Episodic Ataxia Type 2 (EA2) and Spinocerebellar Ataxia Type 6 (SCA6) Due to CAG Repeat Expansion in the CACNA1A Gene on Chromosome 19p

Abstract

Point mutations of the CACNA1A gene coding for the alpha 1A voltage-dependent calcium channel subunit are responsible for familial hemiplegic migraine (FHM) and episodic ataxia type 2 (EA2). In addition, expansions of the CAG repeat motif at the 3' end of the gene, smaller than those responsible for dynamic mutation disorders, were found in patients with a progressive spinocerebellar ataxia, named SCA6. In the present work, the analysis of two new families with small CAG expansions of the CACNA1A gene is presented. In one family, with a clinical diagnosis of EA2, a CAG23 repeat allele segregated in patients showing different interictal symptoms, ranging from nystagmus only to severe progressive cerebellar ataxia. No additional mutations in coding and intron-exon junction sequences in disequilibrium with the CAG expansion were found. In the second family, initially classified as autosomal dominant cerebellar ataxia of unknown type, an inter-generational allele size change showed that a CAG20 allele was associated with an EA2 phenotype and a CAG25 allele with progressive cerebellar ataxia. These results show that EA2 and SCA6 are the same disorder with a high phenotypic variability, at least partly related to the number of repeats, and suggest that the small expansions may not be as stable as previously reported. A refinement of the coding and intron-exon junction sequences of the CACNA1A gene is also provided.

Clinical and molecular advances in autosomal dominant cerebellar ataxias: from genotype to phenotype and physiopathology

“…72,73 Only few expansions exceed 100 repeat units and are associated with infantile cases in SCA2 74 and SCA7. [75][76][77][78] Usually, normal and expanded alleles carry uninterrupted CAG repeats and there is no overlap between the normal and pathological range.…”

“…45 18,110 Episodic ataxia has been described as the presenting sign in some SCA6 patients. 72 The clinical signs associated with the SCA1 mutation are in general broader and homogeneous, and the patients have usually a pyramidal syndrome, often with hyperreflexia.…”

Functional Importance of L- and P/Q-Type Voltage-Gated Calcium Channels in Human Renal Vasculature

“…27 In humans, mutations in the gene encoding the Ca V 2.1 subunit are associated with episodic ataxia type 2, familial hemiplegic migraine, and spinocerebellar ataxia type 6. 28,29 Whether mutations in the Ca V 2.1 subunit gene are involved in the pathogenesis of renal and vascular disorders is unknown.…”

Recent Advances in RNA Interference Therapeutics for CNS Diseases

“…SCA6 is characterized by progressive ataxia, dysarthria, and nystagmus. Onset generally occurs in the fifth decade of life and lifespan is not shortened [108,109]. Neurodegeneration occurs selectively in the PCs of the cerebellum with no neuropathy in other neurons, making it a pure cerebellar ataxia [110].…”