Duchenne Muscular Dystrophy

Inherited and progressive myopathy affecting boys. Presents with muscular, respiratory, and cardiac disease.

DMD; Pseudohypertrophic Muscular Dystrophy; Duchenne Type of Progressive Muscular Dystrophy; Progressive Muscular Dystrophy Type I.

Approximately 1:3500 boys is affected, which makes it the most common form of muscular dystrophy. No preferences in race or nationality have been reported. The disease affects almost exclusively males, although females rarely can be affected, for example, when they have a translocation between autosomal chromosomes and the X chromosome, uniparental disomy (i.e., when the chromosome pair or specific segments of a chromosome pair are inherited from one parent only), or suffer from Turner syndrome.

About one third results from spontaneous mutation (negative family history does not exclude DMD); the rest is inherited in an X-gonosomal recessive way. Simplified, in DMD a frameshift mutation results in the absence of dystrophin, whereas in Becker muscular dystrophy a non-frameshift mutation results in decreased levels of dystrophin. The responsible gene (with 2400 kbp, one of the largest known human genes) has been mapped to the short arm of the X chromosome at position 21 (Xp21).

The DMD gene product, a protein called dystrophin, is absent or nonfunctional in patients with DMD. Dystrophin, an important structural part of a large sarcolemmal glycoprotein complex, stabilizes the sarcolemma and plays an important role in the interaction between sarcoplasm and extracellular matrix. Dystrophin is expressed in skeletal and cardiac muscle and in the brain. In the absence of dystrophin (or its function), the entire function of this sarcolemmal complex appears to be disrupted (dystrophin links the actin filaments to the glycoprotein complex in the sarcolemma). This defect may result in either decreased sarcolemmal stability to the mechanical stress of contraction-relaxation or disturbed calcium homeostasis with excessive calcium influx into the muscle cell and pathologic activation of intracellular enzymes. Finally, this results in destruction and necrosis of muscle fibers, which are eliminated by macrophages (myophagocytosis) and later replaced by scar and fat tissue with endomysial and perimysial fibrosis. Although some muscle fibers may show a compensatory hypertrophy, most often the fibers are atrophic, split, or even missing in later stages of the disease. The clinically diagnosed pseudohypertrophy of muscles (particularly the calves) refers to this phenomenon and is, in fact, the result of scarring and fatty degeneration of the muscles, which is muscle wasting.

The clinical course, elevated plasma levels of creatine phosphokinase and other enzymes (e.g., troponin I, lactate dehydrogenase, and transaminases), and muscle biopsy (fatty degeneration and scarring and immunostaining confirm the lack of dystrophin) lead to the diagnosis. Molecular biology allows for intrauterine diagnosis. Age at diagnosis is before birth (familial context), otherwise between 2 and 5 years (occasionally later). Female carriers of the disease may have increased creatine phosphokinase levels, but most often they are clinically asymptomatic.

Progressive and symmetrical wasting of muscles of the legs and pelvis and later of the thorax and upper limbs. Muscle weakness appears insidiously between 2 and 5 years of age, producing a waddling gait and lordosis. Soon thereafter, the calf muscles become enlarged (pseudohypertrophy). These boys have difficulty standing up (Gowers sign) and climbing stairs, develop contractures, and become wheelchair-bound by age 10 to 12 years (sometimes earlier). Joint deformities, muscle retractions, and degenerations are common. Collapse of the spine results in severe scoliosis and restrictive pulmonary disease. Often these patients are obese (secondary to lack of physical activity and fatty degeneration of the muscles), show mild mental retardation (with an average IQ in the mid-80s), and hypertrophy of the tongue. Clinically apparent dilated cardiomyopathy (which initially may have been hypertrophic), often with persistent sinus tachycardia and conduction system abnormalities (ECG changes, most often consisting of signs of right ventricular hypertrophy and/or right bundle branch block, occur in 40-90% of patients), is a common feature in adolescents with DMD. Occasionally, left-sided endocardial thickening (left atrial and left ventricular) occurs. Echocardiography may reveal normal systolic but pathologic diastolic left ventricular function (i.e., decreased diastolic relaxation). Mitral valve prolapse has been reported in about one fourth of patients and may be secondary to fatty degeneration of the papillary muscles. Weakness of the diaphragm is an ominous sign that usually occurs in the second decade of life and may result in hypoventilation and hypoxia. Death most often occurs late in the second decade from respiratory complications (>90%) and/or cardiac complications (10%).

Obtain a full history of motor milestones, previous complications (especially following surgeries), and familial related disorders. Evaluate pulmonary function test (forced vital capacity [FVC], peak expiratory flow rate, forced expiratory volume (1 sec) [FEV1], FEV2: FRC [functional residual capacity] ratio, arterial blood gas analysis, and chest radiograph). Evaluate cardiac function with ECG, echocardiography, and, if necessary, radionuclide imaging. Blood work should include a complete blood count, serum levels of creatine phosphokinase and electrolytes, and arterial blood gas analysis. Elective surgery under general anesthesia is contraindicated when respiratory and/or cardiac function is severely reduced.

Serious complications, including death associated with anesthesia, have repeatedly been reported. The high complication rate is a result of muscle weakness with respiratory insufficiency, metabolic changes (hyperkalemia and hyperthermia), and cardiomyopathy (late onset). Expect difficult airway management in patients with enlarged tongue and/or ankylosis of the temporomandibular joints. Cervical lordosis may result in tracheal and bronchial compression in the prone position and may not be relieved by tracheal intubation. Hazards of severe hyperthermia have been described (which may be different from malignant hyperthermia unless succinylcholine has been used) with hyperkalemia and myoglobinuria (dark discoloration of urine) secondary to rhabdomyolysis. Renal impairment and acute renal failure can occur as a result of myoglobinuria. Arrhythmias (tachycardia, ventricular fibrillation) and cardiac arrest have been reported. They are mainly, but not exclusively, associated with succinylcholine use and most often occur shortly after succinylcholine administration. However, late and sudden cardiac arrest in the postoperative period following recovery of consciousness is possible. Furthermore, it seems that hyperkalemia can be precipitated by halogenated inhalational anesthetics alone (most often halothane but also isoflurane). Joint deformities and contractures make difficult not only patient positioning on the operating room table (with danger of pressure necrosis) but also vascular access, which is further complicated by obesity and thickening of subcutaneous tissues. Mechanical ventilatory support is almost mandatory following major surgery (spinal fusion). Patient compliance occasionally is reduced because of anxiety and mild mental retardation.

Whether patients are at increased risk to experience a malignant hyperthermia reaction is controversial. For clinical purposes, however, this is not of fundamental importance because both reactions (malignant hyperthermia and nonmalignant hyperthermia) are triggered by the same agents. Succinylcholine (absolute contraindication) and halogenated agents (halothane, particularly if creatine phosphokinase levels are elevated) must be avoided because of a possible and potentially fatal hyperkalemic response. Dantrolene should be easily available. Persisting metabolic acidosis (despite adequate volume status) and hypercapnia in the presence of signs of rhabdomyolysis should always raise concerns about the possibility of a malignant hyperthermia or malignant hyperthermia-like reaction. Calcium-induced hypermetabolism seems to be the common denominator in both situations, and dantrolene has the potential to interrupt the vicious cycle. Muscle relaxants (preferably cis-atracurium) can be used (under control of a peripheral nerve stimulator), but recovery may be significantly prolonged. However, they often are unnecessary because of preexistent muscle weakness. Opioids are not contraindicated but should be used with caution in patients with already compromised respiratory function. If possible, a regional anesthetic technique should be used for postoperative pain therapy. Because of the muscle relaxing effects, benzodiazepines for premedication should be used with caution in these patients.

Becker Muscular Dystrophy (BMD; Adult Pseudohypertrophic Muscular Atrophy; Benign X-Linked Recessive Muscular Hypertrophy; Becker Type of Progressive Muscular Dystrophy; Progressive Muscular Dystrophy type II): Allelic disorder of DMD affecting approximately 1:30,000 males. However, in contrast to DMD, dystrophin in BMD is partially functional, which results in less severe symptoms. Its onset is usually during the second decade of life, with slow progression and normal life expectancy in most cases. However, the same clinical features as in DMD can be observed. As such, cases of BMD with isolated cardiomyopathy and unexpected deaths from a malignant hyperthermia or a malignant hyperthermia-like reaction during anesthesia in undiagnosed cases have been described. Therefore, for anesthetic purposes, the same precautions and considerations apply as in DMD. Unfortunately, generalized myotonia, which is a congenital anomaly of the muscular chloride channels resulting in prolonged contraction of skeletal muscles and significant anesthetic implications, is also called myotonia congenita Becker type or just Becker disease. Do not mix them up.

Bethlem Myopathy: Genetic disorder consisting of a benign congenital myopathy and contractures. Significant anesthetic implications.

Limb-Girdle Muscular Dystrophy (LGMD): Inherited symmetrical muscular weakness, initially of the lower limbs, with slow progression and associated cardiac anomalies.

Emery-Dreifuss Muscular Dystrophy (EDMD): Relatively benign congenital muscular dystrophy usually beginning in childhood or adolescence and characterized by early muscle contractures (mainly shoulders and upper arms) and cardiac conduction disorders.

Schwartz-Jampel Syndrome: Progressive congenital disorder characterized by hypertrophic myotonic myopathy, dwarfism, chondrodystrophy, and ocular and facial abnormalities. Contractures are most severe by mid-adolescence.

Myotonic Dystrophy: Genetic multisystem disorder affecting skeletal and smooth muscles, heart, and CNS with a wide range of clinical expression.

Myotonia Congenita: Rare genetic disorder characterized by myotonia, muscle stiffness, and abnormal muscle hypertrophy giving the impression of a “Herculean” or “bodybuilder-like” appearance. Two main forms of myotonia congenita have been described: Thomsen disease and Becker disease. In Thomsen disease, symptoms and findings usually are apparent from infancy to approximately 2 to 3 years of age. In many cases, muscles of the eyelids, hands, and legs may be most affected. In Becker disease, symptoms most commonly become apparent between the ages of 4 and 12 years. Affected individuals develop progressive myotonia. Muscle rigidity and hypertrophy tend to be more severe.