Objective: To describe a previously unreported variant in the CACNA1A gene in a patient with episodic ataxia type 2 (EA2) phenotype.

Background: EA2 is the most common form of episodic ataxia, characterized by recurrent ataxia lasting for hours with asymptomatic interictal periods with onset in childhood. Interictal oculomotor disturbances are frequent, including down beating nystagmus, but neurological examination can be normal. More than 50% of patients have comorbid migraine. EA2 is caused by heterozygous pathogenic variants in the CACNA1A gene, which encodes the alpha-1a subunit of the P/Q-type calcium channel expressed in cerebellar Purkinje cells.

Method: Retrospective chart review of a single case with a clinical phenotype of EA2 and a previously undescribed variant in the CACNA1A gene.

Results: A 60-year-old man with a history of migraine presented with childhood-onset episodes of imbalance with inability to walk, incoordination, and dysarthria, lasting for hours and with variable frequency from weekly to monthly. Family history was unknown because the patient was adopted. Interictal periods were asymptomatic with unremarkable neurological examination.

The clinical phenotype was consistent with EA2. Sequencing and copy number variation analysis were completed for the episodic ataxia genes, including KCNA1, CACNA1A, CACNB4 and SCL1A3. The CACNA1A gene showed a heterozygous missense variant c.5216 T>C (p.Phe1739Ser) in exon 34, classified as variant of uncertain significance with unknown inheritance pattern. This variant is absent in general population databases and is nearby other pathogenic variants reported in EA2. Missense variants are a common disease mechanism, and in silico models suggest this variant disrupts the gene function. Considering these genetic characteristics, we postulate this variant is likely causative of the EA2 phenotype in our patient. For this reason, the patient was started on acetazolamide for prevention of ataxia episodes.

Conclusion: To our knowledge, the c.5216T>C variant in the CACNA1A gene has not been previously described in EA2. The variant’s absence in general population databases, proximity to known pathogenic variants, in silico models suggestive of disruptive gene function, and associated phenotype consistent with EA2 in our patient, make this variant likely causative of our patient’s symptoms.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/episodic-ataxia-type-2-a-previously-undescribed-variant-in-the-cacna1a-gene/