MIGRAINE, ATAXIA AND EPILEPSY - A CHALLENGING SPECTRUM OF GENETICALLY-DETERMINED CALCIUM CHANNELOPATHIES

Clinical and genetic heterogeneity as well as influence of environment al factors have hampered identification of the genetic factors which a re involved in episodic diseases such as migraine, episodic ataxia and epilepsy. The study of rare, but clearly genetically determined subty pes, may help to unravel the pathogenesis of the more common forms. Re cently, different types of mutation in the brain-specific P/Q type cal cium channel alpha(1A) subunit gene (CACNA1A) on chromosome 19p13 were shown to be involved in three human disorders: familial hemiplegic mi graine (FHM), episodic ataxia type 2 (EA2), and chronic spinocerebella r ataxia type 6 (SCA6). In addition, evidence is accumulating that the same gene is also involved in the common forms of migraine with and w ithout aura. In the tottering and leaner mouse, which are characterise d by epilepsy and ataxia, similar mutations were identified in the mou se homologue of the calcium channel alpha(1A) subunit gene. These find ings add to the growing list of episodic (and now also chronic) neurol ogical disorders, which are caused by inherited abnormalities of volta ge-dependent ion channels. The findings in migraine illustrate that ra re, but monogenic variants of a disorder, may be successfully used to identify candidate genes for the more common, but genetically more com plex, forms.