Case reportNovel Deletion Mutation in GFAP Gene in an Infantile Form of 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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Type I Alexander disease: Update and validation of the clinical evolution-based classification
2023, Molecular Genetics and MetabolismGFAP variants leading to infantile Alexander disease: Phenotype and genotype analysis of 135 cases and report of a de novo variant
2021, Clinical Neurology and NeurosurgeryAlexander disease
2018, Handbook of Clinical NeurologyCitation Excerpt :Most recently, Nam et al. (2015) reported a truncation mutation at position E312, predicting a significantly shortened protein. Two mutations modify the C-terminus, in one case modifying the sequence from D417 on, and in the other at V431, but with an extension of another 11 amino acids ( Murakami et al., 2008; Flint et al., 2012). A complete list of published mutations is accessible at a website maintained by the Waisman Center at the University of Wisconsin-Madison (www.waisman.wisc.edu/alexander/mutation.pdf).
Diagnostic Imaging: Brain
2016, Diagnostic Imaging: BrainImaging in Neurology
2016, Imaging in NeurologyAlexander disease causing mutations in the C-terminal domain of GFAP are deleterious both to assembly and network formation with the potential to both activate caspase 3 and decrease cell viability
2011, Experimental Cell ResearchCitation Excerpt :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.