title: Clinical, genetic, and expression studies of mutations in the potassium channel gene KCNA1 reveal new phenotypic variability.
abstract: Episodic ataxia type 1 (EA1) is an autosomal dominant central nervous system potassium channelopathy characterized by brief attacks of cerebellar ataxia 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 heterozygous point mutations in this gene. Affected members in Family A (KCNA1 G724C) exhibit partial epilepsy and myokymia but no ataxic episodes, supporting the suggestion that there is an association between mutations of KCNA1 and epilepsy. Affected members in Family B (KCNA1 C731A) exhibit myokymia alone, suggesting a new phenotype of isolated myokymia. Family C harbors the first truncation to be reported in KCNA1 (C1249T) and exhibits remarkably drug-resistant EA1. Affected members in Family D (KCNA1 G1210A) exhibit attacks typical of EA1. This mutation has recently been reported in an apparently unrelated family, although no functional studies were attempted. Heterologous expression of the proteins encoded by the mutant KCNA1 genes suggest that the four point mutations impair delayed-rectifier type potassium currents 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 relevant to the new phenotypic observations reported in this study.
authors.affiliation: University Department of Clinical Neurology, Institute of Neurology/University College of London, Queen Square, UK.
authors.forename: L H
authors.initials: LH
authors.lastname: Eunson
authors.forename: R
authors.initials: R
authors.lastname: Rea
authors.forename: S M
authors.initials: SM
authors.lastname: Zuberi
authors.forename: S
authors.initials: S
authors.lastname: Youroukos
authors.forename: C P
authors.initials: CP
authors.lastname: Panayiotopoulos
authors.forename: R
authors.initials: R
authors.lastname: Liguori
authors.forename: P
authors.initials: P
authors.lastname: Avoni
authors.forename: R C
authors.initials: RC
authors.lastname: McWilliam
authors.forename: J B
authors.initials: JB
authors.lastname: Stephenson
authors.forename: M G
authors.initials: MG
authors.lastname: Hanna
authors.forename: D M
authors.initials: DM
authors.lastname: Kullmann
authors.forename: A
authors.initials: A
authors.lastname: Spauschus
mesh_terms: D000200:Action Potentials / Q000235:genetics / Q000502:physiology; D000328:Adult; D002675:Child, Preschool; D005260:Female; D006801:Humans; D051662:Kv1.1 Potassium Channel; D008297:Male; D010375:Pedigree; D010641:Phenotype; D015221:Potassium Channels / Q000235:genetics* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated
chemical_list: C496946:KCNA1 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D051662:Kv1.1 Potassium Channel