How should a newborn presenting with poor feeding, lethargy, vomiting, seizures, respiratory distress, hypotonia, hepatomegaly, metabolic acidosis, hypoglycemia, and hyperammonemia be evaluated and managed for a suspected inborn error of metabolism?

Approach to Suspected Inborn Error of Metabolism in a Newborn

In a newborn presenting with poor feeding, lethargy, vomiting, seizures, respiratory distress, hypotonia, hepatomegaly, metabolic acidosis, hypoglycemia, and hyperammonemia, immediately stop all protein intake, initiate IV glucose (8-10 mg/kg/min) and lipids to prevent catabolism, obtain urgent plasma ammonia, plasma amino acids, urine organic acids, plasma acylcarnitine profile, and plasma carnitine levels, and prepare for emergent hemodialysis if ammonia exceeds 300 μmol/L or remains persistently elevated despite medical therapy. 1

Immediate Stabilization and Differential Diagnosis

Critical First Steps: Rule Out Life-Threatening Mimics

Before pursuing IEM workup, you must exclude conditions that simulate metabolic disease:

• Sepsis vs. IEM distinction: While sepsis may be the initial consideration, IEM should always be in the differential, particularly in a full-term infant with no specific risk factors for infection 2. Both can present identically with lethargy, poor feeding, respiratory distress, and metabolic acidosis 3.

• Congenital heart disease: Any newborn with shock, hepatomegaly, cyanosis, cardiac murmur, or differential upper/lower extremity blood pressures or pulses requires immediate prostaglandin infusion until ductal-dependent congenital heart disease is ruled out by echocardiography 3.

• Key distinguishing feature: The presence of respiratory alkalosis (from hyperventilation) is an important early clue that distinguishes hyperammonemia from other causes of encephalopathy 1. IEMs causing hyperammonemia typically trigger compensatory hyperventilation, whereas sepsis usually causes respiratory acidosis or mixed patterns.

Emergency Metabolic Workup

Immediate Laboratory Testing (Before Any Treatment)

Obtain these specimens urgently, as they provide diagnostic information that may be lost after treatment initiation:

• Plasma ammonia (critical technique): Fasting patient, avoid venous stasis, collect in EDTA tube, immediately place on ice, transport to laboratory at +4°C within 60-90 minutes 1. Levels >100 μmol/L in neonates or ≥50 μmol/L in term infants define hyperammonemia 1.

• Plasma amino acids 3, 4

• Urine organic acids by gas chromatography-mass spectrometry 3, 4

• Plasma acylcarnitine profile by tandem mass spectrometry 3, 4

• Plasma carnitine (free and total) 3, 4

• Blood gas to assess for metabolic acidosis and respiratory compensation 3

• Blood glucose and ionized calcium 3

• Serum lactate and anion gap calculation 4

Pattern Recognition by Laboratory Profile

The combination of findings directs you toward specific IEM categories:

Hyperammonemia (>100 μmol/L) with metabolic acidosis:

• Suggests organic acidemias (methylmalonic acidemia, propionic acidemia, isovaleric acidemia) 3, 5
• Urine organic acids will show characteristic patterns 3
• Plasma acylcarnitine profile confirms specific defects 3

Hyperammonemia WITHOUT metabolic acidosis:

• Suggests primary urea cycle disorders (OTC deficiency, CPS1 deficiency, ASS deficiency, ASL deficiency) 3, 1
• Ornithine transcarbamylase (OTC) deficiency is the most common UCD (1 in 56,500 births) 1
• Elevated plasma glutamine and low citrulline support urea cycle defect 3

Hypoglycemia with hypoketotic state:

• Suggests fatty acid oxidation defects (MCAD, VLCAD, LCHAD deficiency) 3, 2
• Plasma acylcarnitine profile is diagnostic 3

Metabolic acidosis with elevated anion gap:

• Suggests organic acidemias or disorders of energy metabolism 3, 4

Emergency Medical Management

Immediate Interventions (Within First Hour)

Stop all protein intake immediately to halt nitrogen load and ammonia production 1. This is the single most critical intervention.

Initiate IV glucose:

• Maintain glucose infusion rate of 8-10 mg/kg/min to prevent catabolism 1
• Monitor blood glucose every 1-2 hours initially 3
• Correct hypoglycemia aggressively as it worsens neurologic injury 3

Provide IV lipids:

• Start at 0.5 g/kg/day, increase up to 3 g/kg/day 1
• Provides non-protein calories to prevent catabolism 1

Fluid resuscitation if shock present:

• Administer 10 mL/kg boluses, observing for hepatomegaly and increased work of breathing 3
• Up to 60 mL/kg may be required in the first hour 3
• Umbilical arterial and venous line placement is preferred for vascular access 3

Ammonia-Specific Therapy

If ammonia >200 μmol/L, initiate nitrogen scavenger therapy:

• IV sodium benzoate 1:
  • If body weight <20 kg: 250 mg/kg over 90 minutes as loading dose, then 250 mg/kg/day as continuous infusion 1
  • If body weight >20 kg: 5.5 g/m² over 90 minutes as loading dose, then 5.5 g/m²/day as continuous infusion 1

Monitor ammonia levels every 3 hours during acute management 3, 1

Critical Dialysis Thresholds

Prepare for urgent hemodialysis if:

• Ammonia >300 μmol/L with moderate-to-severe encephalopathy or seizures 1
• Ammonia remains persistently elevated despite medical therapy 1
• Clinical deterioration despite nitrogen scavenger therapy 3, 1

Important prognostic principle: The duration of hyperammonemic coma prior to dialysis initiation—not the rate of ammonia clearance—is the most important prognostic factor for neurologic outcome 1. Levels >200 μmol/L are associated with poor neurological outcomes 1, and coma lasting >3 days predicts severe disability 1.

Airway and Respiratory Management

Intubation criteria 3:

• Increased work of breathing
• Inadequate respiratory effort
• Marked hypoxemia
• Altered mental status with inability to protect airway

Critical pitfall: Volume loading is often necessary before intubation because positive pressure ventilation reduces preload 3.

Monitoring requirements 3:

• Continuous pulse oximetry (preductal and postductal)
• Continuous electrocardiogram
• Intra-arterial blood pressure monitoring (umbilical or peripheral)
• Temperature monitoring
• Urine output monitoring (goal >1 mL/kg/h)

Protein Reintroduction

Do not continue protein restriction beyond 48 hours, as prolonged restriction triggers catabolism and paradoxically worsens ammonia production 1.

Reintroduction protocol 1:

• Begin once ammonia decreases to safe level (<100 μmol/L)
• Start with 0.25 g/kg/day
• Gradually increase up to 1.5 g/kg/day based on ammonia monitoring

Specific IEM Categories and Their Presentations

Organic Acidemias

Clinical clues 3, 5:

• Feeding difficulty, seizures, lethargy, dyspnea in neonatal period
• Megaloblastic anemia (especially methylmalonic acidemia with homocysteinemia)
• Liver dysfunction
• Metabolic acidosis with elevated anion gap
• Hyperammonemia

Diagnostic findings 3:

• Urine organic acids show elevated methylmalonic acid, propionic acid, isovaleric acid, or glutaric acid depending on specific defect
• Plasma acylcarnitine profile shows characteristic elevations 3

Incidence: Organic acidemias occur in approximately 1 in 21,000 births 1

Urea Cycle Disorders

Clinical clues 3, 1:

• Lethargy, poor feeding, vomiting within first few days after feeding begins
• Hypotonia and hyperventilation with respiratory alkalosis
• Progression to seizures, coma if untreated
• Hepatomegaly may be present

Diagnostic findings 3, 1:

• Marked hyperammonemia (often >500 μmol/L)
• Normal or mildly elevated anion gap
• Elevated plasma glutamine
• Specific amino acid patterns (e.g., low citrulline in OTC deficiency)
• Elevated urine orotic acid suggests OTC deficiency 3

Fatty Acid Oxidation Defects

Clinical clues 3, 2:

• Hypoketotic hypoglycemia
• May present as sudden death, Reye's-like episode, or cardiomyopathy
• Hepatomegaly and liver dysfunction
• Marked clinical variability

Diagnostic findings 3:

• Plasma acylcarnitine profile is diagnostic
• Low free carnitine
• Specific acylcarnitine elevations (e.g., C8 in MCAD deficiency)

Common Pitfalls to Avoid

Do not wait for seizures or coma to measure ammonia—these represent advanced manifestations, not early signs 1. Lethargy and poor feeding are the earliest indicators.

Do not rely on ammonia levels alone to guide treatment intensity—clinical status (level of consciousness, presence of seizures, evidence of cerebral edema) must guide therapeutic decisions 1.

Do not delay dialysis in severe hyperammonemia—the duration of hyperammonemic coma determines neurologic outcome, not the rate of ammonia clearance 1.

Do not continue protein restriction beyond 48 hours—this triggers catabolism and worsens the metabolic crisis 1.

Do not assume sepsis explains all findings—IEMs can present identically and must be evaluated in parallel, not as an exceptional diagnosis 2, 6.