Disorders in which single gene defects cause clinically significant blocks in metabolic pathways are called inborn errors of metabolism. Once considered rare, the number of recognized inborn errors has increased dramatically and they are now recognized to affect 1:1500 children. Many of these disorders can be treated effectively. Even when treatment is not available, correct diagnosis permits parents to make informed decisions about future offspring.
The pathology in metabolic disorders usually results from accumulation of enzyme substrate behind a metabolic block, or from deficiency of a reaction product. In some cases, the accumulated enzyme substrate is diffusible and has adverse effects on distant organs; in other cases, as in lysosomal storage diseases, the substrate primarily accumulates locally. The clinical manifestations of inborn errors vary widely with both mild and severe forms of virtually every disorder. Many patients do not match the classic phenotype because mutations are not identical in different patients, even though they occur in the same gene.
A first treatment strategy is to enhance the reduced enzyme activity. Gene replacement is a long-term goal, but problems of gene delivery to target organs and control of gene action make this an unrealistic option at present. Enzyme-replacement therapy using intravenously administered recombinant enzyme has been developed as an effective strategy in lysosomal storage disorders. Organ transplantation (liver or bone marrow) can provide a source of enzyme for some conditions. Pharmacologic doses of a cofactor such as a vitamin can sometimes be effective in restoring enzyme activity. Residual activity can be increased by pharmacologically promoting transcription (transcriptional upregulation) or by stabilizing the protein product through therapy with chaperones. Alternatively, some strategies are designed to cope with the consequences of enzyme deficiency. Strategies used to avoid substrate accumulation include restriction of precursor in the diet (eg, low-phenylalanine diet for phenylketonuria), avoidance of catabolism, inhibition of an enzyme in the synthesis of the precursor (eg, NTBC in tyrosinemia type I (see section Hereditary Tyrosinemia), or removal of accumulated substrate pharmacologically (eg, glycine therapy for isovaleric acidemia) or by dialysis. An inadequately produced metabolite can also be supplemented (eg, glucose administration for glycogen storage disease type I).
Inborn errors can manifest at any time, can affect any organ system, and can mimic many common pediatric problems. This chapter focuses on when to consider a metabolic disorder in the differential diagnosis of common pediatric problems. A few of the more important disorders are then discussed in detail.
Inborn errors must be considered in the differential diagnosis of critically ill newborns, children with seizures, neurodegeneration, recurrent vomiting, Reye-like syndrome, parenchymal liver disease, cardiomyopathy, unexplained metabolic acidosis, hyperammonemia, and hypoglycemia. Mental retardation, developmental delay, and failure to thrive are often present but have little specificity. Inborn errors should be suspected when (1) symptoms accompany changes in diet, (2) the child’s development regresses, (3) ...