Objective: To describe a case of two related individuals with cerebellar ataxia with a novel variant in the calcium voltage-gated channel subunit alpha1-A (CACNA1A) gene.

Background: Spinocerebellar ataxias (SCA) are a group of heterogenous neurodegenerative hereditary disorders characterized by progressive loss of balance and coordination, as well as other distinguishing symptoms that vary with the particular type of SCA and involved genetic defect. Pathogenic variants in CACNA1A gene have been implicated in autosomal dominant hereditary spinocerebellar ataxia 6, episodic ataxia type 2, and familial hemiplegia with progressive cerebellar ataxia and developmental epileptic encephalopathy.

Method: Clinical examination, neuropsychological testing, structural neuroimaging, DNA analysis.

Results: Index case, 43-year-old patient, presents with progressive cerebellar ataxic gait clinically manifesting at age 41, horizontal nystagmus and mild cognitive impairment. It is further noted that from ages 3 to 16, he was treated for epileptic seizures. He then indicated that his 66-year-old biological mother, had developed a similar gait dysfunction with frequent falls since the age of 44. Upon examination, the mother was seen to have cerebellar ataxic gait, horizontal nystagmus with saccadic intrusions, ataxic dysarthria, intentional tremor and mild cognitive impairment. Both patients had global cerebellar atrophy on MRI. The patients were tested initially for polyglutamine expansions in the most common SCAs (SCA1-3 and SCA6-7) with negative results. Then the CACNA1A gene was analysed using new generation sequencing and bioinformatic analysis.

In both patients, molecular genetic examination confirmed the presence of the variant c.1672-1G>A in the CACNA1A gene (NM 000068.3), evaluated as pathogenic according to ACMG criteria PVS1, PM2. To our knowledge, this variant is however not yet recorded in literature.

Conclusion: Based on our results, we propose that the above-mentioned variant in gene CACNA1A is likely to be associated with cerebellar ataxia, nystagmus and mild cognitive impairment.

Supported by MH CZ – DRO (FNOl, 00098892)

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MDS Abstracts - https://www.mdsabstracts.org/abstract/novel-cacna1a-splice-site-variant-associated-with-cerebellar-ataxia-and-mild-cognitive-impairment-case-report-of-czech-family/