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.)
Salvatore DiMauro MD, editor. (Dr. DiMauro, Director Emeritus of H Houston Merritt Clinical Center for the Study of Muscular Dystrophy and Related Diseases at Columbia University, has no relevant financial relationships to disclose.)
Originally released September 6, 1993; last updated July 24, 2016; expires July 24, 2019

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 DM1 and DM2. 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 versus proximal), involved muscle fiber types (type 1 versus 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

The 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, weakness, and early onset cataracts (in people younger than 50 years of age). Clinicians considered myotonic dystrophy to be a single disease up until the later part of the 1990s. Steinert and colleagues described the disorder clearly in the early 1900s, and that description is still valid (Harper 2001). Following the discovery of the gene defect responsible for myotonic dystrophy of Steinert in 1992 (Brook et al 1992; Fu et al 1992; Mahadevan et al 1992), DNA testing revealed a group of patients with dominantly inherited myotonia, proximal more than distal weakness, and cataracts who were previously diagnosed as having myotonic dystrophy but who, after testing, 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) and proximal myotonic myopathy (Ricker et al 1994; Meola et al 1996). Later studies demonstrated that many of the families identified as having myotonic dystrophy type 2 or proximal myotonic myopathy had a single disorder that results from an unstable 4-nucleotide repeat expansion on chromosome 3 (Ranum et al 1998; Liquori et al 2001). This disease is similar to, but distinct from, classical myotonic dystrophy of Steinert. It is referred to as myotonic dystrophy type 2 (Thornton et al 1994; Day et al 1999; Day et al 2003). There are also patients with dominantly inherited myotonia, weakness, and early onset cataracts who lack the gene defects for either myotonic dystrophy type 1 or type 2 (Moxley et al 2002; Udd et al 2003; Meola et al 2004). In 1 such report, a genome-wide linkage analysis suggested a linkage to chromosome 15q21-24 in the absence of any repeat expansions in the DMPK or CNBP genes (Le Ber et al 2004). However, some previous reports of patients with yet a third type of myotonic dystrophy, have proven to be inaccurate, and the patients turned out to have myotonic dystrophy type 2 (Day et al 2003). The family posited to have myotonic dystrophy type 3 (Le Ber et al 2004) was subsequently shown to have an unusual presentation of inclusion body myopathy with Paget disease and frontotemporal dementia (IBMFTD) (Udd et al 2006) caused by mutation in VCP (Valosin Carnosin Protein). Careful clinical and laboratory evaluation needs to be carried out before considering a diagnosis of myotonic dystrophy type 3 in all suspected patients.

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 19, is now termed myotonic dystrophy type 1. Patients with the clinical picture of myotonic dystrophy type 2 and proximal myotonic myopathy who have positive DNA testing for the unstable 4 nucleotide repeat expansion on chromosome 3 are now classified as having myotonic dystrophy type 2 or myotonic dystrophy type 2/proximal myotonic myopathy. Patients with myotonia, proximal or distal weakness, and early onset cataracts with negative DNA testing for myotonic dystrophy type 1 and myotonic dystrophy type 2 are classified as having the “proximal myotonic myopathy syndrome,” possible myotonic dystrophy type 3, or an unclassified form of myotonic dystrophy. Reliability of DNA testing to establish the diagnosis of or to exclude myotonic dystrophy type 1 is close to 100% (Harper 2001). However, caution is necessary in excluding the diagnosis of myotonic dystrophy type 2. DNA testing methodology used in the recent past to screen for myotonic dystrophy type 2/proximal myotonic myopathy may have failed to detect as many as 20% of affected individuals (Day et al 2003). It will be necessary to use the more sensitive DNA testing methodologies for myotonic dystrophy type 2 (Bachinski et al 2003; Day et al 2003) to rule out this disorder. Patients need to undergo this more sensitive DNA testing before a care provider raises the possibility that the individual has another form of myotonic dystrophy, such as myotonic dystrophy type 3.

This chapter focuses on myotonic dystrophy type 1 and myotonic dystrophy type 2/proximal myotonic myopathy. The clinical spectrum for both myotonic dystrophy type 1 and myotonic dystrophy type 2 remain “works in progress” in view of the fact that it has been possible to identify these disorders only recently, specifically with DNA testing. Much more information is available on the natural history of myotonic dystrophy type 1 than myotonic dystrophy type 2 at present, but our knowledge of myotonic dystrophy type 2 will increase at a rapid pace over the next several years.

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