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

• Published in: Human molecular genetics Vol. 6; no. 11; pp. 1973 - 1978
• Main Authors: Jodice, Carla, Mantuano, Elide, Veneziano, Liana, Trettel, Flavia, Sabbadini, Guglielmo, Calandriello, Luigi, Francia, Ada, Spadaro, Maria, Pierelli, Francesco, Salvi, Fabrizio, Ophoff, Roel A., Frants, Rune R., Frontali, Marina
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.10.1997
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Biological and medical sciences; Calcium Channels - genetics; Cerebellar Ataxia - genetics; Chromosomes, Human, Pair 19; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Exons; Female; Humans; Introns; Male; Medical sciences; Middle Aged; Mutation; Neurology; Pedigree; Phenotype; Spinocerebellar Degenerations - genetics; Trinucleotide Repeats; Cerebellum; Human; Nervous system diseases; Calcium; Ionic channel; Cerebral disorder; Genetic disease; Spinocerebellar heredodegeneration; Cerebellar disease; Gene; Microsatellite DNA; Central nervous system disease; Phenotype variation; Ataxia; Genetics; Instability; Degenerative disease; Mutation; Neurological disorder; Spinal cord disease; Expansion
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/6.11.1973

Point mutations of the CACNA1A gene coding for the α1A 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 spinocere-bellar 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 pheno-typic 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.