Ryanodine receptor 2 (RYR2) mutation: A potentially novel neurocardiac calcium channelopathy manifesting as primary generalised epilepsy

Purpose: Ryanodine receptor 2 (RYR2) mutation is well-established in the aetiology of an inherited cardiac disorder known as catecholaminergic polymorphic ventricular tachycardia (CPVT). The RYR2 receptor is expressed in cardiomyocytes, and also in the hippocampus. The RYR2 mutation has not been reported as a potential cause of adult-onset genetic generalised epilepsy (GGE).

Method: Case report.

Results: A 32-year-old right-handed female presented with three unprovoked generalised seizures over twelve years. Electroencephalogram showed epileptiform activity which coincided with normal electrocardiogram recording. Her brother survived a cardiac arrest in his 20's and was diagnosed with CPVT and found to be heterozygous for a novel mutation in the RYR2 gene at chromosome 1q43, c.229 G > A p.(Ala77Thr). The patient inherited the same missense variant, predicted to be damaging by numerous in silico analytic tools. This mutation affects the N-terminal domain of the RYR2 receptor which plays a role in channel activation. However, the patient had repeatedly normal cardiac investigations including normal exercise stress tests.

Conclusion: We propose that the RYR2 mutation is a potentially novel neurocardiac calcium channelopathy that may manifest with either CPVT or GGE depending on selective involvement of RYR2 receptors expressed in the heart or in the brain. RYR2 mutant mice have demonstrated spontaneous EEG-positive seizures independent of cardiac arrhythmia. Whole exome sequencing analyses have identified RYR2 as a candidate gene in GGE. This case is a reminder for careful assessment of episodes of transient loss of consciousness in an individual with CPVT, so as to not mistake possible neurogenic seizure for cardiogenic syncope, carrying obvious implications for treatment.