What are the clinical presentations and diagnostic approaches to suspect an Inborn Error of Metabolism (IEM) in a newborn?

Clinical Presentations and Diagnostic Approaches to Suspect Inborn Errors of Metabolism in Newborns

Inborn errors of metabolism (IEMs) should be suspected in any newborn with unexplained lethargy, poor feeding, vomiting, respiratory distress, or neurological symptoms, especially when routine causes like sepsis have been ruled out. 1 Early recognition is critical as prompt intervention can significantly reduce morbidity and mortality in many of these conditions.

Clinical Presentations Suggesting IEM

Acute Metabolic Encephalopathy

• Lethargy progressing to coma
• Poor feeding or feeding refusal
• Recurrent vomiting
• Respiratory abnormalities (apnea or tachypnea)
• Seizures or abnormal movements
• Hypotonia or hypertonia

Metabolic Derangements

• Metabolic acidosis (particularly with increased anion gap)
• Hyperammonemia (may present without acidosis in urea cycle defects)
• Hypoglycemia (especially during fasting or illness)
• Lactic acidosis
• Ketosis or hypoketosis (during hypoglycemia, absence of ketones suggests fatty acid oxidation defect)

Hepatic Dysfunction

• Jaundice unresponsive to phototherapy
• Hepatomegaly
• Coagulopathy
• Elevated liver enzymes

Cardiac Manifestations

• Cardiomyopathy
• Arrhythmias
• Heart failure

Other Presentations

• Dysmorphic features (coarse facies in some lysosomal storage disorders)
• Unusual odor (e.g., "sweaty feet" in isovaleric acidemia)
• Skin findings (rash, abnormal pigmentation)
• Sudden unexpected deterioration after a period of normal development

Timing of Presentation

• Immediate postnatal period: Severe forms of urea cycle defects, organic acidemias
• First 24-72 hours: After protein feeding begins - amino acid disorders, organic acidemias
• 3-7 days: After establishing feeding - fatty acid oxidation defects, galactosemia
• After initial normal period: Following a catabolic stress (infection, prolonged fasting)

Risk Factors to Consider

• Family history of unexplained infant deaths, IEMs, or developmental disabilities 2
• Parental consanguinity
• Previous siblings with similar presentations
• Recurrent events without clear explanation
• Age younger than 2 months with unexplained symptoms 2

Diagnostic Approach

First-Line Investigations (GALAK approach) 1

1. Glucose - hypoglycemia suggests glycogen storage disorders, fatty acid oxidation defects
2. Arterial blood gas - metabolic acidosis common in organic acidemias
3. Lactate - elevated in mitochondrial disorders, some organic acidemias
4. Ammonia - elevated in urea cycle defects, some organic acidemias
5. Ketones - hypoketotic hypoglycemia suggests fatty acid oxidation defects

Second-Line Investigations

• Complete blood count - cytopenias may be present
• Liver function tests - elevated in hepatic-presenting IEMs
• Electrolytes - abnormalities and anion gap calculation
• Urine ketones
• Plasma amino acids
• Urine organic acids
• Plasma acylcarnitine profile - detects disorders of fatty acid oxidation and organic acid metabolism 2

Specialized Testing

• Tandem mass spectrometry (MS/MS) - for acylcarnitine profile analysis 2
• Gas chromatography-mass spectrometry (GCMS) - for organic acid analysis 1
• Enzyme assays in appropriate tissues
• Genetic testing - targeted gene panels or whole exome sequencing

Important Caveats and Pitfalls

• Don't wait for all test results before initiating treatment in critically ill infants
• Samples should be collected before treatment whenever possible
• Newborn screening results should be verified but not all IEMs are included in screening panels 2
• False negatives can occur in newborn screening if samples are collected too early
• Sepsis-like presentation is common - consider IEM in any full-term infant with sepsis-like symptoms without specific risk factors 3
• Normal initial tests don't rule out IEM - some disorders like nonketotic hyperglycinemia may present without acidosis or hyperammonemia 3
• Lactic acid levels >3 mmol/L are more likely to be clinically significant than lower elevations 2

When to Refer to a Metabolic Specialist

• Abnormal newborn screening results
• Unexplained metabolic acidosis
• Hyperammonemia
• Persistent hypoglycemia
• Unusual clinical course not explained by common conditions
• Family history of IEM or unexplained infant deaths

Early recognition of IEMs is crucial as many conditions are treatable if diagnosed promptly. Maintaining a high index of suspicion and initiating appropriate diagnostic testing can significantly improve outcomes for affected newborns.