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Objective: To (1) retrospectively study emerging clinical symptoms and disease course in a cohort of patients with genetically proven CACNA1A mutations and (2) to define occurrence and frequency of overlapping clinical features.

Background: The CACNA1A gene cods for the pore forming alpha 1A subunit of the P/Q-type voltage-gated calcium channel (Cav2.1). Mutations in the CACNA1A gene are known to cause the three allelic disorders spinocerebellar ataxia type 6 (SCA6), episodic ataxia type 2 (EA2) and familial hemiplegic migraine type 1 (FHM1).

Methods: Patients with genetically proven CACNA1A mutations were identified from the clinical database of the Department of Neurology at the Medical University Innsbruck. Medical records were systematically analyzed for demographics, clinical manifestations at onset and in later disease course. Characterization of episodic symptoms was carried out using a standardized protocol considering frequency, duration and associated symptoms.

Results: 46 patients with a mean age of 50 years (range: 6 – 86) were identified from the database. Mean age of onset was 26 years with significant lower onset in EA2 and FHM1 as compared to SCA6. Frequency of attacks was highest in the EA2 group, whereas duration of attacks was considerable longer in FHM1. 14% of SCA6 patients exhibited episodic symptoms mainly short lasting vertigo and gait ataxia, which were evident in early disease and preceded the chronic cerebellar syndrome. Triggers for attacks were mainly identified in EA2 comprising emotional stress, physical exercise and caffeine. Most common ictal symptoms were gait ataxia and dysarthria, which also occurred in one third of FHM1 patients during attacks. Conversely 50% of EA2 patient had a history of migraine associated with attacks or occurring independently. Interictal cerebellar signs were observed in 85% of EA2 and 71% of FHM1 patients. Gaze evoked nystagmus therefore was the most prominent cerebellar feature. Progression of cerebellar syndrome in EA2 and FHM1 was mild over the observation period.

Conclusions: This retrospective analysis further demonstrates high phenotypic variability in allelic CACNA1A disorders. Distinctive clinical manifestations are present in some mutations. In a greater part overlap between these disorders is observed in both ictal as well as interictal symptoms and most prominent between EA2 and FHM1.