Current therapeutics for cardiac phenotypes within Timothy syndrome, including beta-blockers, sodium channel blockers, and pacemakers, provide limited but helpful management of devastating arrhythmias.
This review highlights the genetic and molecular mechanisms of Timothy syndrome-associated arrhythmias and underscores the urgent need for patient-specific iPSC models to develop better targeted therapies.
Abstract Timothy syndrome (TS), characterised by multiple system malfunction especially the prolonged corrected QT interval and synchronised appearance of hand/foot syndactyly, is an extremely rare disease affecting early life with devastating arrhythmia. In this work, firstly, the various mutations in causative geneCACNA1Cencoding cardiac L-type voltage-gated calcium channel (LTCC), regard with the genetic pathogeny and nomenclature of TS are reviewed. Secondly, the expression profile and function ofCACNA1Cgene encoding Cav1.2 proteins, and its gain-of-function mutation in TS leading to multiple organ disease phenotypes especially arrhythmia are discussed. More importantly, we focus on the altered molecular mechanism underlying arrhythmia in TS, and discuss about how LTCC malfunction in TS can cause disorganised calcium handling with excessive intracellular calcium and its triggered dysregulated excitation–transcription coupling. In addition, current therapeutics for TS cardiac phenotypes including LTCC blockers, beta-adrenergic blocking agents, sodium channel blocker, multichannel inhibitors and pacemakers are summarised. Eventually, the research strategy using patient-specific induced pluripotent stem cells is recommended as one of the promising future directions for developing therapeutic approaches. This review updates our understanding on the research progress and future avenues to study the genetics and molecular mechanism underlying the pathogenesis of devastating arrhythmia within TS, and provides novel insights for developing therapeutic measures.
Jiang et al. (2023) conducted a review in Timothy syndrome. Various therapeutics (beta-blockers, sodium channel blockers, pacemakers) was evaluated. Current therapeutics for cardiac phenotypes within Timothy syndrome, including beta-blockers, sodium channel blockers, and pacemakers, provide limited but helpful management of devastating arrhythmias.