risk factors are nearly as likely to have metabolic disease as sepsis Some IEM predispose infants to sepsis Escherichia coli sepsis in galactosemia is the classic example Other IEMs with increased risk of sepsis are the organic acidemias and glycogen storage disorders One of the most important clues to an IEM in the neonate is a history of deterioration after an initial period of apparent good health The most common time that symptoms are manifest is between and days, but can range from hours to weeks For neonates with IEMs of protein metabolism and carbohydrate intolerance disorders, the onset of symptoms occurs after there has been significant accumulation of toxic metabolites following the initiation of feeding Initial symptoms often are poor feeding, vomiting, irritability, and lethargy In the neonatal period, jaundice occurs most commonly with tyrosinemia, galactosemia, and hereditary fructose intolerance Progression to coma, multisystem organ failure, and death is usually rapid Neonates with tyrosinemia may present with intracranial or pulmonary hemorrhage due to coagulopathy Patients with organic acidemias may have recurrent or chronic subdural hemorrhages, sometimes mistakenly attributed to child abuse Fatty acid oxidation disorders, particularly very long-chain acyl-CoA dehydrogenase deficiency, may present during the neonatal period Many of the peroxisomal disorders and some of the mitochondrial and lysosomal disorders also present in the neonatal period; these infants are less likely to have coma as an early manifestation and are more likely to have dysmorphic features, brain abnormalities, skeletal malformations, cardiopulmonary compromise, organomegaly, hepatic dysfunction, myopathy, and/or severe generalized hypotonia, usually evident at birth Intractable seizures due to pyridoxine- or folic acid–responsive disorders usually begin within the first few days of life Infant and young child (1 month to years) Infants and young children with potentially acute lifethreatening IEMs (most commonly partial deficiency of the urea cycle enzyme ornithine transcarbamylase, fatty acid oxidation defects, disorders of carbohydrate intolerance, and disorders of gluconeogenesis and glycogenolysis) typically present during infancy with recurrent episodes of vomiting and lethargy, ataxia, seizures, or coma Amino and organic acidopathies also present during infancy, usually with progressive neurologic deterioration Lysosomal storage disorders, mitochondrial disorders, and peroxisomal disorders also become apparent in infancy and early childhood, usually presenting with dysmorphism or coarse features, organomegaly, myopathy, and/or neurodegeneration More subtle and/or progressive findings in infants and children with IEMs include failure to thrive, chronic dermatoses, dilated or hypertrophic cardiomyopathy, liver dysfunction, hepatomegaly, pancreatitis, musculoskeletal weakness, hypotonia and/or cramping, impairments of hearing and vision, and developmental delay, sometimes with loss of milestones With routine illnesses, children with IEMs may be more symptomatic, develop symptoms more quickly, or take longer than unaffected children to recover Children with disorders of protein metabolism may present with dietary changes Fructose intolerance often manifests between and months of age when fruits are introduced Disorders with decreased tolerance for fasting, particularly fatty acid oxidation defects and defects of gluconeogenesis and glycogenolysis, often manifest when children have poor intake due to illness or surgery and when infants begin to have longer overnight fasts, commonly between and 12 months of age The length of fasting that produces symptoms may be less than hours for disorders of gluconeogenesis and glycogenolysis, and 12 to 24 hours for fatty acid oxidation defects When patients with these disorders present with vomiting, the severity of illness, particularly lethargy, is usually out of proportion to the duration of illness and the amount of vomiting IEMs also explain sudden infant death syndrome (SIDS) in approximately 5% to 10% of cases, most commonly fatty acid oxidation defects that cause cardiac arrest due to arrhythmia and/or cardiomyopathy; the most common of these is medium-chain fatty acylCoA dehydrogenase deficiency Other fatty acid oxidation defects, organic acidemias, and congenital adrenal hyperplasia account for most of the remainder of SIDS cases attributable to genetic defects Child >5 years of age, adolescent, or adult In the older child, adolescent, or adult, undiagnosed metabolic disease should be considered in individuals with subtle neurologic or psychiatric abnormalities which may present with a history waxing/waning symptoms that have been attributed to other causes