The overall goal of Project 2 is to perform a genotype/phenotype correlation in families with mutations in the calcium channel gene CACNA1A to understand how these mutations lead to episodes of vertigo and ataxia. Mutations in CACNA1A result in a spectrum of clinical syndromes from hemiplegic migraine to severe progressive ataxia. We hypothesize that the type and location of mutations and the biophysical and biochemical properties of the abnormal channels will explain the phenotypic variability. Under Specific Aim 1, we will systematically document more than 100 families with episodic ataxia type 2 (EA-2), a prototypical inherited channelopathy due to mutations in CACNA1A. All consenting family members will be interviewed, examined, and, whenever possible, quantitative oculomotor function testing will be performed at UCLA. Specific Aim 2 is to develop a microarray system to rapidly screen for currently known mutations and polymorphisms in CACNA1A. Once completed, the microarray system will allow us to screen large numbers of patients with episodic vertigo and ataxia for mutations in CACNA1A. Under Specific Aim 3, we will screen all of the documented families for mutations in CACNA1A using SSCP and TMHA followed by sequencing to document the specific mutation. If no mutation is found after screening CACNA1A in linked families, all exons will be sequenced beginning with the most conserved region of the gene. Specific Aim 4 will characterize the mutant gene products electrophysiologically using whole-cell and single-channel patch clamp techniques and morphologically using confocal microscopy. We will also assess the effects of acetazolamide on the function of the wildtype and mutated channel. Insights gained from the study of EA-2 will shed light on the mechanisms of the more common episodic vertigo and ataxia syndromes, particularly those associated with migraine.