Myotonic dystrophies: An update on clinical aspects, genetic, pathology, and molecular pathomechanisms

Abstract

Myotonic dystrophy (DM) is the most common adult muscular dystrophy, characterized by autosomal dominant progressive myopathy, myotonia and multiorgan involvement. To date two distinct forms caused by similar mutations have been identified. Myotonic dystrophy type 1 (DM1, Steinert's disease) is caused by a (CTG)n expansion in DMPK, while myotonic dystrophy type 2 (DM2) is caused by a (CCTG)n expansion in ZNF9/CNBP. When transcribed into CUG/CCUG-containing RNA, mutant transcripts aggregate as nuclear foci that sequester RNA-binding proteins, resulting in spliceopathy of downstream effector genes. However, it is now clear that additional pathogenic mechanism like changes in gene expression, protein translation and micro-RNA metabolism may also contribute to disease pathology. Despite clinical and genetic similarities, DM1 and DM2 are distinct disorders requiring different diagnostic and management strategies. This review is an update on the recent advances in the understanding of the molecular mechanisms behind myotonic dystrophies. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.

Electromechanical delay components during skeletal muscle contraction and relaxation in patients with myotonic dystrophy type 1

“…Myotonic dystrophy type 1 (DM1, OMIM 160900) is the most frequent form of inherited muscular dystrophy in adulthood, with a prevalence of about 1:8000 [1]. The adult-onset form is the most prevalent, with common clinical exacerbation in the second or third decade of life.…”

“…The adult-onset form is the most prevalent, with common clinical exacerbation in the second or third decade of life. Clinical manifestations of adult-onset DM1 involve a broad spectrum of systemic complications, such as cardiac conduction abnormalities and cardiomyopathy, cataract, central nervous system dysfunction, gastrointestinal symptoms, and endocrine abnormalities [1][2][3][4]. The main features at the skeletal muscle level are muscle weakness and grip and percussion myotonia [1].…”

“…Clinical manifestations of adult-onset DM1 involve a broad spectrum of systemic complications, such as cardiac conduction abnormalities and cardiomyopathy, cataract, central nervous system dysfunction, gastrointestinal symptoms, and endocrine abnormalities [1][2][3][4]. The main features at the skeletal muscle level are muscle weakness and grip and percussion myotonia [1]. Distal muscles are generally more compromised than the proximal ones [1,5].…”

Identification of variants in MBNL1 in patients with a myotonic dystrophy-like phenotype

“…38 Several studies have addressed the effects of loss of MBNL1 at the molecular and the phenotypical level. 18,23,32,39 Du et al 32 compared a mouse model expressing a (CUG) n expansion with a mbnl1 knockout mouse.…”

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

“…Repeat expansions occurring in noncoding sequences often cause toxicity through a distinct mechanism involving the sequestration of vital RNA binding proteins. In myotonic dystrophy, noncoding repeats in DMPK (type 1) or CNBP (type 2) are transcribed into RNAs that accumulate in ribonuclear foci and sequester essential RNA processing factors, including muscleblind-like proteins, CUG triplet repeat RNA binding protein 1; hnRNP H; and Staufen 1 [118]. Several of these proteins associate with TDP43 [77], hinting at conserved mechanisms of cellular dysfunction in myotonic dystrophy and motor neuron disease.…”