Diagnostic approaches to pediatric cardiomyopathy of metabolic genetic etiologies and their relation to therapy

Inborn errors of metabolism (IEM) account for only 5% of all pediatric cardiomyopathy and 15% of those with known causes, but they are of particular interest to clinicians because many have disease-specific treatments. More than 40 different IEM involving cardiomyopathy exist, including fatty acid oxidation defects, organic acidemias, amino acidopathies, glycogen storage diseases, and congenital disorders of glycosylation as well as peroxisomal, mitochondrial, and lysosomal storage disorders. Most IEM present in infancy or early childhood with signs and symptoms of multi-organ system dysfunction. Except for mitochondrial disorders, each IEM is generally associated with one functional type of cardiomyopathy by echocardiography. Disease pathophysiology may include infiltration of cardiac myocytes with stored substrate, impaired energy production, and/or production of toxic intermediary metabolites. Although the diagnosis of an IEM often is evident from certain key clinical, laboratory, and biopsy findings, underdiagnosis is likely because of the lack of a systematic clinical approach to diagnosis and inadequate diagnostic testing. Dietary modification, avoidance of fasting, and anticipatory management during times of stress are the mainstays of treatment for most “small molecule” diseases, whereas treatment options for mitochondrial diseases remain limited and primarily involve vitamin supplements. Several lysosomal storage disorders are now treatable by enzyme replacement therapy and/or bone marrow transplantation. Newborn screening using tandem mass-spectrometry offers the potential for presymptomatic diagnosis and early treatment for a growing number of IEM, which will likely change their prevalence and natural history of cardiomyopathy.