Terwindt G M, Ophoff R A, Haan J, Sandkuijl L A, Frants R R, Ferrari M D
Department of Neurology, Leiden University Medical Centre, The Netherlands.
Eur J Hum Genet. 1998 Jul-Aug;6(4):297-307. doi: 10.1038/sj.ejhg.5200206.
Clinical and genetic heterogeneity as well as influence of environmental factors have hampered identification of the genetic factors which are involved in episodic diseases such as migraine, episodic ataxia and epilepsy. The study of rare, but clearly genetically determined subtypes, may help to unravel the pathogenesis of the more common forms. Recently, different types of mutation in the brain-specific P/Q type calcium channel alpha 1A subunit gene (CACNA1A) on chromosome 19p13 were shown to be involved in three human disorders: familial hemiplegic migraine (FHM), episodic ataxia type 2 (EA2), and chronic spinocerebellar ataxia type 6 (SCA6). In addition, evidence is accumulating that the same gene is also involved in the common forms of migraine with and without aura. In the tottering and leaner mouse, which are characterised by epilepsy and ataxia, similar mutations were identified in the mouse homologue of the calcium channel alpha 1A subunit gene. These findings add to the growing list of episodic (and now also chronic) neurological disorders, which are caused by inherited abnormalities of voltage-dependent ion channels. The findings in migraine illustrate that rare, but monogenic variants of a disorder, may be successfully used to identify candidate genes for the more common, but genetically more complex, forms.
临床和遗传异质性以及环境因素的影响阻碍了对涉及偏头痛、发作性共济失调和癫痫等发作性疾病的遗传因素的识别。对罕见但明确由基因决定的亚型的研究，可能有助于揭示更常见形式的发病机制。最近，位于19号染色体p13上的脑特异性P/Q型钙通道α1A亚基基因（CACNA1A）的不同类型突变被证明与三种人类疾病有关：家族性偏瘫性偏头痛（FHM）、发作性共济失调2型（EA2）和慢性脊髓小脑共济失调6型（SCA6）。此外，越来越多的证据表明，同一基因也与有先兆和无先兆的常见偏头痛形式有关。在以癫痫和共济失调为特征的蹒跚小鼠和瘦小鼠中，在钙通道α1A亚基基因的小鼠同源物中发现了类似的突变。这些发现增加了由电压依赖性离子通道的遗传异常引起的发作性（现在也包括慢性）神经系统疾病的种类。偏头痛的研究结果表明，一种疾病的罕见但单基因变体，可能成功地用于识别更常见但遗传上更复杂形式的候选基因。
