Objective: Our objective is to describe phenotypic variability across four generations in a family with a specific CACNA1A mutation.

Background: CACNA1A is a gene located at the 19p13.1 that encodes for the pore-forming subunit alpha 1-A of voltage-gated Ca2+ channels [1], which are found at central synapses with high prevalence in cerebellar granule and Purkinje cells and are essential for Ca2+ flux leading to neurotransmitter release [2]. Mutations, including CAG repeat expansion, gain-of-function missense, and loss-of-function variants, have been associated with several phenotypes, including developmental delay/intellectual disability, hemiplegic migraine, episodic ataxia type 2, epilepsy, autism spectrum disorder, paroxysmal tonic upward gaze, and early-onset cerebellar atrophy syndrome [3].

Method: –

Results: We report a family with a variable phenotype associated with a missense mutation across four generations. Our index case presented with late-onset ataxia and progressive supranuclear palsy. At the time of presentation, her great-grandson had been diagnosed with CACNA1A mutation (c.5251 C>T p.(R1751W) “related neurodevelopmental and movement disorder” in childhood due to nystagmus. We learned that her daughter needed speech-language therapy during childhood and was noted to have mild dysarthria during clinic visits. Her granddaughter was evaluated after her son was diagnosed and was found to have the mutation but remains asymptomatic. We performed genetic testing of our index patient and confirmed the presence of the same mutation.

Conclusion: This specific mutation has been reported in the literature with the phenotype of episodic ataxia [9]. This family highlights the phenotypic variability with mutations of this gene.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/phenotypic-variability-across-four-generations-in-a-family-with-cacna1a-mutation/