Congenital ataxia and hemiplegic migraine with cerebral edema associated with a novel gain of function mutation in the calcium channel CACNA1A
Congenital ataxia and hemiplegic migraine with cerebral edema associated with a novel gain of function mutation in the calcium channel CACNA1A
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DOI：
10.1016/j.jns.2014.04.027
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发表时间：
2014-07-15
影响因子：
4.4
通讯作者：
Roulet-Perez, Eliane
中科院分区：
文献类型：
--
作者：
Segarra, Nuria Garcia;Gautschi, Ivan;Roulet-Perez, Eliane
编码电压门控钙通道Ca（V）2.1（P/Q型）α 1亚基的CACNA 1A基因突变与三种神经学表型相关：家族性和散发性偏瘫性偏头痛1型（FHM 1、SHM 1）、发作性共济失调2型（EA 2）和脊髓小脑共济失调6型（SCA 6）。我们报告一个患有先天性共济失调、眼球运动异常和发育迟缓的孩子，他因轻微的头部创伤引发严重的偏瘫性偏头痛，并伴有半球肿胀和癫痫发作。还观察到进行性小脑萎缩。用乙酰唑胺后，发作缓解。在杂合性中发现了从头3 bp缺失，导致在位置1502处的苯丙氨酸残基的丢失，该位置位于有助于孔内部的蛋白质的关键跨膜结构域之一中。我们的特点是在非洲爪蟾卵母细胞在体外系统的电生理学的突变，并表明它会导致获得的通道功能。突变体Ca（V）2.1在比野生型更低的电压阈值下激活。这些发现进一步证明了这种分子机制是FHM 1的病因，并扩大了CACNA 1A突变的表型谱，其中一名儿童表现出严重的SHM 1和先天性发作的非发作性共济失调。(C)2014爱思唯尔有限公司版权所有。
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.