Objective: To identify the disease-causing mutation and to characterize penetrance and phenotypic variability in a large pedigree with episodic ataxia type 2 (EA-2) previously linked to chromosome 19.
Background: Mutations in the CACNA1A gene on chromosome 19 encoding a calcium channel subunit cause EA-2, which is characterized by recurrent attacks of imbalance with interictal eye movement abnormalities.
Methods: The authors used single-strand conformation polymorphism (SSCP) analysis to screen for point mutations, and direct sequencing to identify mutations in CACNA1A. Allele-specific oligonucleotides were designed to detect the presence of the diseased allele in members of their pedigree as well as in normal control subjects.
Results: Reassessment of members of the pedigree revealed two notable clinical features. Diffuse weakness during attacks of ataxia was a prominent complaint. Two affected individuals had had episodic hemiplegia, one with typical migraine headaches. SSCP analysis revealed aberrant bands in exon 29 in affected members but not in normal control subjects. Direct sequencing of exon 29 identified a C-to-T change at position 4914 of the coding sequence of CACNA1A, predicting an early stop code at codon 1547. Two asymptomatic mutation carriers demonstrated the incomplete penetrance of this mutation.
Conclusions: A nonsense mutation in CACNA1A causes episodic ataxia and complaint of weakness, and may be associated with hemiplegia.