discarded pretreatment samples are likely to be more informative than those collected after therapy Collection of samples during acute illness is usually preferred to provocative testing by metabolic challenge performed when the child is otherwise well because this method may not yield diagnostic specimens and may be dangerous The confirmatory specific diagnosis of most IEMs requires additional specialized testing for abnormal metabolites, perturbed enzymatic function, or molecular testing When a child dies in the ED and an IEM is suspected, it is extremely important to attempt to diagnose that disease because of the possibility that asymptomatic family members are affected or future children are at risk Routine autopsy does not usually provide a definitive diagnosis of IEM but may rule out other causes of death and offer clues IEMs can be diagnosed in the child who has just died by collecting the appropriate specimens ( Table 95.6 ) In some situations, exome sequencing, genome sequencing, or metabolomics may be used to evaluate for an underlying cause of decompensation This evaluation is usually guided by specialty consultation Most IEMs can be categorized based on findings of initial laboratory evaluations Nearly all patients with IEMs that present as acute life-threatening disease will have hypoglycemia, metabolic acidosis, and/or hyperammonemia These initial findings will guide immediate treatment and further evaluation Important exceptions are nonketotic hyperglycinemia (usually presents within 48 hours of birth with lethargy, coma, seizures, hypotonia, spasticity, hiccups, and apnea) and pyridoxine deficiency and folinic acid–responsive disorders (which present with intractable seizures with or without encephalopathy as neonate)