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present by middle age Ventricular preexcitation and HCM typically develop during the second decade of life,133,134,140 although earlier presentation is possible.141 Sudden death and heart failure have been reported in approximately 10% to 20% of patients.133,135,142 The mechanism of sudden death is not yet known, but high-grade heart block and supraventricular tachycardia degeneration to ventricular arrhythmias are known causes.135,142 Mitochondrial Disease The cardiac manifestations of mitochondrial disease are variable HCM, DCM, RCM, LVNC cardiomyopathy, and electrophysiologic abnormalities have all been reported.143–148 Among multisystem mitochondrial myopathies, KearnsSayre syndrome, mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes, myoclonic epilepsy with ragged red fibers, and neuropathy, ataxia and retinitis pigmentosa have all been associated with the development of HCM Patients with mitochondrial disease typically develop concentric hypertrophy without obstruction, which may progress to involve systolic dysfunction as well as conduction system disease.143–150 Friedreich Ataxia Friedreich ataxia is an autosomal recessive ataxia characterized by cerebellar signs, neuropathy, diabetes, and HCM151–153; it is caused by mutations in frataxin (FXN, most commonly GAA repeat expansion).154,155 Frataxin is a mitochondrial protein involved in the synthesis of iron-sulfur compounds that is essential for the maintenance of mitochondrial function.156–159 Friedreich ataxia cardiomyopathy is characterized by nonobstructive concentric hypertrophy, myocardial fibrosis, diastolic dysfunction, and atrial arrhythmias.151–153,160–163 Hypertrophy typically develops in the second decade of life or later, whereas approximately 10% to 20% of patients will develop systolic dysfunction over time.152,161,164 There are occasional reports of early-onset cardiac disease, although these appear to be the exception.161 The severity of hypertrophy and relaxation abnormalities appears to be related to, although incompletely explained, by GAA repeat size.152,164,165 There does appear to be a correlation between the age at presentation and cardiomyopathy progression.163,166 Consensus guidelines have been developed and recommend early treatment of systolic dysfunction given the expected course of disease,167 although there are no compelling data regarding the effectiveness of the typical medical therapies for heart failure in Friedreich ataxia A number of studies have examined the role of antioxidants in modifying disease progression and the results have been modest at best, with most studies showing no changes in echocardiographic measures over time.168–172 Anderson-Fabry Disease Anderson-Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A (GLA) gene Mutation in the GLA gene leads to globotriaosylceramide (GL-3) deposition within multiple tissues, notably renal, cardiac and brain tissues Fabry disease cardiomyopathy is characterized by LVH, valvar insufficiency, and arrhythmias.173–178 Valve disease, hypertrophy, and arrhythmias have all been documented in pediatric patients,176,179 although the most severe complications typically occur in late adolescence and adulthood.180 Clinical therapy focuses on timely initiation of enzyme-replacement therapy,181,182 which underscores the importance of early diagnosis and differentiation from other causes of LVH.183,184 Pompe Disease Pompe disease (glycogen storage disease IIa) is an autosomal recessive lysosomal storage disorder caused by a mutation in the acid α-glucosidase (GAA) gene Deficiency of acid α-glucosidase leads to the accumulation of glycogen within cardiac and skeletal muscle.185 The disease is heterogeneous in severity, and patients may present from early infancy through adulthood.186–189 The cardiac manifestations of juvenile- and adult-onset disease appear to be milder or nonexistent,188,190 whereas infantile and childhood forms are associated with the development of concentric hypertrophy with occasional LVOTO.124,186,189 Classically, the electrocardiogram (ECG) shows biventricular hypertrophy with ventricular preexcitation, although this is not uniformly present.186 Enzyme replacement improves LVH and survival in childhood.191–193 Pathology Macroscopic Features The early gross descriptions of what came to be known as HCM began in earnest in the 1950s and 1960s Donald Teare described the asymmetric septal hypertrophy that came to define HCM in the early years.9 With the advent of echocardiography, it soon became evident that other patterns of hypertrophy existed, including concentric, midcavity, and apical hypertrophy.194–197 The right ventricle may also show evidence of hypertrophy.198 Abnormalities of the mitral valve and papillary muscles have been described in HCM The mitral valve leaflets are often elongated and redundant The papillary muscles may be anteriorly rotated and hypertrophied; they have anomalous insertion into the mitral valve, which may contribute to outflow tract obstruction.199–203 Myocardial bridging of a coronary artery occurs in 10% to 40% of patients with HCM and may contribute to angina when there is diastolic narrowing.204–208 Microscopic Features The histologic descriptions of HCM in the 1950s and 1960s remain applicable to date HCM is characterized by myocyte hypertrophy, fiber disarray, bizarre myocyte nuclei, and myocardial fibrosis (Fig 61.1).9,15,16,209 Small intramural myocardial arteries may also be present.210 It is worth noting that the disarray, fibrosis, and intramural arteries are regional in nature and are age-dependent, making adequate sampling at autopsy imperative.210,211 ... by LVH, valvar insufficiency, and arrhythmias.173–178 Valve disease, hypertrophy, and arrhythmias have all been documented in pediatric patients,176,179 although the most severe complications typically occur in late adolescence and adulthood.180 Clinical therapy focuses on timely initiation of