Chapter 79: Inborn Errors of Metabolism

• Inborn errors of metabolism (IEM) that are more likely to present in the emergency department (ED) can be classified into a number of categories.

  • select amino acid disorders

  • urea cycle defects

  • disorder of carbohydrate metabolism

  • organic acid disorders

  • fatty acid oxidation defects

• Age of presentation is often related to the specific IEM and can vary from the newborn period to later in life, even into adulthood.

• With expanded newborn screening for IEM, more patients with one of these disorders will present to the ED with a known diagnosis.

• Patients with IEM can present with no prior history of medical problems. Precipitating events include febrile illness, gastroenteritis, poor oral intake, dietary change (increased protein intake, addition of fructose to the diet), or exercise.

• Clinical symptoms of IEM include vomiting, altered mental status/lethargy, seizures, hypotonia, and tachypnea.

• Hypoglycemia, anion gap acidosis, hyperammonemia, and ketosis are some of the metabolic consequences of IEM.

• General laboratory testing to consider in a patient with a suspected IEM includes glucose, ammonia, liver function, creatine kinase (CK), electrolytes, blood gas, uric acid, urinalysis, and urine-reducing substance.

Inborn errors of metabolism (IEM) or biochemical genetic disorders represent a diverse group of genetically determined diseases.^1,2 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.^2,3 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 79-1 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.^3,4 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 IEM, 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 a 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.^1–6

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 79-2 lists symptoms associated with IEM. In other cases, patients may present to the ED with severe life-threatening problems including coma, severe acidosis, seizures, cardiomyopathy, or hypoglycemia. Reye syndrome and other causes of altered mental states are reviewed in Chapter 5. 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 responsible for the symptoms and problems.

The second step in the evaluation is to identify which general laboratory testing to perform. This step is critical not only to obtain laboratory data to assist in the diagnosis but also, and potentially of greater immediate importance, to identify special areas requiring treatment. For example, in urea cycle defects, organic acid disorders, and fatty acid oxidation defects, it is important to obtain the blood ammonia level to diagnose hyperammonemia. Definitive diagnosis of one of these disorders typically requires special biochemical diagnostic testing, which is not performed in many hospital laboratories. However, initiating this testing following an ED visit or subsequent hospitalization can greatly facilitate the diagnosis of one of these conditions and assist in the patient's medical management.

General laboratory testing can assist in determining if an IEM is present. Table 79-3 lists some of the general laboratory testing performed in this clinical setting. Testing performed in most situations would include glucose levels, evaluation of acid/base status, urine analysis including urine ketones, complete blood count, and evaluation of renal and liver functions. Additional testing may be indicated. For example, lactate level to assess for lactic acidosis and ammonia level for hyperammonemia is indicated in cases of acidosis or altered mental status, respectively. If evidence of myopathy, muscle weakness, or myalgia is present, especially with an elevation in AST/ALT, obtain a creatine kinase (CK) level to evaluate for a myopathic process and rhabdomyolysis. Elevated CK is present in some fatty acid oxidation deficiencies (FAOD).^1,2,7,8 The presence of blood on urinalysis with normal urine RBC count in this setting may be indicative of myoglobinuria. Blood myoglobin levels can be obtained in some hospital laboratories to evaluate this finding further.

Initial laboratory testing is usually guided by the problem present at the time of presentation to the ED. In some situations, the order of testing may be influenced by both the clinical state of the patient and results of initial testing. Figure 79-1 outlines an approach for evaluation of hypoglycemia in a case of a suspected IEM. Hypoglycemia with negative ketone levels may indicate the presence of an FAOD, including medium chain acyl CoA dehydrogenase deficiency (MCADD), while the presence of acidosis, hypoglycemia, and ketosis is more suggestive of an organic acid disorder. Hypoglycemia is also reviewed in Chapter 76, Diabetes Mellitus and Hypoglycemia.

It is important to recognize that complicating factors present at the time of the patient's initial presentation may impact test results and their interpretation. A severely dehydrated child with poor perfusion may also have a secondary lactic acidosis. The patient's clinical course, including laboratory results and response to treatment, usually allows for a determination as to whether the abnormalities are secondary or the consequence of an IEM. Initial treatment of identified laboratory findings usually follows general recommendations.

Table 79-4 lists some of the specialized biochemical genetic testing considered in the evaluation of IEM. Specific testing to be performed is often determined in consultation with the biochemical/clinical geneticist or other metabolic specialist. In many situations, biochemical genetic testing performed at the time of an acute illness can evaluate for specific abnormalities helpful in the IEM diagnostic evaluation. In some situations, diagnostic test results may only be detectable during an acute illness.

With the implementation of tandem mass spectrometry in the diagnosis of IEM through neonatal screening, many of the conditions referred to thus far can be, and are diagnosed in the newborn period. This allows for presymptomatic detection and the institution of a corresponding treatment regimen. Three groups of biochemical genetic disorders are screened for using this technology: amino acid disorders, organic acidemias, and fatty acid oxidation defects. Galactosemia testing is also included on newborn screen testing panels. It is important to note that some disorders cannot be detected with this screening, because either biochemical markers of the disorder are not present or newborn screening does not detect the disorder in all cases. Under optimal conditions, it is expected that newborn screen testing will be completed and reported to the birth hospital and primary MD within 7 days of birth. While guidelines recommend which disorders should be included on newborn screening disease panels, not all state programs test for all disorders.^9,10 Therefore, it is important for physicians caring for newborns and pediatric patients to know which disorders are included in the newborn screen testing panel for their state and how to obtain the test results for an infant.¹⁰ This information is usually not available at night or on weekends, but some data may be obtained from the birth hospital or primary physician. Newborn screen ACT sheets (short for action sheet) are available from the American College of Medical Genetics. These sheets summarize information on newborn screening diseases and medical response to a report of a positive result.¹¹ These ACT sheets can assist the ED physician in cases when the newborn screen is positive for a newborn screen disorder and the family is instructed to have the infant evaluated in the ED. A newborn screen result can provide important information to assist in the evaluation and treatment of a young infant, but a normal newborn screen result does not exclude the diagnosis of an IEM.

In some cases, the result of the newborn screen is not available for an infant being evaluated in the ED. The likelihood of this is greatest in the 2-day to 2-week-old newborn. A group of newborns with IEM will become symptomatic during this time and the possibility of IEM needs to be considered and evaluated. Presenting symptoms and laboratory findings in IEM are reviewed in Tables 79-2 and 79-3. In general, infants in this age group will exhibit these findings. An example of this type of situation can occur with classical galactosemia resulting from GALT deficiency (galactose-1-phosphate uridyltransferase [GALT]).¹² Affected neonates may present in the first days/weeks of life with poor feeding, lethargy, sepsis, and jaundice with hepatic dysfunction. Elevated liver enzymes, some direct (conjugated) hyperbilirubinemia and positive urine-reducing substances are some of the laboratory findings present. Positive urine-reducing substance with a negative glucose urine dipstick may indicate the presence of non–glucose-reducing sugars. However, a negative urine-reducing substance cannot be used to exclude the possibility of classical galactosemia. Suspicion of classical galactosemia requires removal of galactose from the diet with evaluation and treatment of associated problems including sepsis, and hepatic dysfunction and coagulopathy.

The early diagnosis of some IEM through newborn screening has resulted in another category of ER visits for patients with IEM. This group of diagnosed IEM patients is instructed by their treating physicians to take proactive and preventative steps at times of illness, or if there is a change in the child's condition. These instructions as well as testing recommendations and treatments are often summarized in an “emergency protocol.” The emergency protocol typically provides the diagnosis, acute medical problems associated with the disorder, and treatment recommendations. The treating ED physician in this setting evaluates the child for problems, initiates the recommended evaluations, and indicated treatments. In some situations, hospitalization is required to continue the appropriate supportive treatment and to prevent worsening of the patient's metabolic disorder. For many disorders, intravenous caloric support with dextrose can prevent or treat metabolic problems, such as ketosis in organic acid disorders and hypoglycemia in fatty acid oxidation disorders. In general, patients with these disorders cannot be discharged from the ED unless metabolic problems have been resolved and the patient can maintain an adequate oral caloric intake. For some disorders, patients must also be able to take prescribed medications. Arginine and ammonia-conjugating medication (Buphenyl) are needed to control blood ammonia levels in urea cycle defects.^2,3 In cases where metabolic problems are present, consultation with the treating metabolic specialist is required to determine the most appropriate course of treatment.

Initial treatment is determined by the patient's presentation. If the diagnosis of IEM is known, targeted evaluation can be initiated to determine the presence of specific problems associated with the specific IEM. Clinical and laboratory evaluation will identify areas requiring treatment. Additional general laboratory testing should be performed (Table 79-3) to evaluate the patient for associated medical problems. This approach will also increase the likelihood that medical problems such as hyperammonemia or rhabdomyolysis, which require further evaluation and specialized treatment, will be detected. In general, the initial treatment of medical problems in patients with IEM follows recommendations outlined in the respective chapters. In some clinical situations, it is necessary to address multiple problems simultaneously. For example, treatment of dehydration and hypoglycemia in a patient with an FAOD requires administration of fluids with high dextrose content.^13,14 Consultation with a metabolic specialist, such as a biochemical/clinical geneticist, may be indicated for determining the most appropriate course of treatment and diagnostic evaluation. Gene Reviews is an online source for specific information on a number of biochemical and other genetic disorders.

When serious medical problems or complications are present, hospitalization, potentially in a PICU, is indicated. Hospitalization is often required to address medical problems resulting from the acute illness and to prevent worsening of the patient's condition. Typically, ED patients with an IEM who have responded well to initial treatment and have remained stable during a period of observation are capable of resuming their normal routine of diet and medication at home. If there is clinical evidence to suggest that problems might recur, hospitalization is indicated.