Myotonic Dystrophy

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Myotonic dystrophy (DM), or Steinert's disease, is an autosomal dominant multisystem degenerative disease characterized by myotonia, progressive muscular weakness, gonadal atrophy, cataracts, and cardiac dysrhythmias.

Pathogenesis and Pathophysiology. The molecular basis of DM is an unstable trinucleotide repeat sequence, cytosine, thymine, and guanidine (CTG) in the protein kinase-encoding gene (DMK), located at 19q13.3. The repeat is present 50 to several thousands of times in patients with DM rather than the 5 to 30 times in the normal population. The size of the repeat is correlated roughly with severity of symptoms, with more-affected patients having greater numbers of repeats. y The repeat expansion also may account for the anticipation seen in families with DM, in which the severity of symptoms increases and the age of onset decreases with subsequent generations.y It was demonstrated that DMK protein is localized to the postsynaptic side of the neuromuscular junction in skeletal muscle and the intercalated discs in cardiac muscle in humans. Additionally, DMK protein is present in specific structures in rat brain, supporting the hypothesis that it may have selective actions in the central nervous system.y

There have been widely conflicting results in the effort to unravel the precise effect of the expanded repeats; some data support the theory that there is a loss of function of the mutant allele, whereas other data favor increased expression of the allele. Recent work supports a new interpretation of the data. Both normal and expanded DM kinase genes are transcribed in patient muscle, but the expanded RNA has a dominant effect on RNA metabolism by preventing accumulation of poly(A)+ RNA.y

Epidemiology and Risk Factors. There is an estimated prevalence of 3 to 5 per 100,000 population and an incidence of 1 in 8,000 live births, making it the most common adult muscular dystrophy. Although a few isolated

populations have an exceptionally high prevalence, DM has been found in all racial groups. y

Clinical Features and Associated Findings. The phenotype is correlated with the length of the CTG repeat and thus is widely variable, ranging from the single manifestation of cataracts that present in the middle years to severe neonatal hyoptonia that can lead to death if respiratory support is not provided. Traditionally, these different types of symptoms have resulted in the designation of either congenital or noncongenital DM.

The classic presentation of noncongenital DM, which is well described by Harper, includes marked weakness in the face, jaw, and neck muscles and milder distal extremity weakness (.Fig 36-7 ^ Weakness of the extremities is often the first problem perceived by the patient, even when a careful evaluation may reveal a clear history of myotonia (sometimes termed muscle stiffness or cramping by patients), facial weakness, and nasal speech. Patients frequently seem unaware of their illness and symptoms, both in themselves and in family members. Using a percussion hammer, myotonia can be elicited in patients with DM with a brisk tap on the thenar muscle, causing flexion-opposition of the thumb with slow relaxation.

The person with advanced DM has a characteristic appearance: a long, thin face with sunken cheeks due to temporal and masseter wasting, a so-called swan neck because of sternocleidomastoid wasting, and ptosis, with relatively strong muscles in the posterior neck and shoulder girdle.

Congenital DM presents a distinctive picture that is different from other disorders. Facial diplegia and jaw weakness without concomitant extremity weakness are hallmarks. Weakness of the respiratory muscles with respiratory distress is present in at least 50 percent of patients and is the most common cause of death in these infants. Hypotonia is present in severely affected neonates but it may disappear within weeks. Clinical myotonia is generally absent and is usually detectable only by EMG.y

A recent prospective study followed patients of both types for 10 years, with the conclusion that muscle weakness

Figure 36-7 Myotonic dystrophy with typical myopathic facies, frontal balding, and sunken cheefFrom Dubowitz V: Muscle Disorders in Childhood. London, W.B. Saunders, 1995.)

was relatively mild in both types, although it was progressive in the noncongenital form. Weakness was generalized in both types, with no significant differences found in distribution. Additionally, 75 percent of the noncongenital patients and 81 percent of the congenital patients had cardiac abnormalities, primarily conduction defects, demonstrated on EKG. Intellectual function was frequently and severely impaired in the congenital type, whereas only about a third of the noncongenital patients were mildly impaired.y

It cannot be overemphasized that DM is a multisystem disorder. The heart is prominently involved, and the severity of cardiac symptoms does not correlate with severity of other symptoms in this disorder. All patients with DM need to undergo EKG evaluation, because sudden death is well documented, and as many as 90 percent of patients have conduction defects, particularly first-degree heart block and atrial arrhythmias. Both the diaphragm and intercostal muscles may be myotonic and weak, which leads to alveolar hypoventilation. In addition, there are smooth muscle abnormalities throughout the gastrointestinal system. Particularly important are the delayed relaxation of the pharynx and reduced motility in the esophagus that may lead to aspiration, constipation, and anal sphincter abnormalities in children.

Central nervous system involvement includes generalized atrophy and ventricular dilatation, but structural changes in the brain do not seem to be common, even in patients with congenital disorders. However, there are well-known behaviors associated with DM that range from apathy and inertia, with concomitant lower socioeconomic status, to hypersomnolence that is often present without detectable respiratory problems. In addition, numerous endocrinological abnormalities have been reported, several with clinical importance. Hyperinsulinism and reduced numbers of insulin receptors are common, but diabetes is not. Elevations of pituitary FSH and LH occur frequently.

In males, testicular atrophy, Leydig cell hyperplasia, and slightly reduced serum testosterone is common. In females, no consistent ovarian problems have been documented, but the spontaneous abortion rate is high. Fertility in both sexes seems to be reduced to about 75 percent of normal. Finally, in the ocular system, cataracts with characteristic multicolored crystalline subcapsular opacities have been documented since the recognition of DM as an entity. Retinal degeneration, low intraocular pressure, and saccadic eye movement defects have been reported. y

Evaluation and Differential Diagnosis. Faciohumeral dystrophy may have the same distribution of weakness, but there is no myotonia. More rarely, some of the LGMDs may have a similar distribution of weakness, again without myotonia. Molecular analysis can distinguish DM from these disorders, as well as those with marked myotonia, such as myotonia congenita and paramyotonia.

Sometimes the clinical presentation of DM is so distinctive that the experienced clinician uses tools only to confirm a diagnosis already made. EMG should be employed in suspected DM when myotonia is clinically equivocal or absent. The typical pattern is of long-lasting runs with declining frequency and amplitude, with the distal muscles of the upper extremities and the orbicularis orbis most often being involved. A careful slit lamp evaluation will

ascertain characteristic opacities and should be performed on any patient suspected of having this condition. Muscle biopsy may show a constellation of abnormalities, including increased central nuclei, nuclear chains, ringed fibers, sarcoplasmic masses, atrophy of type I fibers, increased numbers of fibers in spindles, and increased arborization at the terminal. y Nerve biopsy shows increased arborization. Other conditions associated with myotonia, such as myotonica congenita (see Chapt§r„37 ) and drug-induced myotonia (see Chapter,,^ ), need to be considered.

Management and Prognosis. Because there is no cure for DM, current management focuses on treatment of the myotonia and associated systemic problems, monitoring of pregnancy, and genetic counseling. Because patients frequently do not perceive their myotonia as being problematic, they may not follow a treatment plan. However, 100 mg of phenytoin taken three times daily is effective in reducing myotonia and does not produce the cardiosuppressive complications of either quinine or procainamide. Anesthesia should be used for these patients only when it cannot be avoided. Myotonia may be increased by the depolarizing relaxants used for inducing anesthesia or the anticholinesterases used to terminate relaxation, although the barbiturates, benzodiazepines, and opiates may produce apnea. Cases have been reported in which the diagnosis of DM has been made only after the patient experienced postoperative apnea. Harper provides a comprehensive discussion of anesthetic management in DM.y A bracelet that identifies the patient as having DM may be helpful.

Because cardiac complications may be life threatening, careful evaluation, including a His bundle electrogram, must be performed to ascertain conduction defects that need pacemakers. Some respiratory problems may be avoided by upright positioning during meals and by spacing meals well ahead of bedtime.

There is increased risk of spontaneous abortion in myotonic mothers, as well as complications during labor and delivery. There may be incoordination of contractions during labor that prolong the first stage, a retained placenta, and postpartum hemorrhage, as well as the previously cited anesthetic sensitivity.

Presymptomatic and prenatal genetic counseling, including a discussion of the increased risks of pregnancy to an affected or carrier mother as well as to the fetus, the phenomenon of anticipation, and congenital DM, should be provided to families with a history of DM. It should be remembered that although a significant number of persons with DM are mentally impaired, some who are not may be perceived as such because of facial weakness.

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