Calcium release deficiency syndrome: an emerging ryanodinopathy

The cardiac ryanodine receptor (RyR2) is a critical calcium release channel essential for normal cardiac contraction. Dysregulation of RyR2 function is a key pathogenic factor in various cardiac diseases, notably arrhythmias and heart failure. The clinical spectrum of RyR2-related diseases (ryanodinopathy) has expanded beyond the well-established gain-of-function (GOF) mutations causing catecholaminergic polymorphic ventricular tachycardia (CPVT). Recent research has now delineated two additional distinct clinical entities: exon 3 deletion syndrome (E3DS), which presents with CPVT along with structural abnormalities, and calcium release deficiency syndrome (CRDS), caused by loss-of-function (LOF) mutations. CRDS is characterized by impaired calcium release from the sarcoplasmic reticulum and fundamentally differs from the classical CPVT phenotype, necessitating distinct approaches to its diagnosis, clinical management, and therapeutic intervention. This review provides a comprehensive overview of the current understanding of CRDS. We discuss its clinical manifestations, scrutinize the underlying molecular mechanisms, evaluate available diagnostic strategies, and explore potential therapeutic avenues. By synthesizing latest findings, this review aims to illuminate the complexities of RyR2-mediated pathologies and foster further progress in this evolving field.