Identification of novel and recurrent CACNA1A gene mutations in fifteen patients with episodic ataxia type 2.
Episodic ataxia type 2 is a rare autosomal dominant disease characterized by recurrent attacks of vertigo and cerebellar ataxia. The disease was caused by mutations in the CACNA1A gene, on chromosome 19p. We perform a mutational screening in a group of 43 unrelated patients. Forty-two patients presented episodes of disequilibrium and ataxia, and one child was studied because of the occurrence of episodic torticollis. The genetic analysis showed 15 mutated patients (35%). In 13 cases we found novel CACNA1A gene mutations, including missense, protein truncating, and aberrant splicing mutations. Two truncating mutations lead to the uppermost premature stop so far reported, challenging recent hypotheses on dominant negative effect. In patients without CACNA1A mutations, molecular testing for CACNB4 gene mutations excluded this genetic subtype. Clinical features of mutated subjects mostly confirmed previous sign and symptoms associated with EA2, including paroxysmal torticollis and mental retardation. CACNA1A mutated patients have an earlier age at onset, interictal nystagmus, and abnormalities of ocular movements. A review of all CACNA1A mutations so far reported showed that they are mainly located downstream exon 18. Our data substantially increase the number of the described CACNA1A mutations, and propose clinical and molecular criteria for a more focused genetic screening.
Mantuano
Elide
E
Institute of Neurobiology and Molecular Medicine, CNR, Rome, Italy.
Romano
Silvia
S
Veneziano
Liana
L
Gellera
Cinzia
C
Castellotti
Barbara
B
Caimi
Sara
S
Testa
Daniela
D
Estienne
Margherita
M
Zorzi
Giovanna
G
Bugiani
Marianna
M
Rajabally
Yusuf A
YA
Barcina
Maria J Garcìa
MJ
Servidei
Serena
S
Panico
Aurora
A
Frontali
Marina
M
Mariotti
Caterina
C
D000293:Adolescent; D000328:Adult; D000368:Aged; D001259:Ataxia / Q000235:genetics*; D015220:Calcium Channels / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype; D055815:Young Adult; D020864:Calcium Channels, N-Type
D015220:Calcium Channels; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type; C107598:CACNB4 protein, human