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

• Published in: Journal of neurology, neurosurgery and psychiatry Vol. 81; no. 8; pp. 840 - 843
• Main Authors: Romaniello, Romina, Zucca, Claudio, Tonelli, Alessandra, Bonato, Sara, Baschirotto, Cinzia, Zanotta, Nicoletta, Epifanio, Roberta, Righini, Andrea, Bresolin, Nereo, Bassi, Maria T, Borgatti, Renato
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01-08-2010; BMJ Publishing Group; BMJ Publishing Group LTD
• Subjects: Age of Onset; Amino Acid Sequence; Ataxia; Biological and medical sciences; Brain - pathology; Calcium Channels - genetics; Cerebral Cortex - pathology; Child; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; DNA Mutational Analysis; Electrodiagnosis; Electroencephalography; Evoked Potentials - physiology; Exons - genetics; Female; Fourth Ventricle - pathology; Headaches; Humans; Medical sciences; Migraine; Migraine with Aura - etiology; Migraine with Aura - genetics; Molecular Sequence Data; Mutation; Mutation - physiology; Mutation, Missense - genetics; Nervous System Diseases - genetics; Nervous System Diseases - pathology; Nervous System Diseases - physiopathology; Neurology; Pedigree; Sleep deprivation; Spinocerebellar Ataxias - etiology; Spinocerebellar Ataxias - genetics; Nervous system diseases; Mutation
• ISSN: 0022-3050; 1468-330X
• DOI: 10.1136/jnnp.2008.163402

BackgroundMutations 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).ObjectiveTo 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 methodsA clinical, molecular, neuroradiological and neurophysiological study was carried out in all subjects.ResultsA 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.ConclusionsThis 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.