Myotonic dystrophy

Giovanni Meola MD (Dr. Meola of University of Milan IRCCS Policlinico San Donato has no relevant financial relationship to disclosure.)
Rosanna Cardani PhD (Dr Cardani of IRCCS Policlinico San Donato has no relevant financial relationships to disclose.)
Emma Ciafaloni MD, editor. (Dr. Ciafaloni of the University of Rochester received consulting fees from Biogen and a research grant from Sarepta.)
Originally released September 6, 1993; last updated November 12, 2018; expires November 12, 2021

This article includes discussion of myotonic dystrophy, Batten-Gibb disease, Batten-Steinert-Curschmann disease, Curschmann-Steinert disease, Curschmann-Steinert syndrome, Curschmann-Steinert-Batten disease, Curschmann-Steinert-Batten syndrome, Deleage disease, dystrophia myotonica, myotonia atrophica, myotonia dystrophica, Steinert disease, PROMM, and proximal myotonic myopathy. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

The myotonic dystrophies are a multisystem, autosomal dominantly inherited, highly variable muscle disease more frequent in adults. So far 2 distinct entities have been described: myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) (PROMM). In this article, the authors review the clinical features, pathogenesis, and crucial management points of both myotonic dystrophy type 1 and the more recently described myotonic dystrophy type 2. This review has been updated to include the published clinical phenotype characteristics, genetic aspects, and pathogenic mechanisms of myotonic dystrophy type 1 and type 2. The authors emphasize both the similarities and differences between the 2 forms.

Key points

 

• The myotonic dystrophies are the commonest cause of adult-onset muscular dystrophy.

 

• Myotonic dystrophy type 1 according to age of onset and symptoms is divided into 5 forms: congenital, childhood, juvenile, adult, and late-onset.

 

Phenotypes of DM1 and DM2 are similar, but there are some important differences, including the presence or absence of congenital form, muscles primarily affected (distal vs. proximal), involved muscle fiber types (type 1 vs. type 2 fibers), and some associated multisystemic phenotypes.

 

• There is currently no cure for the myotonic dystrophies but effective management significantly reduces the morbidity and mortality of patients.

 

• For the enormous understanding of the molecular pathogenesis of myotonic dystrophy type 1 and myotonic dystrophy type 2, these diseases are now called “spliceopathies” and are mediated by a primary disorder of RNA rather than proteins.

 

• Despite clinical and genetic similarities, myotonic dystrophy type 1 and type 2 are distinct disorders requiring different diagnostic and management strategies.

 

Gene therapy for myotonic dystrophy type 1 and myotonic dystrophy type 2 appears to be very close and the near future is an exciting time for clinicians and patients.

Historical note and terminology

Myotonic dystrophies represent a group of dominantly inherited, multisystem (eye, heart, brain, endocrine, gastrointestinal tract, uterus, skin) diseases that share the core features of myotonia, muscle weakness, and early onset cataracts (before 50 years of age). Clinicians considered myotonic dystrophy to be a single disease until 1909 when Steinert and colleagues first clearly described the “classic” form of myotonic dystrophy, which was called Steinert disease (Harper 2001). The gene defect responsible for myotonic dystrophy described by Steinert was discovered in 1992 and was found to be caused by expansion of a CTG repeat in the 3 untranslated region of myotonic dystrophy protein kinase gene (DMPK), a gene located on chromosome 19q13.3, encoding a protein kinase (Brook et al 1992; Fu et al 1992; Mahadevan et al 1992). After the discovery of this gene defect, DNA testing revealed a group of patients with dominantly inherited myotonia, proximal more than distal weakness, and cataracts; these patients were previously diagnosed as having myotonic dystrophy but lacked the gene defect responsible for myotonic dystrophy of Steinert. Subsequent clinical studies of kindreds with patients having these characteristics led to new diagnostic labels for these patients: myotonic dystrophy type 2 (Thornton et al 1994), proximal myotonic myopathy (PROMM) (Ricker et al 1994; Meola et al 1996), or proximal myotonic dystrophy (PDM) (Udd et al 1997). Later studies demonstrated that many of the families that identified as having myotonic dystrophy type 2, PROMM, or PDM had a single disorder that results from an unstable tetranucleotide CCTG repeat expansion in intron 1 of the nucleic acid-binding protein (CNBP) gene (previously known as zinc finger 9 gene, ZNF9) on chromosome 3q21 (Ranum et al 1998; Liquori et al 2001).

The existence of different types of myotonic dystrophy has created a need to develop a diagnostic classification. To address this need the International Myotonic Dystrophy Consortium developed a new nomenclature and guidelines for DNA testing (Anonymous 2000).

Myotonic dystrophy of Steinert, the classical form of myotonic dystrophy that results from an unstable trinucleotide repeat expansion on chromosome 19q13.3, is now termed myotonic dystrophy type 1. Patients with the clinical picture of myotonic dystrophy type 2, PROMM, or PDM who have positive DNA testing for the unstable tetranucleotide repeat expansion on chromosome 3 are now classified as having myotonic dystrophy type 2. Patients with dominantly inherited myotonia, muscle weakness, and early-onset cataracts who lack the gene defects for either myotonic dystrophy type 1 or type 2 were described (Moxley et al 2002; Udd et al 2003; Meola et al 2004). Reliability of DNA testing to establish the diagnosis of or to exclude myotonic dystrophy type 1 is close to 100% (Valaperta et al 2013). However, caution is necessary in the diagnosis of myotonic dystrophy type 2. This chapter focuses on myotonic dystrophy type 1 and myotonic dystrophy type 2. The clinical spectrum for both myotonic dystrophy type 1 and myotonic dystrophy type 2 remains a work in progress in view of the fact that it has been possible to identify these disorders only recently, specifically with DNA testing. At present, much more information is available on the natural history of myotonic dystrophy type 1 than myotonic dystrophy type 2, but knowledge of myotonic dystrophy type 2 will increase at a rapid pace over the next several years.

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