Battistini S, Stenirri S, Piatti M, Gelfi C, Righetti P G, Rocchi R, Giannini F, Battistini N, Guazzi G C, Ferrari M, Carrera P
Institute of Neurological Sciences, University of Siena, Italy.
Neurology. 1999 Jul 13;53(1):38-43. doi: 10.1212/wnl.53.1.38.
To search for mutations in the calcium channel gene CACNA1A and to study the genotype-phenotype correlation in a family with a severe familial hemiplegic migraine (FHM) phenotype and a slowly progressive cerebellar ataxia.
CACNA1A gene mutations on chromosome 19 are involved in approximately 50% of FHM families. The association of FHM and cerebellar ataxia has been reported in a small number of FHM families, all linked to chromosome 19.
The proband, in addition to typical hemiplegic migraine attacks, experienced severe episodes during which hemiplegia was associated with acutely altered consciousness and fever lasting several days. She, as well as her affected sister, developed a permanent, late-onset cerebellar ataxia and cerebellar atrophy evident on MRI. Linkage analysis was performed and the whole CACNA1A gene, 47 exon-intron boundaries, was analyzed by double gradient-denaturing gradient gel electrophoresis (DG-DGGE).
Genetic studies suggested linkage to chromosome 19p13, and DG-DGGE analysis detected a heteroduplex fragment in exon 13 of the CACNA1A gene. By direct sequencing, a G-to-A substitution resulting in an arginine to glutamine change at codon 583 in the second putative voltage sensor domain of the channel alpha1A-subunit, was identified, possibly representing the disease-causing mutation. The proband and her affected sister were treated with acetazolamide, reporting freedom from new FHM attacks but no benefit in the progression of ataxia.
The combination of episodic dysfunction and permanent deficit could depend on the variety of functions of calcium channels and their distribution in the nervous system.
在一个具有严重家族性偏瘫性偏头痛（FHM）表型和缓慢进展性小脑共济失调的家系中，寻找钙通道基因CACNA1A的突变，并研究基因型与表型的相关性。
19号染色体上的CACNA1A基因突变约涉及50%的FHM家系。少数FHM家系报道了FHM与小脑共济失调的关联，均与19号染色体连锁。
先证者除典型的偏瘫性偏头痛发作外，还经历了严重发作，发作期间偏瘫与意识急剧改变和持续数天的发热相关。她以及她患病的妹妹出现了永久性的迟发性小脑共济失调，MRI显示小脑萎缩。进行了连锁分析，并通过双梯度变性梯度凝胶电泳（DG-DGGE）分析了整个CACNA1A基因的47个外显子-内含子边界。
遗传学研究提示与19p13连锁，DG-DGGE分析在CACNA1A基因的第13外显子中检测到一个异源双链片段。通过直接测序，在通道α1A亚基第二个假定电压传感器结构域的第583密码子处鉴定出一个G到A的替换，导致精氨酸变为谷氨酰胺，可能代表致病突变。先证者和她患病的妹妹接受了乙酰唑胺治疗，报告称没有新的FHM发作，但对共济失调的进展没有益处。
发作性功能障碍和永久性缺陷的组合可能取决于钙通道的多种功能及其在神经系统中的分布。
