期刊
JOURNAL OF THE NEUROLOGICAL SCIENCES
卷 342, 期 1-2, 页码 69-78出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jns.2014.04.027
关键词
Severe SHM1; Congenital ataxia; Developmental delay; Acetazolamide response; Novel CACNA1A mutation; Gain of function
资金
- Swiss National Science Foundation [310030-135378]
- Swiss National Science Foundation (SNF) [310030_135378] Funding Source: Swiss National Science Foundation (SNF)
Mutations in the CACNA1A gene, encoding the alpha 1 subunit of the voltage-gated calcium channel Ca(V)2.1 (P/Q-type), have been associated with three neurological phenotypes: familial and sporadic hemiplegic migraine type 1 (FHM1, SHM1), episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6 (SCA6). We report a child with congenital ataxia, abnormal eye movements and developmental delay who presented severe attacks of hemiplegic migraine triggered by minor head traumas and associated with hemispheric swelling and seizures. Progressive cerebellar atrophy was also observed. Remission of the attacks was obtained with acetazolamide. A de novo 3 bp deletion was found in heterozygosity causing loss of a phenylalanine residue at position 1502, in one of the critical transmembrane domains of the protein contributing to the inner part of the pore. We characterized the electrophysiology of this mutant in a Xenopus oocyte in vitro system and showed that it causes gain of function of the channel. The mutant Ca(V)2.1 activates at lower voltage threshold than the wild type. These findings provide further evidence of this molecular mechanism as causative of FHM1 and expand the phenotypic spectrum of CACNA1A mutations with a child exhibiting severe SHM1 and non-episodic ataxia of congenital onset. (C) 2014 Elsevier B.V. All rights reserved.
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