Biology subjects

Mohamed Syazwan, E. S.

Publications and source records attributed to Mohamed Syazwan, E. S..

2 recordsLinked to original sources

bioRxiv2023

Atenolol reduces cardiac-mediated mortality in a genetic mouse model of sudden unexpected death in epilepsy

Sudden Unexpected Death in Epilepsy (SUDEP) is the leading cause of premature mortality in epilepsy. Genetic cardiac risk factors, including loss-of-function KCNH2 variants, have been linked to SUDEP. We hypothesised that seizures and LQTS interact to increase SUDEP risk. To investigate this, we crossed Kcnh2+/- and Gabrg2R43Q/+ mice that model LQTS and genetic epilepsy, respectively. Electrocorticography and electrocardiogram confirmed that Kcnh2+/- mice had a LQTS phenotype, while Gabrg2R43Q/+ mice displayed spontaneous seizures. Double mutant mice (Gabrg2R43Q/+/Kcnh2+/-) had both seizure and LQTS phenotypes that were indistinguishable from the respective single mutant mice. Survival analysis revealed that Gabrg2R43Q/+/Kcnh2+/- mice experienced a disproportionate higher rate of seizure-related death. Long-term oral administration of atenolol, a cardiac-selective {beta}-blocker, significantly improved survival in the Gabrg2R43Q/+/Kcnh2+/- mice. An additional mouse model, Hcn1M294L/+/Kcnh2+/-, based on a HCN1 developmental epileptic encephalopathy variant, also experienced a disproportionately higher rate of premature death that was rescued by atenolol. Kcnh2+/- mice also spent more time in ventricular arrhythmia during proconvulsant-induced seizures. Overall, the data implicates cardiac and loss-of-function KCNH2 variants as an important risk factor, and the potential repurposing of {beta}- blockers as a prevention strategy, for SUDEP in a subset of epilepsy patients.

neuroscience↗

bioRxiv2021

Loss-of-function variants in the cardiac Kv11.1 channel as a genetic biomarker for SUDEP

ObjectiveTo compare the frequency and impact on channel function of KCNH2 variants in SUDEP patients with epilepsy controls comprising patients older than 50 years, a group with low SUDEP risk, and establish loss-of-function KCNH2 variants as predictive biomarkers of SUDEP risk. MethodsWe searched for KCNH2 variants with a minor allele frequency of < 5%. Functional analysis in Xenopus laevis oocytes was performed for all KCNH2 variants identified. ResultsKCNH2 variants were found in 11.1% (10/90) of SUDEP individuals compared to 6.0% (20/332) of epilepsy controls (p = 0.11). Loss-of-function KCNH2 variants, defined as causing > 20% reduction in maximal amplitude, were observed in 8.9% (8/90) SUDEP patients compared to 3.3% (11/332) epilepsy controls suggesting about three-fold enrichment (nominal p = 0.04). KCNH2 variants that did not change channel function occurred at a similar frequency in SUDEP (2.2%; 2/90) and epilepsy control (2.7%; 9/332) cohorts (p > 0.99). Rare KCNH2 variants (< 1% allele frequency) associated with greater loss of function and an [~]11-fold enrichment in the SUDEP cohort (nominal p = 0.03). In silico tools were unable to predict the impact of a variant on function highlighting the need for electrophysiological analysis. ConclusionsThese data show that loss-of-function KCNH2 variants are enriched in SUDEP patients and suggest that cardiac mechanisms contribute to SUDEP risk. We propose that genetic screening in combination with functional analysis can identify loss-of-function KCNH2 variants that could act as biomarkers of an individuals SUDEP risk.

neuroscience↗