A wide spectrum of clinical, neurophysiological and neuroradiological abnormalities in a family with a novel CACNA1A mutation

Background Mutations in the calcium channel voltage dependent P/Q-type α-1A subunit ( CACNA1A ) can cause different neurological disorders which share a wide range of symptoms, including episodic ataxia type 2 (EA2), familial hemiplegic migraine (FHM1) and progressive spinocerebellar ataxia (SCA6). Objective To describe a three generations family in which a spectrum of different phenotypes, ranging from SCA6 (proband), to EA2 (proband's mother) to FHM1 (proband's mother and proband's aunt) was found. All of the family members carried a novel CACNA1A missense mutation. Patients and methods A clinical, molecular, neuroradiological and neurophysiological study was carried out in all subjects. Results A single heterozygous base change in exon 9, c1213G→A, leading to the amino acid substitution pAla405Thr was found to segregate within the family. Brain MRI showed cerebellar and cerebral atrophy signs in all but one mutation carriers. Neurophysiological findings (electroencephalography and evoked potentials) confirmed possible cerebral cortex and white matter involvement regardless of the clinical symptoms displayed. Conclusions This novel CACNA1A mutation adds to the number of mutations associated with a heterogeneous clinical picture in family members. This mutation might affect the interaction between the intracellular loops and the β subunit, leading to a relatively rapid cell death. In order to explain the wide phenotypic variability observed in this family, it is hypothesised that additional genetic and environmental (hormonal) factors play a role in the pathophysiology of the disease.