Inborn errors of metabolism (IEM), or biochemical genetic disorders, represent a diverse group of genetically determined diseases.¹ The majority of these conditions are inherited in an autosomal recessive pattern. A subset of these disorders has an X-linked recessive mode of inheritance. A family history of siblings with similar problems may suggest the presence of one of these disorders. In the case of an X-linked recessive disorder, there may be a history of affected males related through the maternal family. An example of this situation would occur in a family with ornithine transcarbamylase deficiency resulting in affected male infants with hyperammonemia.^1,2 A history of unexplained neonatal deaths in male infants would support this diagnosis. In the majority of suspected IEM cases, the family history is negative depending on an autosomal recessive inheritance pattern with a 25% risk for affected siblings. A history of recurrent illnesses or developmental delays may indicate an IEM. Table 80-1 lists categories and examples of some IEM that may present in the ED.

The ED presentation of patients with IEM will be related to the underlying metabolic defect as well as the patient’s age, health, and nutritional status. Neonatal presentation typically occurs when a severe metabolic defect is present.^2–4 Infants may present during the first weeks of life after an uneventful neonatal hospital course. A number of organic acidemias, urea cycle defects, and maple syrup urine disease (MSUD) can present in this manner. When severe neonatal forms of these disorders are present, symptoms related to the disorder are expected to develop within hours or days after birth. Although neonatal problems can occur in most of the IEMs, the absence of problems does not exclude the diagnosis.

In the majority of patients with an IEM, there is a relationship between onset of symptoms and the patient’s health and nutritional status. The presence of an acute illness, typically viral, is often associated with the development of metabolic problems related to the IEM. An infant with glycogen storage disease will present with hypoglycemia when the feeding interval increases. Catabolism, depletion of glycogen stores, and increased production of toxic metabolites are some of the pathophysiologic mechanisms that can explain this association.¹

A change in diet can precipitate biochemical changes. For example, symptoms can develop in a patient with impaired protein metabolism when transitioned to cow’s milk at the age of 1 year due to the higher protein content, or after introduction of fructose/sucrose to the diet in a patient with hereditary fructose intolerance.

Intermittent forms of some disorders occur, where a patient may experience repeated episodes with vomiting and dehydration. Patients respond to treatment and return to their baseline state of health only to have the pattern repeat with the next illness. In some cases, the child is healthy during the first years of life and the initial presentation occurs much later in life. Given the diverse nature of IEM with the varied symptoms, clinical history, course, and laboratory findings, it is important that biochemical genetic disorders be considered in the differential diagnosis of ED patients with findings consistent with an IEM.^1–4

Patients with an IEM may present with common symptoms including vomiting, diarrhea, and febrile illness. In these situations, the severity and presence of other symptoms or laboratory abnormalities may suggest the presence of an IEM. Examples of findings that are suggestive of IEM include unusual odors (present in an organic acidemia or MSUD), more severe acidosis or ketosis than would be predicted based on the history, or hypoglycemia. Table 80-2 lists symptoms associated with IEM. In some cases, patients may present to the ED with severe life-threatening problems including coma, severe acidosis, seizures, cardiomyopathy, or hypoglycemia. The first step in the evaluation for IEM begins in the ED with the physician considering the possibility that one of these conditions is present and is responsible for the symptoms and problems.