Clinical, genetic, and expression studies of mutations in the potassium channel gene KCNA1 reveal new phenotypic variability

Episodic ataxia type 1 (EA1) is an autosomal dominant central nervous syste m potassium channelopathy characterized by brief attacks of cerebellar atax ia and continuous interictal myokymia. Point mutations in the voltage-gated potassium channel gene KCNA1 on chromosome 12p associate with EA1. We have studied 4 families and identified three new and one previously reported he terozygous point mutations in this gene. Affected members in Family A (KCNA 1 G724C) exhibit partial epilepsy and myokymia but no ataxic episodes, supp orting the suggestion that there is an association between mutations of KCN A1 and epilepsy. Affected members in Family B (KCNA1 C731A) exhibit myokymi a alone, suggesting a new phenotype of isolated myokymia. Family C harbors the first truncation to be reported in KCNA1 (C1249T) and exhibits remarkab ly drug-resistant EA1. Affected members in Family D (KCNA1 G1210A) exhibit attacks typical of EA1. This mutation has recently been reported in an appa rently unrelated family, although no functional studies were attempted. Het erologous expression of the proteins encoded by the mutant KCNA1 genes sugg est that the four point mutations impair delayed-rectifier type potassium c urrents by different mechanisms. Increased neuronal excitability is likely to be the common pathophysiological basis for the disease in these families . The degree and nature of the potassium channel dysfunction may be relevan t to the new phenotypic observations reported in this study.