Myotonic Dystrophy Type 2

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62.1 Clinical Features

and Laboratory Investigations Myotonic dystrophy type 2 (DM 2) is a dominantly in- herited progressive myopathy. DM 2 closely resem- bles adult-onset myotonic dystrophy type 1 (DM 1).

Initially, three different disorders were delineated on the basis of clinical findings: proximal myotonic myopathy (PROMM), proximal myotonic dystrophy (PMD), and myotonic dystrophy type 2 (“DM 2”).

Since all three have been shown to be part of one genetic spectrum, DM 2 is used for all three and has replaced the terms PROMM and PMD.

Patients with PROMM have been reported as being completely asymptomatic, mildly affected, or consid- erably disabled. Clinical onset is between 20 and 60 years of age. Most patients have cataract before the age of 50. The muscle weakness is predominantly proximal. Additional signs include muscle pain, fluc- tuating weakness and stiffness, muscle cramps, fasci- culations, calf hypertrophy, tremor, seizures, sensorineural deafness, frontal baldness, male hypogonadism, insulin-resistant diabetes mellitus, hypothy- roidism, hyperhidrosis, dysphagia, constipation, intermittent episodes of chest pain, and cardiac conduction defects. Cognitive impairment, hypersomnia, and apathy are rare and at most mild.

Patients with PMD have been reported to present with cataract, late-onset sensorineural hearing loss, late-onset prominent proximal weakness, wasting, myotonia and male hypogonadism.

“DM 2” as defined initially includes patients with myotonia, diffuse (proximal and distal) or exclusively distal weakness, frontal balding, cataracts, infertility, and cardiac conduction defects. Additional features include calf hypertrophy and hyperhidrosis.

So, like DM 1, DM2 is a clinically heterogeneous multisystem disorder. Some affected DM 2 patients exhibit remarkable clinical similarity to those with classic DM 1, with myotonia, proximal and distal muscle weakness, frontal balding, cataracts, and cardiac conduction defects, whereas other patients can be more easily distinguished. One clear distinction is the absence of a congenital form of DM 2. Other dif- ferences include a lack of mental retardation in juve- nile patients; less evident central hypersomnia; less distal, facial, and bulbar weakness; and less pro- nounced muscle atrophy.

In a large overview study on DM 2 (Day et al. 2003), 90% of the affected individuals had electrical myotonia, 82% had weakness, 61% cataracts, 23% diabetes mellitus, and 19% cardiac involvement. First symptoms of the disease occur between the ages of 13 and 67, with a median of 48 years. Muscle symptoms, including pain, stiffness, myotonia, and weakness, are the most common symptoms in DM 2 patients. Fluc- tuating or episodic burning muscle pain is frequently present, mainly during the night. Cataracts are a prominent and early feature, sometimes already seen before the age of 20. Cataract extraction may be necessary from as early as 30 years to as late as in the seventies. Cardiac complaints include palpitations, intermittent tachycardia, and episodic syncope. These symptoms increase in frequency with age. Cardiac conduction abnormalities and cardiomyopathy may underlie these complaints. DM 2 patients can develop fatal arrhythmias unexpectedly.

On EMG a broad spectrum of spontaneous activi- ty, such as fibrillations, positive sharp waves, fascicu- lations, myotonic and pseudomyotonic discharges, neuromyotonia-like discharges, and high-frequency bizarre discharges, can be found. Motor unit action potentials may show reduced mean duration, increased polyphasia, and increased satellite potentials.

Serum creatine kinase levels are usually elevated, typ- ically less than five times the upper limit of normal, but may also be normal. g-Glutamyl transferase is normal or mildly elevated. Primary male hypogonadism is found in the majority of the affected men, with elevated LH and FSH, low testosterone, and oligospermia. Hypogammaglobulinemia may be found. Thyroid function tests may indicate hypothy- roidism. In the case of diabetes mellitus, insulin in- sensitivity is found with elevated basal insulin levels or prolonged insulin elevations. ECG shows impulse generation and conduction defects. Echocardiogra- phy may reveal a cardiomyopathy. DNA techniques are available to confirm the diagnosis and for prena- tal diagnosis.

62.2 Pathology

Neuropathological data on DM 2 are lacking.

Myotonic Dystrophy Type 2

Chapter 62

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62.3 Pathogenetic Considerations

DM 2 is caused by an unstable expansion of a cytosine-cytosine-thymine-guanine (CCTG) repeat in in- tron 1 of the zinc finger protein 9 gene (ZNF9), a gene located on chromosome 3q21.3. The repeat length varies between 75–11,000, with a mean of approxi- mately 5,000. Expansion sizes in the blood of affected children are usually shorter than in their parents. No significant correlation is found between the age of onset and expansion size.

The gene has two products, a-ZNF9 and b-ZNF9, produced by alternative splicing. ZNF9, also called cellular nucleic acid binding protein, contains seven zinc finger domains. It is though to be an RNA-binding protein. It is widely expressed, with the highest ex- pression in heart and skeletal muscle. The pathophys- iology of the disease is presently unclear.

Not all families with a DM 2 phenotype display linkage with chromosome 3q21.3. So, there must be still other genes related to this phenotype.

62.4 Therapy

So far, there is no specific treatment for DM 2. Physi- cal therapy may be of some benefit. In patients in whom myotonia is a prominent problem, mexiletine, phenytoin, or carbamazepine may be beneficial.

When cardiac conduction defects are present, antiar- rhythmic drugs should be avoided. Patients should undergo cardiological examination and follow-up as soon as the diagnosis is established. Cataracts may require surgical intervention at some point. Cardiac therapy, including pacemaker implantation, may be necessary. Patients should be checked for hypo-

Chapter 62 Myotonic Dystrophy Type 2 474

Fig. 62.1. The T2-weighted images in this 66-year-old male patient with DM 2 show diffuse cerebral white matter abnormalities with sparing of the corpus callosum and relative sparing of the U fibers. Spots of abnormal signal are present in the basal ganglia.The anterior limb of the internal capsule and the

external capsule are also affected. The lateral ventricles and subarachnoid spaces are mildly dilated. Courtesy of Dr. E.

Hund, Department of Neurology, and Dr. Sartor, Department of Neuroradiology, University of Heidelberg Medical School, Hei- delberg, Germany

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thyroidism regularly. Whether DM 2 patients ex- perience respiratory depression in response to benzodiazepines, opiates, or barbiturates, whether myotonia is aggravated by depolarizing muscle relax- ants, and whether DM 2 patients may develop malig- nant hyperthermia during or after anesthesia is unknown.

62.5 Magnetic Resonance Imaging

MRI of the brain is often normal, but may show rather extensive abnormalities in the cerebral white matter (Figs. 62.1 and 62.2). The U fibers tend to be spared.

The white matter abnormalities may be diffuse (Fig. 62.1) or, more often, patchy (Fig. 62.2). These abnormalities may be accompanied by neurological problems including clinical episodes of stroke, parkinsonian features, seizures, and mental changes.

62.5 Magnetic Resonance Imaging 475

Fig. 62.2. The MRI of this 64-year-old female patient with DM 2 reveals extensive, patchy cerebral white matter abnormalities, sparing the corpus callosum and partially sparing the U fibers. The internal and external capsules are affected. There are spots of abnormal signal in the basal ganglia. The lateral

ventricles and subarachnoid spaces are dilated due to reduced volume of the cerebral white matter. Courtesy of Dr. E. Hund, Department of Neurology, and Dr. Sartor, Department of Neuroradiology, University of Heidelberg Medical School, Hei- delberg, Germany