Brain Advance Access originally published online on October 13, 2004
Brain 2004 127(12):2682-2692; doi:10.1093/brain/awh301
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Brain Vol. 127 No. 12 © Guarantors of Brain 2004; all rights reserved
Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia
1 Departments of Molecular Neuroscience and Clinical and Experimental Epilepsy, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, 2 Department of Paediatrics, University College London, London WC1E 6JJ, UK and 3 Department of Neurology, Louisiana State University School of Medicine, Shreveport, LA 71103, USA
Correspondence to: Dr M. G. Hanna, Box 102, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK E-mail: mhanna{at}ion.ucl.ac.uk
The molecular basis of idiopathic generalized epilepsy remains poorly understood. Absence epilepsy with 3 Hz spike–wave EEG is one of the most common human epilepsies, and is associated with significant morbidity. Several spontaneously occurring genetic mouse models of absence epilepsy are caused by dysfunction of the P/Q-type voltage-gated calcium channel CaV2.1. Such mice exhibit a primary generalized spike–wave EEG, with frequencies in the range of 5–7 Hz, often associated with ataxia, evidence of cerebellar degeneration and abnormal posturing. Previously, we identified a single case of severe primary generalized epilepsy with ataxia associated with CaV2.1 dysfunction, suggesting a possible link between this channel and human absence epilepsy. We now report a family in which absence epilepsy segregates in an autosomal dominant fashion through three generations. Five members exhibit a combination of absence epilepsy (with 3 Hz spike–wave) and cerebellar ataxia. In patients with the absence epilepsy/ataxia phenotype, genetic marker analysis was consistent with linkage to the CACNA1A gene on chromosome 19, which encodes the main pore-forming 
1A subunit of CaV2.1 channels (CaV2.11). DNA sequence analysis identified a novel point mutation resulting in a radical amino acid substitution (E147K) in CaV2.11, which segregated with the epilepsy/ataxia phenotype. Functional expression studies using human CACNA1A cDNA demonstrated that the E147K mutation results in impairment of calcium channel function. Impaired function of the brain calcium channel CaV2.1 may have a central role in the pathogenesis of certain cases of primary generalized epilepsy, particularly when associated with ataxia, which may be wrongly ascribed to anticonvulsant medication.
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