Early ReportHuman epilepsy associated with dysfunction of the brain P/Q-type calcium channel
Introduction
Mutations in ion channel genes cause several rare paroxysmal neurological disorders.1 Brain potassium2, 3 and sodium4 channel genetic defects have been implicated in two, quite rare, human epilepsy phenotypes. However, genes that could be implicated in commoner forms of human epilepsy, such as absence epilepsy, have yet to be identified. Several spontaneously occurring mouse mutants represent good models for human absence epilepsy, notably tottering, leaner, lethargic and stargazer mice.5 These murine models harbour mutations in the genes coding for subunits making up brain P/Q-type voltage-gated Ca2+ ion channels and exhibit absence epilepsy, cerebellar degeneration, and ataxia. Despite these animal data, no convincing link between dysfunction of this channel and human epilepsy has yet been described.
These models also share some features with another autosomal dominant disease, episodic ataxia type 2 (EA2). EA2 is characterised by severe and extended attacks of cerebellar ataxia and dysarthria commonly associated with diplopia or headache. Patients usually develop a progressive interictal cerebellar syndrome due to cerebellar damage,6 which is supported by evidence on magnetic resonance imaging of vermian atrophy.7 EA2 is caused by several different mutations in CACNA1A, localised on chromosome 19p, which codes for the α1A (or CaV2.1) subunit of the P/Q-type Ca2+ channel.8 The mutations reported in EA2 kindreds so far (figure 1) mainly give rise to truncated α1A subunits, either because they code for premature stop codons or because they lead to aberrant splicing.8, 9, 10, 11 The consequences of these truncations for channel function are unknown, however.
We sequenced the coding region of the CACNA1A gene in a child with early-onset absence epilepsy and cerebellar ataxia.
Section snippets
Patient
The patient was a healthy baby delivered at full term, but he had mildly delayed motor and cognitive milestones and was described by his mother as a clumsy child. At the age of 3 years he developed nocturnal generalised tonic-clonic seizures and daytime absence seizures. The generalised tonic-clonic seizures stopped after age 8 years but he continued to have absence seizures. From age 8 years he also developed attacks of gait unsteadiness, dysarthria, and diplopia, sometimes leading to falls
Results
We identified a heterozygous point mutation (C5733T) in CACNA1A, which results in an arginine (CGA) to stop (TGA) change at aminoacid position 1820 (figure 1). This mutation was absent from 200 control chromosomes, including those of both parents. Paternity tests showed that 13 of 14 markers were informative and all 13 were shared by the father and proband. On the basis of allele frequencies, the probability that such sharing would occur in the presence of non-paternity is less than one in a
Discussion
We have described a patient with a complex phenotype, which includes epilepsy, episodic ataxia, and a progressive, disabling, fixed cerebellar syndrome. The epilepsy was regarded as primary generalised, including both generalised tonic-clonic seizures without warning, and frequent absence attacks. The generalised polyspike and wave pattern of the electroencephalogram supports generalised epilepsy. The episodes of ataxia were quite different to the epileptic attacks, and extensive metabolic
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