Objective: This study aims to describe pediatric patients with CACNA1A variants, detailing the clinical phenotype, with emphasis on the movement phenomenologies, genetic variants, electrophysiological and radiological findings, and treatment response

Background: CACNA1A is a calcium channel gene is expressed in the cerebellum, cerebral cortex, striatum, and thalamus and is essential in neurotransmitter release.^1-6 A heterozygous mutation results in various phenotypes, including spinocerebellar ataxia type 6, familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2), and developmental-epileptic encephalopathies (DEE), though overlapping phenotypes may occur.^2,6 Movement phenomenology including dystonia, tremor, and ataxia evolves with time.^1,2,7 Treatment is mainly symptomatic.^2,3,5 Current literature is limited to case series and small multicenter studies from homogeneous populations

Method: This retrospective study included pediatric patients (≤18 years) with pathogenic or likely pathogenic CACNA1A variants. Clinical, laboratory, and radiological data were collected to characterize the phenotypic spectrum and evaluate treatment regimens and their response. This study also aims to explore the influence of ethnic backgrounds on the clinical presentation by including national and international centers in subsequent stages, with the current study reflecting preliminary data from the Hospital for Sick Children

Results: A total of 17 patients were identified (12 females, 5 males). The mean age at onset of neurological symptoms was 19 months, while the mean age of genetic diagnosis was 8 years. The predominant phenotypes included DEE (12 patients), EA2 (6 patients), and FMH1 (4 patients). Initial presentations included seizures, headaches, and developmental delay. Movement disorders were observed in 13 patients, 5 patients had it as the initial symptom, such as dystonia (13 patients), ataxia (4 patients), parkinsonism (1 patient), and tremor (1 patient). Ataxia was treated in 2 patients with acetazolamide and flunarizine, with a partial response. The other movement disorders did not require medical therapy. Brain MRI was performed in 11 patients, revealing diffuse cerebellar volume loss in 4 cases

Conclusion: CACNA1A variants show diverse phenotypes, predominantly with movement symptoms. Treatment response varies, highlighting the need for larger studies to better characterize phenotypes and explore treatment options

References: 1. Indelicato E, Boesch S. From Genotype to Phenotype: Expanding the Clinical Spectrum of CACNA1A Variants in the Era of Next Generation Sequencing. Front Neurol 2021;12:639994
2. Zhang L, Wen Y, Zhang Q, et al. CACNA1A Gene Variants in Eight Chinese Patients With a Wide Range of Phenotypes. Front Pediatr 2020;8:577544
3. Fuerte-Hortigon A, Perez-Noguera R, Dotor Garcia-Soto J, et al. Novel CACNA1A variant may cause cervical dystonia and cerebellar ataxia syndrome. J Neurol Sci 2020;415:116909
4. Fox PM, Malepati S, Manaster L, et al. Developing a pathway to clinical trials for CACNA1A-related epilepsies: A patient organization perspective. Ther Adv Rare Dis 2024;5:26330040241245725
5. Kessi M, Chen B, Pang N, et al. The genotype-phenotype correlations of the CACNA1A-related neurodevelopmental disorders: a small case series and literature reviews. Front Mol Neurosci 2023;16:1222321
6. Lipman AR, Fan X, Shen Y, et al. Clinical and genetic characterization of CACNA1A-related disease. Clin Genet 2022;102:288-295
7. Alshareet M, Alakkas A, Alsinaidi OA, et al. Novel de novo heterozygous CACNA1A gene variant in generalised dystonia: a case report. BMJ Neurol Open 2024;6:e000710

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MDS Abstracts - https://www.mdsabstracts.org/abstract/expanding-the-phenotypic-spectrum-of-cacna1a-variants-a-single-center-experience/