Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNA1A gene on chromosome 19p.
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.
Jodice
C
C
Dipartimento di Biologia, Università di Tor Vergata, Rome, Italy.
Mantuano
E
E
Veneziano
L
L
Trettel
F
F
Sabbadini
G
G
Calandriello
L
L
Francia
A
A
Spadaro
M
M
Pierelli
F
F
Salvi
F
F
Ophoff
R A
RA
Frants
R R
RR
Frontali
M
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D015220:Calcium Channels / Q000235:genetics*; D002524:Cerebellar Ataxia / Q000235:genetics*; D002888:Chromosomes, Human, Pair 19; D005091:Exons; D005260:Female; D006801:Humans; D007438:Introns; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D013132:Spinocerebellar Degenerations / Q000235:genetics*; D018911:Trinucleotide Repeats; D020864:Calcium Channels, N-Type
D015220:Calcium Channels; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type