Desmin-related myopathy

Abstract

Desmin-related myopathy (DRM) is an autosomally inherited skeletal and cardiac myopathy, mainly caused by dominant mutations in the desmin gene (DES). We provide (i) a literature review on DRM, including clinical manifestations, inheritance, molecular genetics, myopathology and management and (ii) a meta-analysis of reported DES mutation carriers, focusing on their clinical characteristics and potential genotype-phenotype correlations. Meta-analysis: DES mutation carriers (n = 159) with 40 different mutations were included. Neurological signs were present in 74% and cardiological signs in 74% of carriers (both neurological and cardiological signs in 49%, isolated neurological signs in 22%, and isolated cardiological signs in 22%). More than 70% of carriers exhibited myopathy or muscular weakness, with normal creatine kinase levels present in one third of them. Up to 50% of carriers had cardiomyopathy and around 60% had cardiac conduction disease or arrhythmias, with atrioventricular block as an important hallmark. Symptoms generally started during the 30s; a quarter of carriers died at a mean age of 49 years. Sudden cardiac death occurred in two patients with a pacemaker, suggesting a ventricular tachyarrhythmia as cause of death. The majority of DES mutations were missense mutations, mostly located in the 2B domain. Mutations in the 2B domain were predominant in patients with an isolated neurological phenotype, whereas head and tail domain mutations were predominant in patients with an isolated cardiological phenotype.

Clinical, pathological, and genetic mutation analysis of sporadic inclusion body myositis in Japanese people

“…Cumulatively, the familial inclusion body myopathies show heterogeneous patterns of inheritance and may present even when there is no family history as a result of recessive inheritance, an incomplete penetrance of the dominant inheritance, or de novo mutations. This explains reports of non-familial, sporadic cases with mutations in these genes [8,16,17].…”

“…Over the past 10 years, there has been an accumulation of evidence suggesting 4 that IBM1, or desmin-related myopathy (DRM; OMIM #601419), is caused by mutations in the Desmin gene on chromosome 2q35 [5]. DRM, a form of myofibrillar myopathy (MFM), is characterized by a combination of skeletal muscle weakness and cardiomyopathy [5,8]. Most of the known mutations of the Desmin gene are autosomal dominant, but some are autosomal recessive and a significant number of these mutations are de novo [8].…”

“…DRM, a form of myofibrillar myopathy (MFM), is characterized by a combination of skeletal muscle weakness and cardiomyopathy [5,8]. Most of the known mutations of the Desmin gene are autosomal dominant, but some are autosomal recessive and a significant number of these mutations are de novo [8]. Autosomal recessive IBM2 (OMIM #600737) is characterized by weakness of distal muscles in the lower limbs but a sparing of quadriceps muscles, and is induced by mutations in the UDP-N-acetylglucosamine-2-epimerase/Nacetylmannosamine kinase (GNE) gene mapped to chromosome 9p13.3 [6].…”

Desmin and αB-crystallin interplay in the maintenance of mitochondrial homeostasis and cardiomyocyte survival

“…These mitochondrial abnormalities lead to cardiomyocyte death and myocardial degeneration, accompanied by inflammation and fibrosis, resulting in dilated cardiomyopathy (DCM) and heart failure (Milner et al, 2000;Mavroidis and Capetanaki 2002;Capetanaki et al, 2007;Psarras et al, 2012;Mavroidis et al, 2015). In humans, over 70 desmin mutations have been linked to desmin-related cardiomyopathies, of which DCM is the most frequent van Spaendonck-Zwarts et al, 2011). In addition, desmin aggregate formation due to caspase cleavage is an important mediator of TNF-α-induced heart failure (Panagopoulou et al, 2008).…”

Genetic determinants of heart failure: facts and numbers

“…LMNA mutation carriers have an increased occurrence of malignant (potentially life‐threatening) ventricular arrhythmias and sudden cardiac death 32. Other examples are TNNT2 33 and DES 34 mutation carriers, who also present with a high arrhythmia risk. In these patients, decisions regarding the primary prophylactic implantation of an implantable cardiac defibrillator should take genetic aspects into account.…”