Infants have a typical response to stress and illness (e.g., lethargy, poor feeding, seizures, temperature derangements, or hypotonia), and these findings are nonspecific. Most acutely ill infants will be treated empirically for sepsis or other serious bacterial infections, and cultures of urine, blood, and possibly cerebrospinal fluid will be sent. The possibility of occult trauma (intracranial hemorrhage, blunt abdominal injury) is also a consideration. Inborn errors of metabolism also need to be considered because it is often said that, in some form, these disorders are “individually rare but collectively not so rare.” Although it is beyond the scope of this chapter to consider even the most common of the hundreds of individual diseases or their diagnosis and management, there are general clues that may provide clues for screening for a metabolic defect.

Broadly, children who are “puzzles,” that is, who do not respond as expected to specific therapy, who do not have a clear etiology for their presentation despite a thorough search, who become excessively ill in response to what should be a mild infection, who have repeated episodes (of shock, vomiting, altered mental status, seizures, etc.), or an inexorable deterioration (e.g., progressive encephalopathy or myopathy) deserve a workup for a metabolic abnormality. Other clues include dysmorphology, chronically ill siblings or parents, and siblings who have died or been miscarried. Children who have acidosis without poor perfusion may have a defect in cellular energy consumption or in the production of substrates, such as glucose or ketones, or may have a defect that results in the buildup of an amino acid or another organic acid.

Altered mental status or seizures may be due to poor perfusion, toxic ingestion, infection or other causes of inflammation, intracranial blood or a mass lesion, hypoglycemia or electrolyte abnormalities, or a focal lesion acting as a seizure focus or causing hydrocephalus. However, if the initial evaluation
for these entities is negative, the consideration of metabolic encephalopathies such as hyperammonemia needs to be entertained. Saudubray and Charpentier (2007) provide a thorough approach to diagnostic testing.