Objective: To describe a case of episodic ataxia type 2 (EA2) with features of periodic paralysis (PP) associated with a novel mutation in CACNA1A.

Background: EA2 and PP are phenotypically and genotypically heterogenous disorders with autosomal dominant inheritance affecting various voltage-gated ion channels in neurons and/or muscle. EA2 is caused by mutations in CACNA1A and typically presents with paroxysmal attacks of ataxia and other related symptoms and responds to acetazolamide. PP typically presents with attacks of flaccid weakness and may respond to dichlorphenamide. There is only one other published report of an overlap of EA2 and PP symptoms in a patient with a novel mutation in CACNA1A.

Method: –

Results: An otherwise healthy 35-year-old male presented with frequent episodes of profound muscle weakness and other neurologic symptoms since early childhood. The episodes are variable combinations of weakness, dizziness, inability to speak, nystagmus, diplopia, pupillary dilatation, and severe headache; weakness is the most consistent and bothersome symptom. Triggers include heat, greasy food, stress, and illness. The episodes last from 20 minutes to 7+ hours and resolve with time and rest. Between episodes he experiences slight generalized weakness. Neurologic exam performed between episodes was normal.  EMG long exercise test was abnormal and consistent with a muscle membrane excitability disorder using the modified McManis protocol, concerning for potential PP. Whole exome sequencing (GeneDx) revealed a novel VUS in CACNA1A (c.5216 T>C. P.(F1739S).  Interestingly, three other affected family members (mother, sister, niece) with more typical EA2 paroxysms harbor the same VUS, implicating its potential pathogenicity in his case. He was initially treated with acetazolamide, which reportedly worsened his symptoms. Treatment with dichlorphenamide dramatically improved his symptoms, including reduction in frequency, severity, and duration of his episodes.

Conclusion: We present a unique case of clinical overlap of EA2 and PP symptoms in a patient with a novel variant in CACNA1A, widening the existing clinical and genetic heterogeneity of EA2. This case also provides support for treatment of EA2 with dichlorphenamide, particularly in those with the CACNA1A (c.5216 T>C. P.(F1739S) mutation who do not initially respond to acetazolamide.

References: Park, D., Kim, SH., Lee, Y.J. et al. A novel CACNA1A mutation associated with episodic ataxia 2 presenting with periodic paralysis. Acta Neurol Belg 118, 137–139 (2018). https://doi.org/10.1007/s13760-018-0895-y.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-clinical-overlap-presentation-of-episodic-ataxia-type-2-and-periodic-paralysis-with-a-novel-mutation-in-cacna1a/