Current and future therapeutic approaches to the congenitalmyopathies

Abstract

tThe congenital myopathies – including Central Core Disease (CCD), Multi-minicore Disease (MmD), Cen-tronuclear Myopathy (CNM), Nemaline Myopathy (NM) and Congenital Fibre Type Disproportion (CFTD)– are a genetically heterogeneous group of early-onset neuromuscular conditions characterized by dis-tinct histopathological features, and associated with a substantial individual and societal disease burden.Appropriate supportive management has substantially improved patient morbidity and mortality butthere is currently no cure.Recent years have seen an exponential increase in the genetic and molecular understanding of theseconditions, leading to the identification of underlying defects in proteins involved in calcium homeostasisand excitation-contraction coupling, thick/thin filament assembly and function, redox regulation, mem-brane trafficking and/or autophagic pathways. Based on these findings, specific therapies are currentlybeing developed, or are already approaching the clinical trial stage. Despite undeniable progress, therapydevelopment faces considerable challenges, considering the rarity and diversity of specific conditions,and the size and complexity of some of the genes and proteins involved.The present review will summarize the key genetic, histopathological and clinical features of specificcongenital myopathies, and outline therapies already available or currently being developed in the con-text of known pathogenic mechanisms. The relevance of newly discovered molecular mechanisms andnovel gene editing strategies for future therapy development will be discussed