Background Histopathology & Immunohistochemistry Differential Diagnosis Myotonic Dystrophy, Congenital Type

BACKGROUND AND CLINICAL INFORMATION: Head

Summary Genetics Diagnostic Test Molecular Mechanism Clinical Features Anaesthetic Risk

Summary: Myotonic dystrophy (dystrophia myotonica or Steinert's disease) is the commonest adult form of muscular dystrophy, incidence is about 50 per 1,000,000 population). It is a trinucleotide-repeat disease transmitted by an autosomal dominant mechanism with a high level of penetrance. Myotonic dystrophy is a systemic disorder but the muscular symptomatology is most characteristic. The typical picture is slow relaxation of muscles in the hands, forearm, tngue and facial muscles. Patients also have various kinds of endocrine and systemic abnormalities. The onset of adult type is usually in adolescence or early adulthood. There are no specific pathologic changes but atrophy of type 1 fibers, ring fibers and chains of centrally located nuclei are usually seen.

Myotonia is characterized by the persistence of a strong contraction of muscle after stimulation has ceased. The contraction can be initiated volunatrily, mechanically, or electrically.

Genetics: The etiology is due to abnormally large CTG repeats in the untranslated region of the myotonic dystrophy gene (coding for myotonin protein kinase) on chromosome 19q3.3. In contrast to the congenital form, this is more often inherited from the father.

· Size of repeat: normal range is 5 to 37; instability range is 37 to 50; pathologic range is 50 to several thousand. There is a female bias for repeat expansion.

· Genetic anticipation: increase in severity and earlier onset of disease in subsequent generations.

· The size of the abnormally large repeats varies among affected siblings and increases in size through successive generations (genetic anticipation). The clinical severity of a patient is roughly proportional to the size of the abnormal repeat.

· The size of end product of genetic anticipation also increases with age. Patients that are born to carrier mother will have larger repeats if they are born at higher maternal age.

Diagnostic test: PCR or Southern blot. Since the size of the repeats may be thousands of base pairs in length and may be too big for PCR testing, southern blot can be used for diagnosis. Prenatal diagnosis is possible. Genetic gest is especially useful to rule out proximal myotonic myopathy (PROMM).

Molecular mechanisms: There may be abnormal phosphorylation of an intrinsic membrane protein, one of the sodium channels, related to abnormal myotonin protein kinase. The molecular mechanism is still largely unknown.

· Myotonin protein kinase is a cyclic AMP dependent serine-threonine muscle protein kinase.

· Expression: Myotonic dystrophy is the most highly variable expressivity and age-dependent penetrance of any known disease that afflict humans. Clinical signs and symptoms appear in virtually every organ system, but the disease can be so variable that a person carrying the genetic mutation may also show no signs or symptoms.

Clinical features: The clinical presentation is variable. The typical picture is slow relaxation of muscles in the hands, forearm, tngue and facial muscles. Some patients have generalized myotonia but few dystroopghic features but atrophy and weakness may be prominent in others. The distribution of muscle weakness characteristically starts from the face and progress down.

Cardiac problem: Patients have cardiac problem and may have sudden death. Arrythmia due to conduction problem.

Skeletal muscle:

· Early: Muscular wasting usually become evidence around early adulthood but it may present in childhood. The most commonly involved muscles at the begining are the small muscles of the hands and extensor muscles of the forearms and are often the first to be become atrophied. Ptosis of the eyelids and thinness and slackness of the facial muscles may also be the earliest sign. The disease progress slowly. Mytonia is usually an early symptom, may preceed weakness for several years, and often affects the hands, with inability to release a grasp.

· Diagnostic sign: The distribution of myotonia that can be elicited often involves small muscles, particularly in the hand, jaw, and tongue (percussion myotonia of the tongue). EMG is often used to search for repetitive (myotonic) discharges in skeletal muscle.

Full-blown picture:

· Typical facial appearance: Narrowing of the lower half of the face, and the mandible is slender and malpositioned so that the teeth do not occlude properly, ptosis, frontal bladness (in male), and wrinkled forehead.

· Other muscle: Muscle weakness includes ptosis and facial weakness and sternoidcleidomastoids, involvement of distal rather than proximal limb muscles. There may be external ophthalmoplegia, swallowing difficulties, and dysaarthria. Pharyngeal and laryngeal weakness results in a weak, monotonous, nasal voice.

· Heart: Cardiac manifestations of myotonic dystrophy can be fatal. Cardiac failure is rare but sudden death has been well recognized. Cardiac involvement has been documented in approximately 80% of patients. Bradycardia, conduction problems prolonged PR-interval, arrhythmias, and other serious cariac manifestation can be seen and also be found in "normal" family members who are, in fact, carriers. Cardiac manifestation can preceed any other symptoms.

· By PET scan, a reduction in glucose metabolism and myocardial hexokinase activation appeared to be correlated with the sizes of the abnormal repeats measured in leukocytes. Myotonin protein kinase may not only affect phosphorylation of sodium channels but probably other proteins.

Neurologic/Psychiatric: Increased incidences of mild mental retardation and socialization difficulties and hypersomnolence.

Others: Diaphgramatic weakness with hypoventilation resulting in chronic bronchitis and bronchiectasis; cataract; hyperinsulinemia in response to a glucose bolus; gonadal atrophy; dilated esophagus; weakened uterine muscle interfering with normal parturition; constipation and megacolon.

Anaesthetic risk: They are particularly sensitive to relaxants and also to sedation and analgesia. The risk is independent of clinical severity.

HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY: Head

Muscle Heart

Muscle:

· In the early stages, type I fibers appear small, either due to selective atrophy or due to selective hypertrophy of the type II fibers.

· Presence of multiple internal nuclei forming lengthy chains along the centers of muscle fibers particularly in type II fibers.

· Sarcoplasmic masses may be present and ring fibers are prominent. Motheaten change is common.

· Ring fiber: The ring is formed by a bundle of peripheral myofibrils that are circumferentially oriented such that they encircle the internal portion of the sarcoplasm which is normal in structure and orientation. Rings are best seen with PTAH stains, semi-thin sections, or under phase contrast or polarizing microscopes. Under the electron microscope the pathologically oriented myofibrils are generally normal in structure except for hypercontraction of the sarcomeres. Ring fibers are seen in myotonic muscular dystrophy, limb girdle dystrophy and trauma and several other conditions.

· Degeneration and regeneration is usually only seen in severely affected muscles.

Heart: Fibrosis, fatty infiltration, and atrophy

DIFFERENTIAL DIAGNOSIS: Head

Proximal myotonic myopathy (PROMM): clinically can closely simulate myotonic dystrophy.