Objective: To study the clinical presentation of ataxic patients with CACNA1A mutations in a Taiwanese cohort.

Background: Mutations of CACNA1A gene is the genetic cause of episodic ataxia type 2 (EA2). The classical phenotype is episodic attacks of ataxia and cerebellar signs; however, recent reports described some patients presenting with progressive ataxia and cerebellar signs. Moreover, symptoms other than cerebellar ataxia such as seizure, mental retard, or hyperkinetic movement have been mentioned in CACNA1A mutation carriers. The variability between phenotype and genotype in CACNA1A was also noted for a long time, and there is no good mechanism to explain it until now.

Methods: We analyzed the clinical phenotypes of 16 ataxic patients from 12 Taiwanese families with CACNA1A point mutations. The genetic analysis of CACNA1A mutations was carried out by candidate next generation sequencing and was confirmed by Sanger sequencing.

Results: There are six different missense mutations of CACNA1A gene identified, including G1265A (Exon 10, R422Q), C2261T (Exon 18, A754V), A2978T (Exon 19, E993V), A2978T (Exon 19, E993V) plus G2754C (Exon 19, E921D), G4537T (Exon 27, R1437L), and T5126C (Exon 33, I1709T). Half of cases carried mutation at A2978T (Exon 19, E993V) plus G2754C (Exon 19, E921D). The average age at onset was 28.8± 15.7 years (range 5-50 years). Gender ratio was 7:9 (Female:Male). The most common phenotype is progressive unsteady gait (68.7%), while episodic ataxia occurred in 31.3% of patients. In addition to cerebellar signs or symptoms, 43.8 % cases had bulbar symptoms such as dysarthria and dysphagia, and cerebellar atrophy was evident in 75% of patients on brain MRI. Half of patients had interictal gaze-evoked nystagmus, some cases (18.75%) showed impaired persuit and some cases (12.5%) had slow saccade. Episodic dizziness was reported only in 25% of cases. Migraine was rarely reported but 12.5% cases had seizure history. Besides, tremor was noticed in 43.8% of patients and cognition impairment was found in 25% cases. Although previous studies¹ showed seizure phenotype in patients with mutation at A2978T (Exon 19, E993V) plus G2754C (Exon 19, E921D), seizure is infrequent in our patients with the same mutations.

Conclusions: This study demonstrated widening clinical phenotypes of mutations in CACNA1A gene in Taiwanese ataxic patients.

References: 1. Rajakulendran S, Graves T. D., Labrum R. W., et al. Genetic and functional characterisation of the P/Q calcium channel in episodic ataxia with epilepsy. J Physiol 2010;588:1905–1913.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-and-genetic-analysis-of-ataxic-patients-with-cacna1a-mutations-in-taiwan/