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General Principles

Inborn errors of metabolism (IEMs) are generally defined as disorders resulting from pathogenic genetic variants affecting the enzymes or transport proteins involved in metabolizing specific nutrient-derived substrates.

  • Most frequently, these are due to pathogenic variants that decrease enzyme activity, resulting in backup of a toxic substrate or production of an abnormal toxic substrate, an inefficiency of energy production, loss of necessary intermediates, and/or abnormal storage of substrate.

  • IEMs vary in their timing of onset and symptomatology.

  • Newborn screening has allowed for early identification of many individuals with IEMs; however, many IEMs are not part of the newborn screen.

  • Several clinical scenarios in which IEMs may be suspected are detailed in Table 17-1. This chapter provides a broad overview of types of IEMs and their common presentations; however, it is not an exhaustive exploration of all of these ultrarare diseases.

  • IEMs should be on the differential diagnosis for patients with almost any unexplained symptoms, especially if multiple organ systems are involved. Early involvement of a biochemical geneticist is recommended for any confirmed or suspected inborn error of metabolism.

Table 17-1Clinical Presentations of IEMs

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