Myotonic Myopathy (PROMM, DM2).” A critical element in the pathogenesis of this disease in both types is the intranuclear accumulation of the expanded RNA sequences; these disrupt the regulation of alternative splicing of mRNA and perturb the expression of many genes, thus the multiple systems affected clinically.
Clinical Features of Myotonic Dystrophy 1 (DM1, DMPK Mutation)
In most instances of myotonic dystrophy, the weakness and muscular wasting do not become evident until early adult life, but they may present in childhood, usually with facial weakness and ptosis. Myotonia is perhaps more obvious and earlier in this disorder than in most others that display the sign as one component. Myotonic dystrophy is, for example, far more common than myotonia congenita. Myotonia combined with distal weakness in DM1 stands out from other myopathies. Cardiac arrhythmias, sometimes evident on in conduction defects in EKG, are common as noted below. A severe neonatal (congenital) form of the disease is well known and is described separately further on.
In the common early adult form of the disease, the small muscles of the hands along with the extensor muscles of the forearms are often the first to become atrophied. Difficulty grapsing (due to weakness of hand muscles) and then releasing objects (because of the myotonia) is typical. In other cases, ptosis of the eyelids and thinness and slackness of the facial muscles may be the earliest signs, preceding other muscular involvement by many years. Atrophy of the masseters leads to narrowing of the lower half of the face, and the mandible is slender and malpositioned so that the teeth do not occlude properly. This, along with the ptosis, frontal baldness, and wrinkled forehead, imparts a distinctive appearance that, once seen, can be recognized at a glance (“hatchet” face). The sternocleidomastoids are almost invariably thin and weak and are associated with an exaggerated forward curvature of the neck (“swan neck”). Atrophy of the anterior tibial muscle groups, leading to foot-drop, is an early sign in some families.
Pharyngeal and laryngeal weakness results in a weak, monotonous, nasal voice. The uterine muscle may be weakened, interfering with normal parturition, and the esophagus is often dilated because of loss of muscle fibers in the striated as well as smooth muscle parts. Megacolon occurs in some patients. Diaphragmatic weakness and alveolar hypoventilation, resulting in chronic bronchitis and bronchiectasis, are common late features, as are cardiac abnormalities; the latter are most often a result of disease of the conducting apparatus, giving rise to bradycardia and a prolonged P-R interval. Patients with extreme bradycardia atrial tachyarrhythmia or high degrees of atrioventricular block may die suddenly; for such individuals, insertion of a pacemaker is often recommended (Moorman et al; Groh et al). Mitral valve prolapse and left ventricular dysfunction (cardiomyopathy) are less frequent abnormalities. In this disorder, as in Emery-Dreifuss dystrophy, careful assessment by a knowledgeable cardiologist is required.
The disease progresses slowly, with gradual involvement of the proximal muscles of the limbs and muscles of the trunk. Tendon reflexes are lost or much reduced. Contracture is rarely seen, and the thin, flattened hands are consequently soft and pliable. Most patients are confined to a wheelchair or bed within 15 to 20 years of the first signs, and death occurs before the normal age from pulmonary infection, heart block, or heart failure.