hypertrophic cardiomyopathy Cardiac involvement may occasionally precede the onset of neurologic manifestations.266 Cardiac symptoms are present in approximately one-third of the patients and consist mainly of exertional dyspnea, palpitations, and angina Clinical findings of cardiac disease are not present in every case When they are, they include systolic murmurs at the left sternal border and apex, together with third and fourth heart sounds The pulse may have a rapid upstroke Evaluation of the severity of heart disease by physical examination is often difficult because of the presence of scoliosis and the lack of consistent cardiovascular signs Interestingly, the degree of cardiac involvement appears to correlate with the size of the GAA repeat of the smaller allele or with the mean size of the repeats in both alleles.267 Pathologic studies reveal cardiac dilation with ventricular hypertrophy Histologically there is a degeneration of myocardial cells with myocardial fibrosis Intracellular granular deposits of calcium and iron are seen It is hypothesized that iron-catalyzed mitochondrial damage may lead to the pathologic findings in the myocardium.268 Electrocardiographic changes are present in over two-thirds of patients, and they progress in relation to the duration of the disease The most frequent changes involve the ST segments and T waves These are nonspecific and are presumably caused by repolarization disturbances from the underlying myocardial fibrosis Signs of ventricular hypertrophy are also frequent, and right- or left-axis deviation is common Arrhythmias are not frequent When present, they include supraventricular and ventricular premature beats, supraventricular tachycardia, atrial flutter, and atrial fibrillation.269 The presence of scoliosis makes radiographic evaluation of the heart difficult Heart size is usually normal Most patients have an abnormal echocardiogram The most common anomalies reflect the presence of a symmetric concentric hypertrophic cardiomyopathy There is an increase in left ventricular wall and septal thickness Asymmetric septal hypertrophy is seen on occasion.270 Impaired left ventricular function has also been shown echocardiographically and may be the end stage of the cardiomyopathic process, as reduced fractional shortening of the left ventricle is common The systolic function of the posterior wall is more severely affected than that of the septum Abnormal diastolic function may antedate systolic abnormalities Interestingly, a constant feature is delay in mitral valve opening The clinical course is marked by steadily progressive deterioration Cardiac failure, which appears late in the course of the disease, has a poor prognosis and is often a preterminal event Most patients with Friedreich ataxia die from cardiac causes Heart failure accounts for half of the deaths Cardiac arrhythmias and respiratory complications are the other major causes of death Although conventional methods for treating hypertrophic and dilated cardiomyopathy are frequently employed, newer therapeutic options for patients with Friedreich ataxia have come to light in recent years Idebenone, a freeradical scavenger, was tested under the hypothesis that iron overload leads to damage of iron-sulfur cluster–containing enzymes, which may lead to the damage seen in the myocardium.271 Although the treatment remains somewhat controversial and is not universally accepted, several small trials show a consistent benefit in terms of reduction of cardiac mass and improvement in function.272,273 Arthrogryposis Multiplex Congenita This condition presents with joint contractures at birth in at least two different areas of the body A typical presentation includes equinovarus deformities of the feet, abducted hips, incompletely extended knees and elbows, pronated forearms, and claw hands The majority of those affected have a neurogenic cause with patchy loss of anterior horn cells, although some cases are caused by primary myopathic disorders They may result from environmental factors or may demonstrate a familial propensity The heart is rarely involved A report of the myopathic form of arthrogryposis multiplex congenita revealed congenital heart disease in one-quarter of the patients.274 These cases resulted from consanguineous parents, and five of six with congenital heart disease resulted from one pairing.275 Patency of the arterial duct, congenital aortic stenosis, and mitral stenosis have been reported.276,277 Hereditary Motor and Sensory Neuropathy (Peroneal Muscular Atrophy, Charcot-MarieTooth Disease) The hereditary motor and sensory neuropathies are a diverse group of disorders typically inherited in an autosomal or X-linked dominant fashion Links to defects in connexins and other Schwann cell proteins are well described.278 They are predominantly a motor neuropathy producing atrophy and weakness of the distal muscles This determines the typical “inverted bottle” appearance of the legs Bilateral club foot is a frequent association The hand and forearm muscles may also be involved There is a decrease or loss of the deep tendon reflexes Electromyographic studies show slowing of nerve conduction velocity or signs of denervation The cardiac involvement has classically been related to supraventricular arrhythmias and conduction system abnormalities Sick sinus syndrome, right bundle branch block, complete heart block, Wolff-Parkinson-White syndrome, atrial fibrillation, and atrial flutter have been described.279,280 It has been postulated that there is a primary degeneration of the conduction system rather than changes secondary to a cardiomyopathy.281 In addition to dysrhythmias, left ventricular hypertrabeculation/noncompaction has been reported in a patient with Charcot-Marie-Tooth disease type IA and a duplication defect on chromosome 17 involving the peripheral myelin protein 22.282 The Roussy-Lévy syndrome is a phenotypic variant of Charcot-Marie-Tooth type IA and shares many features with this disease.283 Dilated cardiomyopathy has also been reported.284 Spinal Muscular Atrophy Type III (Juvenile Spinal Muscular Atrophy, Kugelberg-Welander Syndrome) Juvenile spinal muscular atrophy appears in childhood or adolescence Initially it is manifest by weakness and atrophy of the proximal limb muscles, which is later followed by distal disease The usual presentation is with difficulty in walking, climbing stairs and lifting the arms Fasciculation is seen in half of those affected The clinical course is slowly progressive There is evidence from electromyography and muscle biopsy to indicate lower motor neuron disease Some patients have an associated dilated cardiomyopathy, although this may be secondary to associated respiratory disturbances.285 Rhythm disturbances are very frequent and include atrial premature beats, atrial fibrillation, atrial flutter, and advanced degrees of atrioventricular block Some patients require the implantation of a pacemaker.286 The ECG frequently shows a fine tremor on the isoelectric line, which represents fasciculations characteristic of this disease.287 The syndrome is transmitted in autosomal recessive fashion and is due to defects in the survival motor neuron 1 (SMN1) gene.288 The infantile form of spinal