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.
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. Phenotypes vary from classic to more rare clinical presentations based on residual enzyme activity, which is in large part determined by specific mutations in a common gene.
A first treatment strategy is to enhance the reduced enzyme activity. Gene replacement is a long-term goal. Previous problems with gene delivery to target organs and control of gene action made this clinically unavailable; however, numerous clinical research trials are now occurring and offer hope for success. Enzyme-replacement therapies using intravenously, intrathecally, or intraventricularly administered recombinant enzymes have been developed as effective strategies in many lysosomal storage disorders and more continue to be developed. Subcutaneous enzyme replacement therapy is also under development. Enzyme substitution therapy via subcutaneous injection with a modified bacterial enzyme is also now available for at least one disorder. Organ transplantation (liver, kidney, heart, 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 (fasting or vomiting illnesses), inhibition of an enzyme in the synthesis of the precursor (eg, 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) therapy 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 age, affect any organ system, and 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 ...