CACNA1A mutation in a EA-2 patient responsive to acetazolamide and valproic acid.
BACKGROUND
Episodic ataxia type-2 (EA-2) is an autosomal dominant neurological disorder that has been shown to result from mutations in the CACNA1A gene encoding the P/Q-type calcium channel. Affected individuals experience episodes of cerebellar ataxia usually associated with migraine symptoms, interictal nystagmus, mild residual and in some cases a progressive cerebellar incoordination and respond to acetazolamide treatment. We identified a patient with a positive family history for episodic ataxia, who was originally diagnosed with epilepsy and treated with valproic acid. Subsequent examination revealed that the symptoms were consistent with a diagnosis of EA-2. The patient responded positively to a combination of acetazolamide and valproic acid. Molecular genetic analysis of the CACNA1A gene was performed in order to confirm a diagnosis of EA-2.


METHODS
The CACNA1A gene was evaluated for mutations using single strand conformational polymorphism analysis and direct DNA sequencing. Allele specific oligo hybridization was used to confirm that the mutation was segregating with only affected family members and was not present in the control group.


RESULTS
In this study we identified a new missense mutation in exon 12 of the CACNA1A gene from a patient with EA-2 whose symptoms could be controlled with a combination of acetazolamide and valproic acid. This G to A transition changes a highly conserved glutamic acid residue to a lysine residue in domain II S2 of the P/Q-type calcium channel alpha1A subunit.


CONCLUSIONS
The use of valproic acid in treating patients with EA-2 is not well documented. Here we describe a patient with a novel mutation in the CACNA1A gene who responded positively to a combination of acetazolamide and valproic acid.
Scoggan
Kylie A
KA
Ottawa Health Research Institute, Ottawa, ON, Canada.
Friedman
Joseph H
JH
Bulman
Dennis E
DE
D000086:Acetazolamide / Q000627:therapeutic use*; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D015220:Calcium Channels / Q000235:genetics*; D003937:Diagnosis, Differential; D004827:Epilepsy / Q000175:diagnosis; D005260:Female; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D017385:Sequence Homology; D020754:Spinocerebellar Ataxias / Q000188:drug therapy / Q000235:genetics*; D014635:Valproic Acid / Q000627:therapeutic use*; D020864:Calcium Channels, N-Type
D000086:Acetazolamide; D000927:Anticonvulsants; D015220:Calcium Channels; D014635:Valproic Acid; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type