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Myotonic dystrophy type 1
09 February 2009

Authors
C.E.M. de Die-Smulders, M.D., Ph.D.

Other experts in the Netherlands

B.G.M. van Engelen, M.D., Ph.D. professor in neuromuscular disorders


Clinical features
Myotonic dystrophy type 1 (DM1) is the most common of all inherited muscle diseases. Apart from muscle weakness, many other organs are affected during the extended course of the disease. DM1 was identified in 1909 as a distinct disorder, different from myotonia congenita, by Steinert in Germany and by Batten and Gibb in the UK. 1 2 It then took almost a century before its main clinical features were delineated, but there still are a number of obscure aspects in its clinical presentation. DM1 affects the skeletal-, cardiac- and smooth musculature and many other tissues. Read more

Natural course and prognosis
The course of the disease strongly depends on the age at onset. The late onset form is supposed to be benign and life expectancy is supposed to be within the normal range. Controlled prospective studies are lacking however. In the adult (classical) type , muscular weakness usually increases very slowly over several decades leading after 20 to 30 years to proximal limb weakness and in up to 50% of the patients to wheelchair dependency. 16 As muscle weakness progresses, myotonia may disappear. Read more

Epidemiology

Data on the epidemiology of the disease reveal striking differences in prevalence between regions and ethnic groups. In older textbooks the prevalence was estimated to vary from 2.4 to 5.5 per 100.000.45 The figures obtained in Caucasians since 1990 are higher and range from 7 to an exceptional high number of 189 per 100.000, the latter figure is presumed to be due to a founder effect in part of Canada.


Pathophysiology / etiology

The molecular mechanism underlying DM1 has not yet been unraveled completely. The DM1 gene encodes a proteine kinase (PK) that is expressed in different tissues, such as muscle, brain, heart, eye, testis.32 Its function is at present not clear. Knockout-mice do not have myotonia or muscle weakness, indicating that deficiency of the protein kinase is not the main cause of the disease. The CTG expansion also does not result in the production of an abnormal protein. It suppresses the expression of neighboring genes but this does not seem to fully explain the DM1 manifestations. The mutant RNA produced by the abnormal DMPK gene appears to have a toxic effect on muscle cells. A recent hypothesis proposes therefore that the disease is caused by toxic gain-of-function of mutant RNA.33


Differential diagnosis

DM2 (PROMM) is a recently delineated autosomal dominant disorder with features resembling those in DM1.29 The main features of DM2 are muscle weakness and myotonia, cataract and occasionally abnormal cardiac conduction. As limb muscle weakness in these patients is usually proximal, the disorder was initially labeled ‘proximal myotonic myopathy’ or PROMM. The mutation is an unstable expanded CCTG- repeat in the ZNF9 gene on chromosome 3.30
Furthermore, the non-dystrophic myotonias (myotonia congenita, paramyotonia congenita and periodic paralysis), all muscle ion channelopathies, need to be considered in the differential diagnosis of myotonia.


Ancillary investigations
The clinical features of the different types of DM1 are essential for diagnosis. These are (myotonic) cataract, myotonia, muscle weakness, the specific distribution of atrophy, mental handicap and congenital hypotonia with paralysis of the facial musculature. In classically affected patients the clinical diagnosis DM1 is straightforward, based on the typical facial features and the characteristic pattern of muscle weakness, combined with myotonia. 31 It is however not sufficient to diagnose DM1, one should also establish the type of DM1, the stage and the duration of the disease. Read more

Genetics
DM1 is an autosomal dominant disorder with very variable expression. Its inheritance is characterized by anticipation, an earlier age of onset and increasing severity in successive generations. 34-36 . Read more

Therapy
Muscles Although myotonia may sometimes hinder patients, it provides no major difficulties and does not usually cause patients to ask for medical advice or for treatment. Mexilitine is the most frequently used drug for treatment of myotonia. Most other drugs with an antimyotonic effect delay cardiac conduction and are therefore contraindicated. The limitations caused by muscle weakness can be made easier to live with, by aids and appliances (e.g. a rollator) and can be compensated for by adjustments. Read more

References
Steinert H. Myopathologische Beitrage. 1. Ueber das klinische und anatomische Bild des Muskelschwunds der Myotoniker. Dtsch Z Nervenheilkunde 1909;37:58-104. Read more
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