What is the initial workup for a newborn suspected of having an inborn error of metabolism (IEM)?

Initial Workup for Suspected Inborn Error of Metabolism in Newborns

When a newborn is suspected of having an inborn error of metabolism, immediately obtain plasma amino acids, urine organic acids, plasma acylcarnitine profile, and plasma carnitine (free and total) as the core diagnostic panel. 1

Critical Clinical Context for Testing

Timing of Sample Collection

• Collect urine at the time of acute decompensation when the patient is symptomatic, as diagnostic metabolites are highest during metabolic crisis 1
• If the infant is not acutely ill, a random urine sample is acceptable, though acylcarnitine analysis can detect fatty acid oxidation disorders even when the patient is well 1
• Blood samples should be collected 48 hours after birth for optimal screening 2

Clinical Presentations Requiring Metabolic Workup

• Acute metabolic encephalopathy: lethargy, poor feeding, apnea or tachypnea, recurrent vomiting 3
• Metabolic acidosis and/or hyperammonemia (though notable exceptions exist including nonketotic hyperglycinemia) 3
• Hypoglycemia, particularly nonketotic hypoglycemia suggesting fatty acid oxidation defects or glycogen storage disorders 1, 3
• Hepatic dysfunction: jaundice, elevated transaminases, coagulopathy 3
• Cardiomyopathy or sudden death presentation 1, 3
• Specific features: macrocephaly (Canavan disease, glutaric acidemia type I), coarse facial features, organomegaly 1, 3

Core Diagnostic Laboratory Panel

First-Tier Essential Tests

1. Plasma Acylcarnitine Profile (via Tandem Mass Spectrometry)

• Detects fatty acid oxidation disorders and organic acidemias 1
• Identifies conditions including MCAD deficiency, VLCAD deficiency, CPT-I/II deficiency, LCHAD deficiency, carnitine uptake defect, and multiple organic acidemias 1
• Analysis takes only seconds using MS/MS technology 1

2. Plasma Amino Acids

• Essential for detecting aminoacidopathies including phenylketonuria, maple syrup urine disease, tyrosinemia, homocystinuria, and urea cycle defects 1, 4
• Should be performed by the same laboratory as acylcarnitine profile for integrated interpretation 1

3. Urine Organic Acids

• Detects organic acidemias (propionic acidemia, methylmalonic acidemia, glutaric acidemia) 1
• Requires 1-5 mL of urine, frozen as soon as possible 1
• Results normalized to creatinine concentration 1

4. Plasma Carnitine (Free and Total)

• Identifies primary carnitine deficiency and secondary carnitine depletion 1
• Critical for assessing overall metabolic status 1

Additional Concurrent Testing Based on Presentation

For Acute Metabolic Decompensation:

• Blood glucose (to detect hypo- or hyperglycemia) 1, 5
• Complete metabolic panel including electrolytes, BUN, creatinine 5
• Ammonia level (if hepatic encephalopathy or urea cycle defect suspected) 5
• Blood gas analysis (if metabolic acidosis suspected) 5
• Liver function tests (transaminases, bilirubin, albumin, INR) 1, 5
• Complete blood count with differential 5
• Creatine phosphokinase (CPK) if cardiomyopathy or rhabdomyolysis suspected 1

Specimen Handling Requirements

Critical Collection and Storage Parameters

• Urine: collect in clean container without preservatives, freeze immediately, store at -20°C or lower 1
• Ship to laboratory on dry ice via overnight courier 1
• Ammonia samples: collect in EDTA-containing tube, avoid venous stasis, place immediately on ice, transport within 60-90 minutes at +4°C 5
• Samples are stable for several years if properly frozen 1

Interpretation Framework

Understanding Test Results

• Acylcarnitine profile results may be diagnostic for specific disorders (e.g., elevated C14 and C14:1 for VLCAD deficiency) 1
• Further confirmatory testing is often required: mutation analysis, enzyme assay, or functional probe studies 1, 6
• A comprehensive metabolic evaluation integrates all test results together rather than interpreting each in isolation 1

Confirmatory Testing Algorithm

• If initial metabolic screening is abnormal: proceed to mutation analysis 1, 6
• Zero mutations detected: disease unlikely if metabolites are normal (unless consanguineous) 1
• One mutation detected: proceed to enzyme assay or functional probe 1
• Two known pathogenic mutations in trans: confirms diagnosis 1

Critical Pitfalls to Avoid

Common Diagnostic Errors

• Never rely solely on "zone gray" metabolite results without confirmatory testing 6
• A normal newborn screen does NOT exclude an inborn error of metabolism if clinical suspicion exists 1
• Initial negative testing does NOT rule out most disorders - confirmatory testing is essential 1, 6
• Do not dismiss metabolic disorders in favor of sepsis without appropriate metabolic testing, particularly in full-term infants without specific risk factors 3
• Avoid sample contamination from lubricants or soaps which can cause false elevations of glycerol, palmitic acid, and stearic acid 1

Clinical Context Requirements

• Provide the laboratory with clinical indication, patient's clinical state at time of testing, concurrent medications, and diet 1
• Ensure laboratory has contact information for urgent/emergent result communication 1

Expected Diagnostic Yield

Real-World Performance

• In targeted metabolic workup of symptomatic neonates, approximately 5.6% will have a confirmed IEM 7
• 68.4% of tested neonates can have an IEM excluded based on normal results 7
• Only 8.5% of infants with confirmed IEM are symptomatic at the time of newborn screening result 2
• The positive predictive value of abnormal newborn screening is approximately 10% nationally, meaning 9 of 10 abnormal results are false positives 6

Most Common Diagnoses

• Hyperphenylalaninemia (1/6661 incidence) 2
• MCAD deficiency (1/13,787 incidence) 2
• Other fatty acid oxidation disorders (VLCAD, LCHAD, carnitine deficiency) 2
• Organic acidemias (propionic acidemia, methylmalonic acidemia, glutaric acidemia type 1) 2

Follow-Up Considerations

• 13-31% of infants who fail initial screening do not return for follow-up - establish robust tracking systems 6
• All biochemically confirmed cases should proceed to genetic diagnosis, which identifies pathogenic variants in specific genes 2
• Ideally, all metabolic tests should be performed by the same laboratory with integrated interpretation of results 1