Myocardial involvement is very common It is uncertain at what stage it begins, since the physical incapacity limits its manifestation The heart can be involved from an early age, though, and in ambulatory patients, subclinical disease may become symptomatic with exercise In nonambulatory patients, a resting tachycardia,224 decreased heart rate variability,225 echocardiographic evidence of systolic and diastolic dysfunction,226 and abnormal myocardial strain changes on magnetic resonance imaging227 may help to alert the clinician to subclinical myocardial involvement so that medical therapy can be initiated The roles of cardiac troponins and brain natriuretic peptide are also being evaluated in the assessment of these patients.228 The cardiac dysfunction is progressive, ultimately resulting in a dilated cardiomyopathy, and the benefits of early medical therapy are controversial Some advocate early use of afterload reduction therapy,229,230 but others have only shown a benefit when afterload reduction is combined with β blockade.231 There is a distinctive ECG pattern in 50% to 90% of patients This includes tall R waves over the right precordial leads with increased R:S amplitude ratios, together with narrow and deep Q waves in the limb and left precordial leads Female carriers may also have an abnormal ECG.232 These findings correspond to pathologic observations There is fatty and fibrous tissue replacement of the myocardium with selective scarring of the posterolateral wall of the left ventricle and, sometimes, involvement of the posterolateral papillary muscle Conduction abnormalities are also frequently seen Among these are prolonged intra-atrial conduction, right bundle branch block, a superior QRS axis, and a short PR interval Histologic studies of the conduction system show areas of fibrosis, vacuolization, and fatty infiltration.233 The echocardiogram reveals impairment of both systolic and diastolic function Thickness of the left ventricular wall is decreased, and this is not related to physical inactivity The end-diastolic and end-systolic dimensions of the left ventricle increase as systolic function deteriorates The diagnosis is made from the clinical characteristics, the high levels of creatine kinase activity, and biopsy of the skeletal muscles Creatine kinase activity is 100 to 300 times normal at 1 to 5 years of age Other muscle enzymes —such as aldolase, glutamic oxalic transaminase, lactic dehydrogenase, and pyruvate kinase—are also grossly elevated Creatine kinase levels diminish later in the disease but still remain well above normal limits Muscle biopsy shows scattered hyaline fibers with active muscle necrosis and regeneration There is splitting of the muscle fibers with fatty replacement The muscle fascicles also become surrounded by perimysial and endomysial connective tissue Electromyography reveals a decrease in the mean action potential voltage and its duration An increase in the number of polyphasic potentials is also seen Careful general medical management is critical Since bed rest is harmful, regular physical activity and exercise are to be encouraged Avoidance of obesity is an important general measure, along with the prevention of muscle contractures by passive stretching Because of the risks of anesthesia and immobilization, the benefit from major orthopedic procedures must be carefully considered Prevention of scoliosis and thoracic deformities in the wheelchair phase help to avoid respiratory impairment and slow the deterioration of respiratory function Death is usually from respiratory infections and insufficiency, heart failure, or cardiac arrhythmias Detection of carriers is important for appropriate genetic counseling Over half the carriers can be identified by their elevated creatine kinase levels, electromyography, and muscle biopsy The analysis of the pedigree is particularly useful Novel treatments for this myopathy are actively being investigated and include gene therapy,234 protease inhibitors,235 membrane stabilizers,236 and muscle precursor cell transplantation.237 Childhood Limb-Girdle Muscular Dystrophy The childhood limb-girdle muscular dystrophies (LGMDs) are a heterogeneous group of genetic muscular disorders At least 17 different types have been described They can be inherited in either an autosomal dominant or recessive fashion Seven genetic defects have been identified in the dominant forms (LGMD 1) and 11 in the recessive forms (LGMD 2) The age at onset is variable, but symptoms generally appear between 5 and 10 years of age Weakness of the pelvic and shoulder muscles predominates The disease is slowly progressive, and the patients often become unable to walk by their twenties The disease is first suspected when limb-girdle weakness occurs, although Duchenne or Becker muscular dystrophy must be ruled out An elevated creatine kinase will not differentiate between LGMD and the dystrophinopathies This can be done through analysis of the dystrophin gene and by examination of a muscle biopsy Various forms of LGMD affect the heart Patients with LGMD 1b, due to a mutation in the lamin A/C gene, frequently develop arrhythmias that can be lethal and may require placement of an implantable defibrillator Atrioventricular block can also occur, necessitating placement of a pacemaker.238 This disorder can also result in a dilated cardiomyopathy Patients with LGMD 2I, caused by a defect in the gene encoding the fukutinrelated protein (FKRP), may develop a dilated cardiomyopathy by the third decade Evidence of dysrhythmias is not seen.239 Myotonic Muscular Dystrophy (Steinert Disease) The involvement of systemic tissues together with the presence of myotonia and muscular atrophy separate myotonic muscular dystrophy from the other muscular dystrophies Myotonic muscular dystrophy has a high incidence, calculated at 13.5 per 100,000 live births Onset is usually between 20 and 50 years of age, but many cases are clinically apparent during childhood This disease is due to an expansion of a CTG trinucleotide repeat on the q arm of chromosome 19.240 It is transmitted in an autosomal dominant fashion and demonstrates genetic anticipation Myotonia is the presenting clinical feature in one-third of cases Others present with weakness of the hands, foot drop, or a tendency to fall The heart may occasionally become involved prior to diagnosis of the neuromuscular disorder The facial, masticatory, sternomastoid, forearm, anterior tibial, and peroneal muscles are those first affected by weakness Later weakness extends to neighboring muscle groups The typical facies are characterized by lack of facial expression and difficulty in closing the eyes and moving the mouth Ptosis and dysarthria are frequent Myotonia is often limited to the tongue, forearms, and hands, but it may be generalized The tendon reflexes in the affected muscle groups are reduced Cataracts are present in almost all those affected Impaired pulmonary vital capacity and maximum breathing capacity are common Abnormal contractions of the esophagus are thought to be the cause of dysphagia and pulmonary aspiration Testicular atrophy, DM, increased metabolism of immunoglobin G with low serum levels, progressive dementia, and subnormal intelligence are frequent associations Cardiac involvement is common and manifests with conduction defects and arrhythmias First-degree atrioventricular block is commonly seen, and this may progress to complete heart block requiring pacemaker implantation.241 No relationship exists between the degree of