From Genotype to Phenotype: Expanding the Clinical Spectrum of CACNA1A Variants in the Era of Next Generation Sequencing.
From Genotype to Phenotype: Expanding the Clinical Spectrum of CACNA1A Variants in the Era of Next Generation Sequencing.
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从基因型到表型：在下一代测序时代扩大CACNA1A变体的临床谱。
DOI：
10.3389/fneur.2021.639994
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发表时间：
2021
影响因子：
3.4
通讯作者：
Boesch S
中科院分区：
文献类型：
--
作者：
Indelicato E;Boesch S
离子通道功能障碍是发作性神经功能障碍的重要病理基础。与发作性运动障碍相关的经典基因是CACNA1A，它编码神经元钙通道P/Q的致孔亚单位。非多谷氨酰胺CACNA1a变异导致家族性偏瘫共济失调1型(FHM1)和发作性共济失调2型(EA2)。FHM1的典型发作性表现是偏头痛发作，在此之前有运动先兆，包括偏瘫、失语和意识障碍，直到昏迷。患有EA2的患者反复发作眩晕、平衡失调、复视和呕吐。除了这些典型的表现外，一些报告强调了与P/Q通道病相关的多种临床特征，从慢性进行性小脑性共济失调到癫痫和精神障碍。这些表现往往比典型的间歇性症状持续时间更长，从而导致诊断工作中的缺陷。最近，下一代测序技术的普及将从头CACNA1A变体与更广泛的表型谱联系起来，包括早期发育迟缓、自闭症谱系障碍、癫痫脑病和早发性阵发性肌张力障碍。年龄依赖性代表了这些表型的一个引人注目的新方面，并突出了P/Q通道在特定时间窗口中在中枢神经系统发育中的关键作用。虽然一些综述涉及FHM1和EA2的临床表现和治疗，但缺乏对新描述的年龄依赖表现的概述。在这篇简短的综述中，我们介绍了临床最新进展，描述了基因型-表型的相关性，并总结了与CACNA1A变异相关的扩展表型潜在的病理生理机制的证据。
Ion channel dysfunction is a key pathological substrate of episodic neurological disorders. A classical gene associated to paroxysmal movement disorders is CACNA1A, which codes for the pore-forming subunit of the neuronal calcium channel P/Q. Non-polyglutamine CACNA1A variants underlie familial hemiplegic ataxia type 1 (FHM1) and episodic ataxia type 2 (EA2). Classical paroxysmal manifestations of FHM1 are migraine attacks preceded by motor aura consisting of hemiparesis, aphasia, and disturbances of consciousness until coma. Patients with EA2 suffer of recurrent episodes of vertigo, unbalance, diplopia, and vomiting. Beyond these typical presentations, several reports highlighted manifold clinical features associated with P/Q channelopathies, from chronic progressive cerebellar ataxia to epilepsy and psychiatric disturbances. These manifestations may often outlast the burden of classical episodic symptoms leading to pitfalls in the diagnostic work-up. Lately, the spreading of next generation sequencing techniques linked de novo CACNA1A variants to an even broader phenotypic spectrum including early developmental delay, autism spectrum disorders, epileptic encephalopathy, and early onset paroxysmal dystonia. The age-dependency represents a striking new aspect of these phenotypes und highlights a pivotal role for P/Q channels in the development of the central nervous system in a defined time window. While several reviews addressed the clinical presentation and treatment of FHM1 and EA2, an overview of the newly described age-dependent manifestations is lacking. In this Mini-Review we present a clinical update, delineate genotype-phenotype correlations as well as summarize evidence on the pathophysiological mechanisms underlying the expanded phenotype associated with CACNA1A variants.
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影响因子：
4.9
作者：
Debiais, S.;Hommet, C.;Autret, A.
通讯作者：
Autret, A.
影响因子：
64.5
作者：
Du X;Wang J;Zhu H;Rinaldo L;Lamar KM;Palmenberg AC;Hansel C;Gomez CM
通讯作者：
Gomez CM
DOI：
10.1073/pnas.1009500107
发表时间：
2010-10-26
影响因子：
11.1
作者：
Adams, Paul J.;Rungta, Ravi L.;Snutch, Terrance P.
通讯作者：
Snutch, Terrance P.
影响因子：
2.4
作者：
Beauvais, K;Cavé-Riant, F;Furby, A
通讯作者：
Furby, A
影响因子：
16.2
作者：
Du, Xiaofei;Wei, Cenfu;Gomez, Christopher M.
通讯作者：
Gomez, Christopher M.