title: Early-onset progressive ataxia associated with the first CACNA1A mutation identified within the I-II loop.
abstract: Familial hemiplegic migraine type 1, spinocerebellar ataxia type 6 (SCA6) and episodic ataxia type 2 (EA2) are allelic disorders associated with mutations in the CACNA1A gene, which encodes the alpha1 subunit of the P/Q-type calcium channel (Ca(V)2.1). SCA6 and EA2 share a number of clinical features, such as prominent cerebellar involvement and good response to acetazolamide therapy. However, while SCA6 develops as a late-onset, progressive ataxia, EA2 has an earlier, and episodic, onset. We report on two sisters with a heterogeneous clinical phenotype. The first developed progressive cerebellar ataxia after age 30, without noticeable episodes of vertigo or headache. A 1 year trial with acetazolamide did not produce significant results. The other reported episodes of vertigo, headache and gait imbalance since late childhood, with good response to acetazolamide, before developing moderate chronic cerebellar ataxia. Brain MRI showed cerebellar atrophy, especially in the vermis, in both patients. Direct sequencing of CACNA1A identified a heterozygous 1360G>A mutation in exon 11 resulting in the substitution of alanine for threonine at residue 454 (p.Ala454Thr). This is the first description of a change residing in the cytoplasmic I-II loop associated with a clinical phenotype.
authors.affiliation: IRCCS San Raffaele, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Cricchi
authors.forename: C
authors.initials: C
authors.lastname: Di Lorenzo
authors.forename: G S
authors.initials: GS
authors.lastname: Grieco
authors.forename: C
authors.initials: C
authors.lastname: Rengo
authors.forename: A
authors.initials: A
authors.lastname: Cardinale
authors.forename: M
authors.initials: M
authors.lastname: Racaniello
authors.forename: F M
authors.initials: FM
authors.lastname: Santorelli
authors.forename: G
authors.initials: G
authors.lastname: Nappi
authors.forename: F
authors.initials: F
authors.lastname: Pierelli
authors.forename: C
authors.initials: C
authors.lastname: Casali
mesh_terms: D000086:Acetazolamide / Q000627:therapeutic use; D017668:Age of Onset; D019943:Amino Acid Substitution / Q000235:genetics; D015220:Calcium Channels / Q000235:genetics*; D002257:Carbonic Anhydrase Inhibitors / Q000627:therapeutic use; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005091:Exons / Q000235:genetics; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D013132:Spinocerebellar Degenerations / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D016896:Treatment Outcome; D020864:Calcium Channels, N-Type
chemical_list: D000086:Acetazolamide; D015220:Calcium Channels; D002257:Carbonic Anhydrase Inhibitors; D005819:Genetic Markers; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type