Inborn Errors of Metabolism Workup

Laboratory abnormalities can be transient. Therefore, values within the reference range do not rule out an inborn error of metabolism (IEM).

Studies may need to be repeated during other episodes of illness.

Most IEMs with acute life-threatening presentation can be categorized based on findings of initial laboratory evaluations with the presence of at least 1 of the following (see Table 1 below):

• Metabolic acidosis: Metabolic acidosis usually with elevated anion gap occurs with many IEMs and is a hallmark of organic acidemias. Manifestations include tachypnea, vomiting, lethargy.
• Hypoglycemia: A prospective study revealed that in the ED, hypoglycemia (plasma glucose level < 50 mg/dL) is rare in children (0.44% of those tested), even during periods of poor enteral intake. In a study of 40 children with hypoglycemia, 32 had a metabolic workup performed on initial samples, and 28% of those had a previously undiagnosed fatty acid oxidation defect or endocrine disorder.
• Hyperammonemia: Early manifestations include anorexia, abdominal pain, headache, irritability, fatigue, late-tachypnea, vomiting, lethargy, seizures, coma, and death. Ammonia level greater than 100 mcg/dL in the neonate and greater than 80 mcg/dL beyond the neonatal period is considered elevated. Ammonia is highest in the urea cycle defects often exceeding 1000 mcg/dL and causing primary respiratory alkalosis sometimes with compensatory metabolic acidosis. Ammonia in organic acidemias, if elevated, rarely exceeds 500 mcg/dL, and in fatty acid oxidation defects is usually less than 250 mcg/dL.
• Major exceptions include nonketotic hyperglycinemia (lethargy, coma, seizures, hypotonia, spasticity, hiccups, apnea), and pyridoxine deficiency (encephalopathy, intractable seizures).

Initial laboratory evaluation (see ED Care)

• Obtain complete blood count (CBC) to screen for neutropenia, anemia, and thrombocytopenia.
• Obtain serum electrolytes, bicarbonate, and blood gases levels to detect electrolyte imbalances and to evaluate anion gap (usually elevated) and acid/base status.
• Obtain blood urea nitrogen and creatinine levels to evaluate renal function.
• Obtain bilirubin level, transaminases levels, prothrombin time, and activated partial thromboplastin time to evaluate hepatic function.
• Obtain ammonia levels if altered level of consciousness, persistent or recurrent vomiting, primary metabolic acidosis with increased anion gap, or primary respiratory alkalosis in the absence of toxic ingestion. Preferably, use an arterial sample, because skeletal muscle releases ammonia. If a venous sample is obtained, the sample must be flow free (no tourniquet). Ice the sample immediately and assay promptly. Normal values are less than 100 mcg/dL in the neonate and less than 80 mcg/dL in those older than 1 month.
• Obtain blood glucose and urine pH, ketones, and reducing substances levels to evaluate for hypoglycemia.

  • False-positive results for reducing substances are caused by penicillin and glucuronides.
  • Neonates - Inappropriate ketones (ie, ketonuria)
  • Child - Ketonuria with normal glucose, low or absent ketones with hypoglycemia
• Obtain lactate dehydrogenase, aldolase, creatinine kinase, and urine myoglobin levels in patients with evidence of neuromyopathy.

The table below outlines clinical and lab findings associated with various inborn errors of metabolism.

Table 1. Clinical and Laboratory Findings of Inborn Errors of Metabolism (Open Table in a new window)

ECG, radiography, CT, MRI, ultrasonography, and/or ECHO should be obtained as clinically indicated.

Enzyme assay or DNA analysis may be indicated in leukocytes, erythrocytes, skin fibroblasts, liver, or other tissues.

Histologic evaluation of affected tissues such as skin, liver, brain, heart, kidney, and skeletal muscle should be completed.

Secondary studies

• If initial test results are outside the reference range, consider consultation with an inborn error of metabolism (IEM) specialist to determine which tests are appropriate, how specimens are to be collected and stored, and where they should be sent.
• Plasma quantitative amino acids and acylcarnitines (1-2 mL in ethylenediaminetetraacetic acid [EDTA] or heparin tube, on ice)
• Urine organic acids, acylglycine, and/or orotic acid (5-10 mL, freeze immediately)
• Serum lactate and pyruvate levels (These may be helpful but are often difficult to interpret in the critically ill child because of multiple factors that may contribute to lactic acidosis.)
• Cerebrospinal fluid (CSF) lactate, pyruvate, organic acids, neurotransmitters, and/or disease-specific metabolites collected at the same time as plasma (1-2 mL)
• EEG, nerve conduction studies, evoked potential studies, and/or electromyelography may be valuable but are rarely indicated in the emergency department.

For patients with known IEM, studies should be disease and patient specific. Results should be compared to previous as available.

For neonates with positive newborn screening results, disease-specific evaluative and confirmatory testing, which usually includes testing for metabolic derangements, repeat newborn screen as well as specialized testing, should be performed even if the neonate appears to be asymptomatic. ACTion sheets and algorithms, developed by the American College of Medical Genetics, provide guidelines based on the specific newborn screen abnormality (see Newborn Screening ACT Sheets and Confirmatory Algorithms.^[4]

If a child has died, attempting to diagnose a metabolic disease is still important because of the possibility that presently asymptomatic siblings are affected or that future children will be affected.

• Plasma, serum, urine, and possibly CSF, skin, and selected organ specimens should be collected and frozen. If permission for autopsy is not granted, as appropriate, discuss with the family the possibility/importance of obtaining vitreous humor, skin biopsy, and/or organ needle biopsy for evaluation.
• Pictures and/or radiographs may be useful in the child with dysmorphism.

A metabolic specialist may be helpful in directing the evaluation of patients with suspected or known inborn errors of metabolism or the neonate with positive newborn screening results.