Myotonic Dystrophy Type 1

61.1 Clinical Features

and Laboratory Investigations Myotonic dystrophy type 1 (DM 1) or Curschmann–

Steinert disease is a dominantly inherited progressive myopathy. It is one of the most frequent muscle dis- orders, with a prevalence of approximately 1:8,000.

Symptoms of the disease usually become apparent between the ages of 15 and 40 years, but may be found in childhood. Major symptoms include myotonia, progressive muscle weakness, and atrophy. In partic- ular the face, jaw, neck, and distal muscles of the arms and legs are affected. Involvement of the bulbar mus- cles causes dysphagia and dysarthria. Myotonia leads to a prolonged after-contraction of the affected mus- cles, which persists after the voluntary muscle con- traction has ceased. Myotonia is increased by fatigue, emotion, and cold. Other features of the disease in- clude cataract, early frontal baldness (more conspicu- ous in males than in females), hearing impairment, and testicular atrophy leading to impotence and in- fertility. The heart is often affected. Cardiac conduc- tion defects and dilated cardiomyopathy may occur and may contribute to a shortened life span. Smooth muscles, particularly those of the pharynx, esopha- gus, and gastrointestinal tract, are also involved. Hy- perinsulinism occurs with enhanced frequency. Mild- ly impaired intelligence is frequently present. Hyper- somnia may occur.

DM 1 has a congenital variant, with variable hypo- tonia and weakness present at birth. This variant is present in 10–15% of the patients. In congenital DM 1 respiratory problems and feeding difficulties are common. Joint deformities may be present. Myotonia is not usually present in neonates and seldom devel- ops until later in childhood. Cataracts and endocrine abnormalities usually develop even later. Mental re- tardation is present in nearly all patients with con- genital DM 1 and is more severe than the cognitive problems seen in patients with adolescent and adult- onset disease. Some patients do not survive the neonatal period.

A characteristic feature of DM 1 is the tendency of the symptomatology to have an earlier onset and in- creasing severity with transmission to subsequent generations, a phenomenon called anticipation. In early generations, cataract is often the only abnor- mality; in a subsequent generation adult myotonia and weakness occur, while in the next generation con-

genital DM 1 is seen. The disease is transmitted as an autosomal dominant trait, but the mother is the af- fected parent in over 90% of the cases of congenital DM 1.

Diagnosis is established by clinical examination and EMG. On EMG prolonged trains of high-frequen- cy discharges arising from single fibers or groups of muscle fibers occur in response to electrode insertion or movement. EMG can be negative in young patients.

Serum creatine kinase levels may be mildly elevated.

DNA techniques are available to confirm the diagno- sis and for prenatal diagnosis.

61.2 Pathology

Neuropathological data on DM 1 are scarce. Some ex- ternal atrophy of the cerebral hemispheres may be present. Microscopic examination may reveal lesions within the cerebral white matter, especially in the sub- cortical areas. Microscopically, they are characterized by myelin paucity and preservation of myelin sheaths in perivascular regions in a tigroid pattern. Axons are relatively preserved. Macrophages containing fatty material and fibrillary astrocytes are scanty. It has been demonstrated that the areas of myelin paucity correspond with areas of signal abnormality on MRI.

Additional findings that have been reported are variable neuronal loss and astrocytosis in the fron- toparietal and occipital cortices, neurofibrillary tan- gles in the limbic cortex, intracytoplasmic inclusion bodies within neurons of the thalamus and substan- tia nigra, disordered cortical architecture, and neu- ronal heterotopias. The neuronal heterotopias are fre- quently found adjacent to the areas of myelin paucity.

The absence of gliosis and lipid-laden macro- phages within the areas of abnormal white matter as well as their association with neuronal heterotopias suggest that the white matter lesions are developmen- tal abnormalities and not caused by demyelination.

61.3 Pathogenetic Considerations

DM 1 is caused by an expansion of an unstable cyto- sine-thymine-guanine (CTG) trinucleotide repeat in the 3’ untranslated region of a protein kinase gene, DMPK, located on chromosome 19q13.3. In the nor- mal population, the repeat length ranges between

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Chapter 61

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4 and 37 copies, whereas alleles in DM 1 patients vary from 50 to several thousands of CTG repeats. The longer the CTG repeat sequence, the earlier the onset and more severe the clinical symptomatology. Alleles with 50–80 repeats are classified as protomutations, with which the DM 1 phenotype is mild and often does not cause subjective symptoms. Alleles with more than 80 repeats usually cause the classic DM 1 phenotype. The phenomenon of anticipation is asso- ciated with an increase in the length of the CTG repeat sequence with transmission to subsequent genera- tions. Rare cases of reverse mutations have been re- ported, in which the prolonged CTG repeat sequence in the parent is decreased in size to a normal length in the offspring.

The expanded repeat is located in the 3’ untranslat- ed part of the gene. Three models have been proposed to explain how an expansion of this untranslated CTG repeat may cause the dominantly inherited DM 1 phe- notype. Haploinsufficiency of the DMPK gene may produce cellular dysfunction. Alternatively, the ex- panded repeat may lead to a dominant gain of func- tion. Finally, the CTG repeat expansion may change the chromatin structure, which interferes with the ex- pression of adjacent genes.

The in vivo biological substrates of the enzyme DMPK are unknown. Since DMPK exhibits kinase ac- tivity, any perturbation of its expression or activity will potentially affect other molecules. Because DM 1 is characterized by muscle dysfunction and myoto- nia, ion channels could be substrates for DMPK. How- ever, other proteins of as yet unknown function have also been found associated with DMPK. Dysfunction of such proteins may explain the extramuscular symptoms, including the mental deficit.

61.4 Therapy

First and most important is awareness of the potential problems associated with DM 1. Anesthesia and surgery come with particular hazards due to the com- bination of respiratory muscle weakness and in- creased sensitivity to anesthetics and muscle relax- ants. Cardiac problems such as atrial fibrillation and flutter and heart block are important causes of death and require careful attention and treatment. Aware- ness of smooth muscle dysfunction and the associat- ed potential gastrointestinal complaints including abdominal pains and pseudo-obstruction may pre- vent unnecessary surgery. Symptomatic relief of the myotonia can, if necessary, be obtained by drugs such as procainamide, diphenylhydantoin (phenytoin), and mexiletine. The effect of these drugs lies in the stabilization of the muscle membrane; they have no effect on muscle weakness. Physical therapy may be necessary. Cataract extraction can be important in or- der to preserve visual acuity.

61.5 Magnetic Resonance Imaging

It was already known from CT that mild ventricular enlargement and white matter hypodensity are not rare in DM 1.

MRI confirms the frequent presence of mild ven- triculomegaly and enlargement of subarachnoid spaces (Figs. 61.1–61.4). In the majority of the DM 1 patients MRI also shows white matter abnormalities in the cerebral hemispheres (Figs. 61.1–61.4). The dis- tribution of the white matter lesions is variable, rang- ing in location from predominantly in the periven-

Chapter 61 Myotonic Dystrophy Type 1 470

Fig. 61.1. These T

-weighted MR images show the white mat- ter changes in a 60-year-old female patient with DM 1. The white matter abnormalities are patchy and predominantly located in the subcortical areas. The temporal white matter is

involved as well. There is some atrophy with enlargement of the subarachnoid spaces. From Damain et al. (1992), with per- mission

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tricular region to predominantly in the deep white matter or predominantly in the subcortical areas. In particular the anterior part of the temporal lobes is frequently involved (Figs. 61.1–61.4). The white mat- ter changes are often patchy with in part isolated and in part irregularly confluent lesions of variable size.

The lesions tend to be bilateral but are often not sym- metrical in detail. The extent of the white matter changes varies from minor, with some small white matter lesions (Figs. 61.4 and 61.5), to more extensive and more confluent lesions (Figs. 61.1–61.3). In ex- ceptional patients, the cerebral white matter abnor- malities are diffuse. The white matter abnormalities may show an increase over time. The white matter changes occur both in congenital MD1 and later-on- set forms and have the same imaging characteristics

in both conditions. Patients with congenital DM 1 tend more often to have enlargement of the lateral ventricles and a small corpus callosum.

Magnetization transfer ratios have found to be decreased not only in the MRI-visible white matter lesions, but also in the normal-appearing white mat- ter, suggesting presence of more widespread structur- al abnormalities. T

relaxation measurements simi- larly revealed increased values within the white mat- ter lesions, but again also in the normal-appearing white matter.

The pattern of MRI abnormalities with multifocal and often not entirely symmetrical lesions would rather suggest acquired disorders, especially inflam- matory and infectious disorders. The pattern is particularly similar to that seen in congenital cyto-

61.5 Magnetic Resonance Imaging 471

Fig. 61.2. A 63-year old female patient with DM 1. The patchy, multifocal white matter abnormalities mainly involve the deep cerebral white matter. The abnormalities are asymmetrical in distribution. The lateral ventricles and subarachnoid spaces

are mildly dilated. Note the temporal white matter abnormali- ties. Courtesy of Dr. G. Bachmann, Department of Diagnostic Radiology, Kerckhoff-Klinik, Bad Nauheim, Germany

Fig. 61.3. The T

-weighted images in a 61-year-old male pa- tient with DM 1 reveal similar abnormalities, again with a slightly asymmetrical distribution. Courtesy of Dr. A. Di Costan-

zo, Department of Neurological Sciences, Second University of Naples, Italy

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megalovirus infection. In the latter condition, multi- focal lesions are seen, mainly in the deep cerebral white matter, and the anterior temporal lobes are frequently involved. However, in congenital cyto- megalovirus infection, the largest lesions are as a rule present in the parietal region, which is not the case in DM 1. Of course, in the presence of myotonia, there is little reason for confusion.

Chapter 61 Myotonic Dystrophy Type 1 472

Fig. 61.4. This 54-year-old female patient with DM 1 has only mild white matter abnormalities. The temporal abnormalities are most pronounced. Courtesy of Dr. G. Bachmann, Depart-

ment of Diagnostic Radiology, Kerckhoff-Klinik, Bad Nauheim, Germany

Fig. 61.5. This 34-year-old female patient with DM 1 has min- imal white matter abnormalities. There is an indication of slight abnormalities in the anterior temporal white matter.

Courtesy of Dr. A. Di Costanzo, Department of Neurological Sci- ences, Second University of Naples, Italy

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