Inborn Errors of Metabolism Workup

Updated: Sep 20, 2017
  • Author: Debra L Weiner, MD, PhD; Chief Editor: Robert P Hoffman, MD  more...
  • Print
Workup

Approach Considerations

With the advent of tandem mass spectrometry, expanded newborn screening has become a widely accepted global approach. The technology allows inexpensive simultaneous detection of more than 30 different metabolic disorders in one single blood spot specimen. The sensitivity and specificity of this method can be up to 99% and 99.995%, respectively, for most amino acid disorders, organic acidemias, and fatty acid oxidation defects. [1]  

For neonates with positive newborn screening results, disease-specific evaluative and confirmatory testing, which usually includes testing for metabolic derangements, repeat newborn screen and 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]

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.

If a child has died, attempting to diagnose a metabolic disease is still important because of the possibility that currently 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.

Next:

Laboratory Studies

Emergent Evaluation

Make every effort to collect specimens for definitive diagnosis while the child is acutely ill (particularly samples for biochemical analysis, since biochemical abnormalities may be transient).

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 (see the Anion Gap calculator). 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 are 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

Obtain the following tests:

  • Complete blood count (CBC) to screen for neutropenia, anemia, and thrombocytopenia.

  • Serum electrolytes, bicarbonate, and blood gases levels to detect electrolyte imbalances and to evaluate anion gap (usually elevated) and acid/base status.

  • Blood urea nitrogen and creatinine levels to evaluate renal function.

  • Bilirubin level, transaminases levels, prothrombin time, and activated partial thromboplastin time to evaluate hepatic function.

  • 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)

Clinical Findings*

AA

OA

UCD

CD

GSD

FAD

LSD

PD

MD

Episodic decompensation

X

+

++

+

X

+

-

-

X

Poor feeding, vomiting, failure to thrive

X

+

++

+

X

X

+

+

+

Dysmorphic features and/or skeletal or organ malformations

X

X

-

-

X

X

+

X

X

Abnormal hair and/or dermatitis

-

X

X

-

-

-

-

-

-

Cardiomegaly and/or arrhythmias

-

X

-

-

X

X

+

-

X

Hepatosplenomegaly and/or splenomegaly

X

+

+

+

+

+

+

X

X

Developmental delay +/- neuroregression

+

+

+

X

X

X

++

+

+

Lethargy or coma

X

++

++

+

X

++

-

-

X

Seizures

X

X

+

X

X

X

+

+

X

Hypotonia or hypertonia

+

+

+

+

X

+

X

+

X

Ataxia

-

X

+

X

-

X

X

-

-

Abnormal odor

X

+

X

-

-

-

-

-

-

Laboratory Findings*

 

 

 

 

 

 

 

 

 

Primary metabolic acidosis

X

++

+

+

X

+

-

-

X

Primary respiratory alkalosis

-

-

+

-

-

-

-

-

-

Hyperammonemia

X

+

++

X

-

+

-

-

X

Hypoglycemia

X

X

-

+

X

+

-

-

X

Liver dysfunction

X

X

X

+

X

+

X

X

X

Reducing substances

X

-

-

+

-

-

-

-

-

Ketones

A

H

A

A

L/A

L

A

A

H/A

*Within disease categories, not all diseases have all findings. For disorders with episodic decompensation, clinical and laboratory findings may be present only during acute crisis. For progressive disorders, findings may not be present early in the course of disease.

AA = Amino acidopathy

OA = Organic acidopathy

UCD = Urea cycle defect

CD = Carbohydrate disorder

GSD = Glycogen storage disorder

FAD = Fatty acid oxidation defect

LSD = Lysosomal storage disease

PD = Peroxisomal disorder

MD = Mitochondrial disorder

++ = Always present

+ = Usually present

X = Sometimes present

- = Absent

H = Inappropriately high

L = Inappropriately low

A = Appropriate

Secondary studies

If initial test results are outside the reference range, consider consultation with an 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.

Previous