Objective: To report a partial gene deletion in CaCNA1A associated with ataxia.

Background: CaCNA1A gene, located on chromosome 19p, encodes the alpha-1a subunit of the P/Q-type calcium channel Cav2.1. Allelic disorders associated with this gene include episodic ataxia type 2 (EA2), spinocerebellar ataxia type 6, and familial hemiplegic migraine.^[1] EA2 manifests with vertigo and nystagmus and may also be associated with dysarthria, diplopia, hemiplegia, and headaches. ^[2,3]

Method: A 41-year-old woman (A) presented for evaluation of episodic vertigo and persistent gait imbalance. She had motor delay (walking at 18 months) and speech delay with learning difficulties. At age 8 she developed episodic vertigo and ataxia. These episodes increased in frequency to 1-2 times daily, lasting approximately 1 hour. She developed intermittent falls and ataxia became persistent, necessitating a wheelchair by her mid-30’s. Her maternal uncle (B), age 59, was evaluated for similar symptoms. He developed episodic ataxia, vertigo, and falls at age 10, with episodes triggered by running. Over time, ataxia became persistent. Family history was notable for similar symptoms in the proband’s mother (B’s sister), half-sister (same mother), maternal aunt (B’s mother), and a cousin. Exam of both patients showed midline gait ataxia requiring assistance to walk. Only mild limb dysmetria was noted for each. Both had slightly slurred speech. A had incomplete abduction of right eye and supraduction of left eye, whereas B had full extraocular movements. Nystagmus was not seen on either’s exam at baseline, but A developed nystagmus on rightward gaze after walking triggered an episode of severe vertigo. Walking similarly caused significant vertigo for B. Both had mild cognitive difficulties on screening cognitive testing.

Results: Repeat expansion testing failed to reveal a genetic basis for the ataxia. Whole exome sequencing subsequently revealed a heterozygous intragenic deletion involving at least exons 27-29 of CaCNA1A gene in both (NM_001127221.1, Genomic coordinates: arr[GRCh37] 19p13.2(13365835_13370716)x1). This deletion has not been previously reported in the literature, though other large deletions have been associated with EA2.^[3]

Conclusion: We report episodic ataxia evolving to persistent ataxia in context of a previously unreported intragenic deletion in CACNA1A.

References: [1] Lipman, A. R., Fan, X., Shen, Y., & Chung, W. K. (2022). Clinical and genetic characterization of CACNA1A-related disease. Clinical genetics, 102(4), 288–295.

[2] Nachbauer, W., Nocker, M., Karner, E., Stankovic, I., Unterberger, I., Eigentler, A., Schneider, R., Poewe, W., Delazer, M., & Boesch, S. (2014). Episodic ataxia type 2: phenotype characteristics of a novel CACNA1A mutation and review of the literature. Journal of neurology, 261(5), 983–991.

[3] Riant, F., Lescoat, C., Vahedi, K., Kaphan, E., Toutain, A., Soisson, T., Wiener-Vacher, S. R., & Tournier-Lasserve, E. (2010). Identification of CACNA1A large deletions in four patients with episodic ataxia. Neurogenetics, 11(1), 101–106.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/novel-partial-gene-deletion-in-cacna1a-presenting-with-gait-ataxia-vertigo-and-abnormal-eye-movements/