–insertion of two amino acids (K86V87delinsEF) [3], a duplication (R126L127dup) [3], an insertion (Y349Q350insHL) [11], and D417M14X out-of-frame mutation, in which 16 amino acids at the C-terminal of the tail domain are completely altered [12]. All mutations detected so far are heterozygous coding mutations, which are genetically dominant and therefore are expected to act in a gain-of-function fashion.

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