Objective: To highlight the complex genotype-phenotype associations of CACNA1A-related disorders and demonstrate that clinical presentation may not always align with current genetic classifications.

Background: Pathogenic variants in CACNA1A are linked to a spectrum of neurological disorders: episodic ataxia type 2 (EA2), familial hemiplegic migraine type 1 (FHM1), and spinocerebellar ataxia type 6 (SCA6). EA2 is caused by haploinsufficiency (e.g., deletions) and SCA6 by a trinucleotide repeat expansion. However, substantial clinical overlap complicates traditional genotype-phenotype correlations.

Method: A 69-year-old male presented with progressively worsening involuntary mouth movements beginning at age 50. Symptoms included continuous non-rhythmic symmetric jerky dystonic grimacing, lip pursing, and jaw clenching, which interfered with speech, resulting in dysphonia and dysarthria. Exam also revealed sialorrhea, gaze-evoked nystagmus, hyporeflexia, length-dependent sensory impairments, and a mildly ataxic gait. ENT evaluation revealed involvement of the larynx and pharynx. Brain MRI was unremarkable, and family history was noncontributory.

Results: Genetic testing identified a heterozygous likely pathogenic variant in CACNA1A (c.1817_1818del), initially classified as EA2. While the observed gazed-evoked nystagmus is consistent with EA2, the absence of episodic symptoms challenged this diagnosis. Also, the adult-onset mild progressive ataxia suggested a closer alignment with SCA6. Following further discussion with the lab and a literature review identifying cases with overlapping EA2 and SCA6 phenotypes, the variant classification was amended to the broader category of CACNA1A-related disorders to better reflect the clinical spectrum.

Conclusion: We identified a patient with a CACNA1A variant presenting with adult-onset, progressive lower cranial dystonia as the predominant clinical feature, without preceding episodic ataxia. Dystonia is a recognized but uncommon feature of CACNA1A-related disorders, seen in <25% of SCA6 cases and as a rare late interictal feature of EA2. When present, dystonia most commonly involves cervical dystonia or blepharospasm. This case expands upon the complex genotype-phenotype associations in CACNA1A-related disorders. In cases where molecular findings do not fully align with established phenotypes, a more inclusive diagnosis of CACNA1A-related disorders may be appropriate.

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