Inborn errors of metabolism (IEMs) are a group of disorders highly relevant to practitioners treating newborns; immediate diagnosis and appropriate treatment of these conditions can be directly linked to patient outcome to the extremes of avoiding death or irreversible brain damage. Pediatricians may feel overwhelmed by the number and complexity of these disorders (Table 100–1) and the interpretation of laboratory tests needed to establish the diagnosis. To assist clinicians, this chapter focuses on the symptom patterns, laboratory tests and their interpretation, and the initial stabilization of the patient rather than discussing details of the specific biochemical and genetic defects or special treatment measures of IEMs. Usually, the patient’s ongoing treatment is supervised by a geneticist specially trained in biochemical genetics.
Classification by time of onset. In this neonatal manual, we concentrate on metabolic disorders with onset in the neonatal period and early infancy, but some IEMs may present later in infancy, childhood, or even adolescence and adulthood. Even with comprehensive and well-executed newborn screening programs, a number of IEMs may present clinically before they are detected by screening tests or before the test result is available to the treating physicians. The use of tandem mass spectrometry (MS/MS) in newborn screening is now common practice. Due to the large amount of biochemical information obtained through MS/MS analysis, physicians involved in newborn care are often involved in follow-up evaluations and referrals of patients with a positive screening test.
Classification by clinical presentation. Categorizing IEMs by clinical presentation has great utility when establishing the diagnosis. It is noted that some syndromes with dysmorphic features are now known to be IEMs (eg, Smith-Lemli-Opitz syndrome or Zellweger syndrome [see Section IX.A and B]). Other classic examples of IEMs are discussed only briefly because they are clinically asymptomatic in the neonatal period (see Section XI; phenylketonuria [PKU]). Note that some skeletal dysplasias and disorders affecting bone and cartilage formation (not discussed here) are, strictly speaking, also IEMs (eg, rhizomelic chondrodysplasia punctata and hypophosphatasia). The following classification system forms the basis for the more detailed sections of this chapter; IEMs may present with the following:
Encephalopathy with or without metabolic acidosis (see Section VI)
Impairment of liver function (see Section VII)
Impairment of cardiac function (see Section VIII)
Dysmorphic syndromes (see Section IX)
Nonimmune hydrops fetalis due to inborn errors of metabolism (less common) (see Section X)
Classification according to the biochemical basis of the disease. Subdividing IEMs according to their biochemical characteristics assists with understanding of the pathogenesis and different treatment approaches but is of limited utility for those providing patient care.
By some estimates, IEMs may account for as much as 20% of disease among severely ill full-term infants not known to have been born at any risk. Cumulatively, an IEM may be present in >1 in 500 live births.