Inborn errors of metabolism

Background

• Clinical manifestations are due to accumulation of toxic metabolites
• Suspect in any sick neonate
• Newborn screening varies by state
• May present as late as early adulthood
• Must rule-out sepsis (more common in these patients due to organic acid-induced bone marrow suppression) and other physiologic stressors that might be precipitating decompensation

Clinical Features

Varies depending on disorder

• Lethargy, AMS, encephalopathy (often hyperammonemic)
• Seizure
• Hypotonia
• Nausea/vomiting, diarrhea
• Difficulty feeding
• Failure to thrive
• Unusual odors
• Hypoglycemia
• Organomegaly
• +/- Skin rashes
• +/- Eye findings
• Signs/symptoms of dehydration
• Infections

Differential Diagnosis

Sick Neonate

THE MISFITS

• Trauma
• Heart
  • Congenital heart disease
  • Hypovolemia
• Endocrine
  • hypoglycemia
  • Hypothyroidism
  • Congenital adrenal hyperplasia
• Metabolic
  • Sodium
  • Calcium
  • Glucose
• Inborn errors of metabolism
• Seizure
• Formula / feeding problems
  • Hyponatremia
  • Hypocalcemia
  • FPIES / Food protein-induced enterocolitis syndrome
• Intestinal Disasters
  • Duodenal atresia
  • Midgut volvulus
  • Necrotizing enterocolitis
  • Intussusception
• Toxin
• Sepsis

Evaluation

• Evaluate for metabolic derangement +/- precipitant of decompensation
• Labs:
  • Glucose level (most important/time sensitive!)
  • Ketones (urine or serum beta hydroxybutyrate)- helpful to obtain prior to giving dextrose in hypoglycemic patients, if possible
  • Ammonia
    • Should be <100 in normal neonate
  • BMP, LFTs
    • Anion gap (if >20, suggests an organic acidemia)
    • May see hypoglycemia, metabolic acidosis
  • VBG
  • Lactate and pyruvate (drawn at same time)
  • CBC
  • Blood culture, urine culture, +/- CSF
  • Additional tests to aid in definitive diagnosis (consider setting aside blood sample on ice prior to dextrose admin)
    • Muscle function tests (e.g. CPK, LDH, myoglobin)
    • Serum/plasma pyruvate, amino acids, acylcarnitine profile
    • Urine organic acids, acylglycines, orotic acid
• Consider head CT (evaluate for cerebral edema and alternate etiologies of symptoms)
• Evaluate for alternate etiologies

Management

• Patients with diagnosed inborn errors often have pre-established plans for "sick day" or emergency guidance
• Early consultation with specialists

Resuscitate, stop catabolism/accumulation of toxins

• Keep NPO
  • Removes potential inciting metabolic substrates
• IVF
  • Normal saline 10-20 mL/kg boluses
    • Reassess after each bolus, as congenital heart disease may mimic symptoms of inborn errors
  • IVF with dextrose (D10) and 0.45 or 0.9% NS at 1.5-2x maintenance
    • Aggressive hydration increases urinary excretion of toxic metabolites, dextrose provides metabolic substrate

Hyperammonemia

• <500 micromoles/L
  • sodium phenylacetate/sodium benzoate (Ammonul) 250mg/kg in D10 over 90min; then 250mg/kg/d infusion
  • Arginine 210mg/kg IV/IO in D10 over 90min; then 210mg/kg/d infusion
  • +/- carnitine, 400 mg IV/IO in consultation w/specialist
  • May require dialysis if refractory/severe

Acidosis

• Sodium bicarbonate 0.5 mEq/kg/h if pH <7.0
  • Reserve for severe and/or refractory acidosis due to potential side effects of sodium overload, cerebral edema, cardiac dysfunction
• Caution intubating any child in metabolic crisis due to potential worsening of acidosis

Cerebral edema

• Hyperammonemia is risk factor
  • Mannitol 0.5gm/kg IV/IO
  • Do not give steroids (worsens hyperammonemia)

Seizure

• Consider vitamin B6 (pyridoxine) in addition to usual care

Infection/Sepsis

• Consider empiric antibiotics in all infants in metabolic crisis

Dispo

• Admit or transfer to tertiary care children's hospital

See Also

• Neonatal Resuscitation