Desminopathy

Abstract

Abstract Desminopathy is one of the newly identified myopathies caused by mutations in desmin ( DES ), an intermediate filament, or αB‐crystallin ( CRYAB ), a chaperone for DES . The condition is defined as skeletal and cardiac myopathy characterised by the presence of chimeric aggregates in muscle fibre areas that consist of DES , CRYAB and other proteins. Identification of pathogenic mutations, analysis of underlying disease phenotypes and successful modelling of these conditions in cell cultures and transgenic mice specified critical pathogenic events. As the range of desminopathy clinical manifestations is extremely wide and myopathology not specific, diagnostic criteria need to be reliably outlined and molecular testing readily available to ensure prevention of sudden death from cardiac arrhythmias and other complications. Key Concepts: Desminopathy is associated with mutations in desmin ( DES ) and αB‐crystallin ( CRYAB ) genes. DES is a muscle‐specific type III intermediate filament; most of the known disease‐associated DES mutations affect domains that are crucial for filament assembly. CRYAB serves as a chaperone for DES and, if mutated, causes a disease identical to desminopathy. In humans and transgenic mice, DES and CRYAB mutants invoke accumulation of chimeric intracellular aggregates containing DES , CRYAB and other cytoskeletal proteins. DES mutations show diverse pathogenic effects depending on the structural relationships these mutations disrupt and the type of inheritance. Desminopathy is a skeletal and cardiac myopathy. Muscle imaging (CT and MRI) is helpful in identifying characteristic patterns of skeletal muscle involvement. Atrioventricular conduction abnormalities and arrhythmias are regularly present in desminopathy patients; they require urgent implantation of a permanent pacemaker or an implantable cardioverter defibrillator (ICD). Respiratory insufficiency can be a major cause of disability and death and may require continuous positive airway pressure (CPAP). Molecular testing of patients for DES and CRYAB mutations is available and should be used to ensure prevention of sudden death from cardiac arrhythmias and other complications.