noted Dilated cardiomyopathy is an early manifestation, with 70% of patients with Barth syndrome having cardiomyopathy before 1 year of age and evidence of cardiomyopathy related to Barth has been seen as early as 18 weeks’ gestation.161,162 Response to standard heart failure treatment is good, but cardiac transplantation has been reported in refractory cases.163 Sudden death has also been reported; this may be due to the increased risk of ventricular arrhythmias independent of the severity of cardiomyopathy and may require implantation of a defibrillator.164 Death typically results from infectious complications or from cardiac disease Propionic Acidemia Propionic acidemia is a rare metabolic disorder due to a deficiency of propionylCoA carboxylase, an enzyme involved in the catabolism of valine, leucine, isoleucine, methionine, threonine, cholesterol, and fatty acids Gene mutations mapped to chromosomes 3 and 13 have been described.165 Diagnosis is suspected by analysis of urinary organic acids, with elevations of propionate, propionylglycine, and methylcitrate Confirmation of the diagnosis rests with demonstration of reduced activity of propionyl-CoA carboxylase in skin fibroblasts There is a wide spectrum of clinical presentations, from severe early onset of the disease in the first days of life to relatively mild forms presenting in adulthood Patients develop hypoglycinemia, hyperammonemia, hypoglycemia, and deficits in the central nervous system, particularly in times of metabolic stress such as occurs with minor infections Cardiomyopathy and sudden death are relatively frequent late complications.166 The latter may be due to an increased prevalence of prolongation of the QT interval in these patients, a phenomenon seen more frequently with age.167 Because of this, regular electrocardiographic screening is necessary When involved, the heart is typically dilated with depressed function, although hypertrophy is also seen.168 Poor ventricular contractility can complicate acute metabolic crises, and patients presenting with encephalopathy should be assessed for left ventricular systolic dysfunction One series found that 23% of those surviving infancy developed dilated cardiomyopathy at an average age of 7 years The development was independent of apparent disease severity and frequency of metabolic crises In two patients treated with liver transplantation, the cardiomyopathy was reversed.169 The precise etiology of the cardiomyopathy is not known, but disordered carnitine metabolism and toxicity of byproducts in the metabolic pathway of propionyl-CoA carboxylase are leading suspects Treatment consists of restriction of protein and supplementation with L-carnitine and antibiotics Methylmalonic Aciduria Methylmalonic aciduria is clinically similar to propionic acidemia and is due to a deficiency of methylmalonyl-CoA mutase It can also be due to defects in adenosylcobalamin, its cofactor.170 The enzyme is required for the metabolism of valine, leucine, isoleucine, methionine, and threonine and yields succinylCoA for the tricarboxylic acid cycle Deficiency can lead to dilated cardiomyopathy, although the pathogenesis is not known.171 Some patients, who likely have residual enzymatic activity or whose disease is the result of defective or deficient cofactor, can respond favorably to supplemental cyanocobalamin Those with deficiency of the enzyme itself are managed on a low-protein diet with carnitine supplementation Despite therapy, however, the risk of metabolic crisis during acute illnesses remains high Hepatocyte-directed gene delivery has been shown to correct the enzymatic activity in vitro and may hold promise as a future corrective therapy.172 Disorders of Fatty Acid Metabolism The heart utilizes fatty acids for energy production by converting long-chain free fatty acids to long-chain acyl-CoA via acyl-CoA synthetase These acyl-CoA compounds are then transferred into the mitochondria, where they are degraded to produce acetyl-CoA for use in the tricarboxylic acid cycle Carnitine-acylcarnitine translocase mediates entry of fatty acyl-CoA compounds into mitochondria Deficiency often results in early death due to severe metabolic collapse with encephalopathy and hypertrophic cardiomyopathy, although patients with milder variants can present later Treatment with medium-chain triglycerides and carnitine supplementation can potentially avert the severe neurologic outcomes usually associated with this disease.173 Carnitine palmitoyltransferase II converts acylcarnitine back to acyl-CoA for β-oxidation once it has crossed the inner mitochondrial membrane Deficiency of this enzyme leads to nonketotic hypoglycemia with seizures, hepatomegaly, and hypertrophic cardiomyopathy Milder forms can present later with fasting or during periods of metabolic stress Treatment consists of a low-fat diet, supplementation with medium-chain triglycerides, carnitine supplementation, and avoidance of fasting.174 The acyl-CoA dehydrogenases mediate the reactions yielding acetyl-CoA from acyl-CoA compounds of varying lengths These enzymes are referred to as short, medium, long, and very long acyl dehydrogenases Deficiency of any of these can yield a generalized myopathy along with nonketotic hypoglycemia and cardiomyopathy.175