Diagnostic and therapeutic challenges in Andersen-Tawil syndrome

Andersen-Tawil syndrome is a rare autosomal dominant multisystem disorder characterized by ventricular arrhythmias, periodic paralysis, and dysmorphic features. However, marked phenotypic heterogeneity is observed, contributing to significant diagnostic delays. Andersen-Tawil syndrome is most commonly caused by loss-of-function variants in KCNJ2, which encodes the α-subunit of the inward rectifier potassium channel Kir2.1, resulting in impaired I_K1 currents. Impaired I_K1 destabilizes terminal repolarization and depolarization kinetics, promoting prominent U waves, ventricular ectopy, and complex ventricular arrhythmias. Management remains challenging owing to limited evidence and variable treatment responses. β-Blockers and flecainide are commonly used, whereas implantable cardioverter defibrillators are reserved for high-risk cases. Potassium supplementation and acetazolamide should be considered in selected patients with periodic paralysis. Given the incomplete penetrance and the absence of validated risk stratification tools, careful multidisciplinary evaluation and individualized management are essential.