Proximal Myotonic Dystrophy Research Articles

The Nondystrophic Myotonias

The nondystrophic myotonias are a heterogeneous set of rare diseases that demonstrate clinical myotonia, electrical myotonia, or both. These disorders are distinguished from myotonic dystrophy type 1 (DM-1), the more recently described proximal myotonic myopathy/myotonic dystrophy type 2 (PROMM/DM-2), and proximal myotonic dystrophy (a variant of DM-2) by characteristic clinical features, lack of abnormal nucleotide repeat expansions in the DM-1 and DM-2 genes, lack of cataracts and endocrine disturbances, and absence of significant histopathology in the muscle biopsy. The present article reviews each of the nondystrophic myotonias by exploring the unique clinical features, electrodiagnostic findings, diagnostic criteria, gene mutations, and response to pharmacologic therapy. These diseases are divided into those with chloride channel dysfunction (the myotonia congenita disorders) and those with sodium channel dysfunction (paramyotonia congenita, potassium-aggravated myotonia, and hyperkalemic periodic paralysis with myotonia). The variants that occur in each of these conditions are commented on. The differentiating features of the nondystrophic myotonias are summarized, and their predominant clinical, electrodiagnostic, and genetic characteristics are tabulated. For a comprehensive review of pertinent research and studies with application to diagnosis and treatment of individuals with nondystrophic myotonic disorders, the present article is best read in the context of other articles in this issue, especially those on ion channel physiology (Cannon) and pharmacology (Conte-Camerino), and on hyperkalemic periodic paralysis (Lehmann-Horn).

Proximal myotonic dystrophy associated with parkinsonism

Although mental changes and cognitive disorders are seen frequently in myotonic dystrophy (MD) there are only three cases of MD associated with parkinsonism reported in the literature. We report another case of this extremely rare combination.

Clinical and molecular aspects of the myotonic dystrophies: A review

Type 1 myotonic dystrophy or DM1 (Steinert's disease), which is the commonest muscular dystrophy in adults, has intrigued physicians for over a century. Unusual features, compared with other dystrophies, include myotonia, anticipation, and involvement of other organs, notably the brain, eyes, smooth muscle, cardiac conduction apparatus, and endocrine system. Morbidity is high, with a substantial mortality relating to cardiorespiratory dysfunction. More recently a second form of multisystem myotonic disorder has been recognized and variously designated as proximal myotonic myopathy (PROMM), proximal myotonic dystrophy (PDM), or DM2. For both DM1 and DM2 the molecular basis is expansion of an unstable repeat sequence in a noncoding part of a gene (DMPK in DM1 and ZNF9 in DM2). There is accumulating evidence that the basic molecular mechanism is disruption of mRNA metabolism, which has far-reaching effects on many other genes, in part through the induction of aberrant splicing, explaining the multisystemic nature of the disease. The unstable nature of the expansion provides a molecular explanation for anticipation. This review emphasizes the clinical similarities and differences between DM1 and DM2. It examines current views about the molecular basis of these disorders, and contrasts them with other repeat expansion disorders that have increasingly been recognized as a cause of neurological disease.

Confirmation of the Type 2 Myotonic Dystrophy (CCTG) n Expansion Mutation in Patients with Proximal Myotonic Myopathy/Proximal Myotonic Dystrophy of Different European Origins: A Single Shared Haplotype Indicates an Ancestral Founder Effect

Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, is a clinically and genetically heterogeneous neuromuscular disorder. DM is characterized by autosomal dominant inheritance, muscular dystrophy, myotonia, and multisystem involvement. Type 1 DM (DM1) is caused by a (CTG)(n) expansion in the 3' untranslated region of DMPK in 19q13.3. Multiple families, predominantly of German descent and with clinically variable presentation that included proximal myotonic myopathy (PROMM) and type 2 DM (DM2) but without the DM1 mutation, showed linkage to the 3q21 region and were recently shown to segregate a (CCTG)(n) expansion mutation in intron 1 of ZNF9. Here, we present linkage to 3q21 and mutational confirmation in 17 kindreds of European origin with PROMM and proximal myotonic dystrophy, from geographically distinct populations. All patients have the DM2 (CCTG)(n) expansion. To study the evolution of this mutation, we constructed a comprehensive physical map of the DM2 region around ZNF9. High-resolution haplotype analysis of disease chromosomes with five microsatellite and 22 single-nucleotide polymorphism markers around the DM2 mutation identified extensive linkage disequilibrium and a single shared haplotype of at least 132 kb among patients from the different populations. With the exception of the (CCTG)(n) expansion, the available markers indicate that the DM2 haplotype is identical to the most common haplotype in normal individuals. This situation is reminiscent of that seen in DM1. Taken together, these data suggest a single founding mutation in DM2 patients of European origin. We estimate the age of the founding haplotype and of the DM2 (CCTG) expansion mutation to be approximately 200-540 generations.

Report of the 115th ENMC workshop: DM2/PROMM and other myotonic dystrophies: 3rd Workshop, 14–16 February 2003, Naarden, The Netherlands

Myotonic dystrophy (DM1, Steinert’s disease) has been known for about 100 years. Its core features are myotonia, muscle weakness, and cataracts [1]. In 1994 another disorder was published with similar core features but lacking the DM1 mutation [2,3]. The name given to this disorder was proximal myotonic myopathy (PROMM, OMIM *160900). The first ENMC workshop on PROMM in 1997 established the clinical criteria for PROMM [4]. Prior to the second ENMC Workshop on PROMM in 2000, a major breakthrough had been accomplished when, in 1998, Ranum and Day [5] described the mapping of a new genetic locus in a large Minnesota family with myotonic dystrophy-like features on chromosome 3q21. This locus was named DM2. As a result, a new nomenclature emerged and the locus for myotonic dystrophy/Steinert’s disease was renamed DM1 [6]. Subsequent work showed that most PROMM families also mapped to the DM2 locus, whereas another smaller group of PROMM families appeared not to be linked to this locus. One separately described family with marked proximal atrophies, called proximal myotonic dystrophy [7], also mapped to the DM2 locus [8], and the workshop adopted the term myotonic dystrophy type 2 (DM2) for all the progressive myotonic multiorgan disorders linked to the DM2 locus. The clinical course of DM2 appeared to be more favourable compared to DM1. Families with DM2 did not have the severe congenital form of illness that occurs in DM1. Abnormalities in the social and cognitive abilities of adults with DM2 were typically mild or absent, and there was no prominent weakness of the facial and bulbar muscles. In DM2 the manual skills largely remained intact, and hypersomnia and mental retardation were not prominent findings. All these characteristic features of DM2 have not changed since the first ENMC Workshop[4]. They are still valid. In the advent of this 3rd workshop on DM2/PROMM, the definitive milestone of research efforts was achieved in 2001 with the identification of the mutation underlying DM2 by Ranum and Day, in collaboration with Ricker [9]. The mutation is a huge (CCTG)n microsatellite repeat expansion in the first intron of the ZNF9 gene and is thus similar to the (CTG)n repeat causing DM1. The aims with this 3rd ENMC Workshop on DM2/PROMM were:

Myotonic dystrophy type 2.

Myotonic dystrophy type 2 (DM2) is a clinically but not genetically heterogeneous, multisystem disorder, that is clinically similar to, but distinct from myotonic dystrophy type 1 (DM1). Initially, different phenotypes of DM2 were described by Ricker (proximal myotonic myopathy, PROMM), Ranum (myotonic dystrophy 2, DM2) and Udd (proximal myotonic dystrophy, PDM). Clinical features these three phenotypes had in common were diffuse, proximal or distal weakness, wasting, myotonia, cataract, cerebral, endocrine and cardiac abnormalities. Initially, the clinical differences between DM1 and PROMM seemed unmistakable, but meanwhile it has become apparent that the clinical differences between these entities are blurring. In 1999, Day et al., Meola et al. and Ricker et al. mapped the mutated gene of all three phenotypes to chromosome 3q. In 2001, the three different phenotypes were found to rely on the same mutation in the ZNF9 gene on chromosome 3q21.3. Although DM2 may be clinically heterogeneous, it is by result of a mutation in a single gene. The mutation responsible for DM2 is a CCTG-repeat expansion of 75-11 000 repeats in intron 1 of the ZNF9 gene on chromosome 3q21.3. Because of the clinical heterogeneity, the diagnosis of DM2 should rely on DNA analysis alone.

Report of the 84th ENMC Workshop: PROMM (Proximal Myotonic Myopathy) and Other Myotonic Dystrophy-Like Syndromes: 2nd Workshop. 13–15th October, 2000, Loosdrecht, The Netherlands

Report of the 84th ENMC Workshop: PROMM (Proximal Myotonic Myopathy) and Other Myotonic Dystrophy-Like Syndromes: 2nd Workshop. 13–15th October, 2000, Loosdrecht, The Netherlands

Myotonic dystrophies.

This review demonstrates genetic and phenotypic heterogeneity in all of the multisystemic myotonic disorders collectively called 'myotonic dystrophies' according to the new nomenclature: myotonic dystrophy type 1, myotonic dystrophy type 2, proximal myotonic myopathy and proximal myotonic dystrophy. Only two loci have so far been assigned (19q 13.3 in myotonic dystrophy type 1, and 3q 21.3 in myotonic dystrophy type 2). Although the diagnosis of these disorders may be suspected clinically, it needs to be confirmed by DNA analysis.

Clinical and genetic heterogeneity in myotonic dystrophies

This review of myotonic dystrophies primarily concentrates on the clinical and genetic findings that can distinguish a novel form of myotonic dystrophy, myotonic dystrophy type 2 (DM2); proximal myotonic myopathy (PROMM); and proximal myotonic dystrophy (PDM) from myotonic dystrophy type 1 (DM1). The multisystemic nature of these disorders leads to a spectrum of symptoms and signs. Careful clinical evaluation of patients with DM2/PROMM shows that the similarities among the multisystemic myotonic disorders outweigh the differences. An important point in the comparison of the phenotypes of DM1 and DM2/PROMM is that no severe congenital type of DM2/PROMM has yet been described. Genetic linkage analyses show that myotonic dystrophies can be divided into three types: the conventional Steinert type linked to chromosome 19q13.3 (DM1); DM2/PROMM and PDM linked to chromosome 3q21.3; and families not linked to either chromosomal site. Although the diagnosis may be clinically suspected, it depends on DNA analysis.

5-33-06 Proximal myotonic dystrophy — a family with autosomal dominant muscular dystrophy, cataracts, hearing loss, male hypogonadism and insulin resistance

5-33-06 Proximal myotonic dystrophy — a family with autosomal dominant muscular dystrophy, cataracts, hearing loss, male hypogonadism and insulin resistance

Proximal myotonic dystrophy—a family with autosomal dominant muscular dystrophy, cataracts, hearing loss and hypogonadism: heterogeneity of proximal myotonic syndromes?

We describe a family with an autosomal dominant, multisystem disorder, consisting of late-onset proximal muscular dystrophy, electrophysiological myotonia, cataracts, late-onset deafness and male hypogonadism. Four patients were available for clinical examinations. Examination of asymptomatic family members revealed another patient with bilateral cataracts but without definite muscle disorder. Five deceased members of the family had proximal muscle weakness, reportedly or confirmed in medical records. Molecular examination of genomic DNA showed no expansion of the unstable (CTG)n trinucleotide repeat on chromosome 19q13.3 associated with myotonic dystrophy (DM). Linkage to two loci implicated in other myotonic disorders, the muscle chloride channel ( CLCN1) gene, and the muscle sodium channel ( SCN4A) gene, was assessed and excluded. The clinical findings differ from those described in proximal myotonic myopathy (PROMM), in terms of the more severe muscle involvement with atrophy of affected muscles and the hearing loss. These findings suggest phenotypic and probably genetic heterogeneity among the proximal myotonic syndromes.