The neuropsychiatric phenotype in CACNA1A mutations: a retrospective single center study and review of the literature

Background and purpose CACNA1A encodes the alpha 1 subunit of the neuronal calcium channel P/Q. CACNA1A mutations underlie three allelic disorders: familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6). A clear-cut genotype-phenotype correlation is often lacking since clinical manifestations may overlap. Several case reports have described cognitive and behavioral features in CACNA1A disorders, but studies in larger case series are lacking. Methods Genetically confirmed CACNA1A cases were retrieved from the database of the ataxia outpatient clinic of the Department of Neurology at Innsbruck Medical University. Clinical charts and neuropsychological test results were retrospectively analyzed. In addition, a review of the literature including only genetically confirmed cases was performed. Results Forty-four CACNA1A cases were identified in our database. Delayed psychomotor milestones and poor school performance were described in seven (four FHM1, three EA2) and eight (three FHM1, five EA2) patients, respectively. Psychiatric comorbidities were diagnosed in eight patients (two FHM1, six EA2). Neuropsychological testing was available for 23 patients (11 FHM1, 10 EA2, two SCA6). Various cognitive deficits were documented in 21 cases (all patients except one SCA6). Impairments were predominantly seen in figural memory, visuoconstructive abilities and verbal fluency. In the literature, an early psychomotor delay is described in several children with EA2 and FHM1, whilst reports of cognitive and psychiatric findings from adult cases are scarce. Conclusions Neuropsychiatric manifestations are common in episodic CACNA1A disorders. In the case of otherwise unexplained developmental delay and a positive family history, CACNA1A mutations should be considered in the differential diagnosis.