Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia

Abstract

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 alpha1A subunit of CaV2.1 channels (CaV2.1alpha1). DNA sequence analysis identified a novel point mutation resulting in a radical amino acid substitution (E147K) in CaV2.1alpha1, 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.

Molecular Targets for Antiepileptic Drug Development

“…A syndrome of absence epilepsy with episodic ataxia similar to that observed in mice has been described in a family with a mutation in the ␣ 1A subunit (Ca v 2.1). 84 In childhood absence epilepsy (CAE), 12 mutations involving CACNA1H (encoding the ␣ 1 subunit Ca v 3.2) have been reported. 85,86 Functional expression studies with several of these mutations have revealed a gain of function.…”

CaV2.1 voltage activated calcium channels and synaptic transmission in familial hemiplegic migraine pathogenesis

“…Disorders not associated with FHM are episodic ataxia type 2 (Zafeiriou et al 2009, Cuenca-Leon et al 2009, Cricchi et al 2007, Jen et al 2004, 2008, Ophoff et al 1996, progressive ataxia (Yue et al 1997), spinocerebellar ataxia type 6 (Tsou et al , Restituito et al 2000, Ishikawa et al 1999, Zhuchenko et al 1997) and absence (Imbrici et al 2004) and generalized epilepsy (Haan et al 2005, Jouvenceau et al 2001). In addition FHM1 mutations were also found in family members who had only "normal" no-paretic migraine but no FHM.…”

Familial Hemiplegic Migraine

“…In humans, mutations in the CACNA1A gene cause, in addition to FHM1, a few autosomal dominant neurological disorders characterized by cerebellar dysfunction, such as episodic ataxia type 2 (that may be associated with absence epilepsy in a few cases) and spinocerebellar ataxia type 6 9,26,27 (compare, Strupp 28 and Gomez 29 31,35,37,38 Recently, the generation of knockin mice carrying two different FHM1 mutations (R192Q and S218L) allowed the first analysis of mutant channels expressed at their endogenous level in neurons. [39][40][41] The studies in heterologous expression systems showed that the FHM1 mutations alter many biophysical properties of human Ca V 2.1 channels, in a complex way.…”