Expanding the Phenotypic Spectrum of CACNA1H Mutations.

BACKGROUND: The CACNA1H gene mutations encoding the α1H subunit of Cav3.2 T-type calcium channels have been associated with generalized epilepsy. Focal or multifocal epilepsy and systemic (immunologic and gastrointestinal) involvement associated with these mutations have not been described previously. We detail the clinical characteristics of five patients with CACNA1H mutations and expand its phenotypic spectrum.

METHODS: A case series of five patients with pathogenic CACNA1H mutations was evaluated. The pathogenicity of the mutations was predicted by polymorphism phenotyping (Polyphen-2) and sorting-intolerant-from-tolerant analysis.

RESULTS: Mean age of seizure onset was 8.2 ± 3.7 years. Three patients had de novo mutations in the CACNA1H gene, and two patients inherited the mutation from an asymptomatic parent. The patients experienced different types of seizures including absence, focal seizures without awareness, focal seizures with secondary generalization, and myoclonic, atonic, and generalized tonic-clonic seizures. Electroencephalography showed focal, multifocal, or generalized discharges. One patient had autism and global developmental delay. Two patients had failure to thrive and selective antibody deficiency.

CONCLUSIONS: CACNA1H mutations can be associated with susceptibility to develop generalized epilepsy and focal or multifocal epilepsy of varying severity. Phenotypic features involving other organ systems (immune, gastrointestinal) can occur in addition to epilepsy, developmental delay, and autism.