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

Abstract

A B S T R A C TPurpose: 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.

RyR2 disease mutations at the C-terminal domain intersubunit interface alter closed-state stability and channel activation

“…Interestingly, in addition to cardiac phenotypes, the CTD G4955E mutation is also associated with neuronal phenotypes, including delayed development, intellectual disability, attention deficit, hyperactivity, and seizure (45). Similarly, previous studies have also linked RyR2 mutations to intellectual disability (13) and seizures (64)(65)(66). However, the mechanism by which RyR2 mutations cause neuronal phenotypes is not completely understood.…”

Genetic Testing in Epilepsy

“…For example, in the first half of 2019, two more genes (RYR2 and IRF2BL) have already been reported to be associated with epilepsy. 3,4 While new genes continue to be reported, several genes are repeatedly identified in broad epilepsy studies (►Table 2). Most of the studies which have looked at potential single gene variants causing epilepsy have been carried out in people with epileptic encephalopathies, often with an early age of onset and normal imaging findings.…”

CHD4 variants are associated with childhood idiopathic epilepsy with sinus arrhythmia

“… 21 Several genes related to both epilepsy and cardiac disorders present risk of sudden unexpected death in epilepsy, which is the leading cause of epilepsy‐related premature mortality. 47 , 48 , 49 Thus, special attention should be paid to the patients with CHD4 mutations, who may present not only benign epilepsies such as BECTS/CAE but also potentially had sinus arrhythmia, which requires specialized health consultation and extra follow‐up. Further investigations are required to determine the risk of cardiogenic sudden death caused by CHD4 mutations.…”