12.1 Inborn Errors of Metabolism | Neonatology Academy

Bedside Message

Act before the diagnosis — delay injures the brain

Do not wait for sepsis cultures, newborn-screen results, or send-out metabolic testing before treating a sick newborn in whom an IEM is plausible.
Think IEM early when a term or late-preterm infant has a normal interval followed by poor feeding, vomiting, lethargy, abnormal tone, seizures, unexplained hypoglycemia, metabolic acidosis, respiratory alkalosis, liver failure, or hyperammonemia.
The first metabolic screen is simple: blood gas, glucose, electrolytes with anion gap, ammonia, lactate, urinalysis/ketones, CBC — then plasma amino acids, acylcarnitine profile, and urine organic acids before specialized therapy when possible.
Call a metabolic-genetics specialist early. Hyperammonemia and organic acidemia are time-critical, brain-threatening emergencies.

1. Purpose and Scope

This chapter provides a NICU-facing approach to newborns with suspected inborn errors of metabolism (IEM). It is designed for bedside stabilization while definitive diagnosis is being pursued by a metabolic-genetics team. It does not replace a local metabolic emergency protocol, pharmacy dosing policy, dialysis guideline, or newborn-screen follow-up program.

2. When to Suspect an IEM

Clinical Trigger	Pattern That Should Raise Suspicion	Examples / First Thoughts
Normal interval then decline	Healthy-appearing newborn becomes progressively sleepy, stops feeding, vomits, develops abnormal tone, or has seizures after hours to days of life.	Intoxication disorders: urea-cycle defects, organic acidemias, maple syrup urine disease.
Encephalopathy with respiratory alkalosis	Tachypnea or hyperventilation without lung disease; ammonia may be very high before acidosis appears.	Urea-cycle disorder until proven otherwise.
Encephalopathy with high-anion-gap metabolic acidosis	Low bicarbonate, elevated anion gap, ketones, lactic acidosis, cytopenias, or shock-like presentation.	Organic acidemia; consider propionic, methylmalonic, isovaleric acidemia.
Hypoglycemia	Especially recurrent, severe, hypoketotic, or associated with hepatomegaly, liver dysfunction, cardiomyopathy, or rhabdomyolysis.	Fatty-acid oxidation disorder, glycogen-storage disease, gluconeogenesis defect, mitochondrial disease, hyperinsulinism.
Liver disease	Conjugated jaundice, coagulopathy, hepatomegaly, hypoglycemia, ascites, or liver failure.	Galactosemia, tyrosinemia type 1, mitochondrial disease, FAOD, urea-cycle disorder, bile-acid or peroxisomal disorder.
Seizures or apnea in a term baby	Intractable seizures, burst suppression, apnea/periodic breathing, hiccups, abnormal movements, or poor response to standard antiseizure therapy.	Pyridoxine/pyridoxal phosphate responsive epilepsy, non-ketotic hyperglycinemia, sulfite oxidase or molybdenum cofactor deficiency, GLUT1, serine synthesis defect.
Fetal or maternal clues	Nonimmune hydrops, dysmorphism, cardiomyopathy, maternal acute fatty liver of pregnancy, HELLP, unexplained prior neonatal deaths, or consanguinity.	Lysosomal storage disease, mitochondrial disorder, LCHAD/FAOD, peroxisomal disease, autosomal-recessive IEM.

Do not be falsely reassured by sepsis risk

IEM and sepsis can look identical, and sepsis can precipitate metabolic decompensation.
Classic galactosemia may present with E. coli sepsis before the newborn screen returns.
A sepsis evaluation should happen with, not instead of, metabolic sampling when the clinical pattern is unusual.

3. Functional Classification for Bedside Thinking

IEM Group	Typical Timing / Physiology	Common Clues	Immediate Bedside Priority
Intoxication disorders	Accumulation of toxic metabolites after feeding or catabolic stress; often a symptom-free interval.	Poor feeding, vomiting, encephalopathy, seizures, abnormal tone, hyperammonemia, high anion gap acidosis or ketosis depending on disorder.	Stop protein temporarily, reverse catabolism with high glucose calories, treat hyperammonemia, collect diagnostic blood/urine before metabolites clear.
Energy-production / energy-utilization disorders	Defect in maintaining ATP or glucose homeostasis; may present from birth or during fasting/illness.	Hypoglycemia, lactic acidosis, liver failure, cardiomyopathy, myopathy, rhabdomyolysis, sudden deterioration.	Avoid fasting, provide glucose, avoid excessive lipid in suspected FAOD until metabolic guidance, assess cardiac/liver status.
Complex-molecule disorders	Progressive disorders of synthesis/breakdown of large molecules; less dependent on feeding interval.	Hydrops, dysmorphism, organomegaly, corneal clouding, skeletal features, progressive disease.	Stabilize acute issues, involve genetics, plan targeted enzyme/genetic testing and disease-specific therapy.
Single-system metabolic disorders	One organ/system may dominate.	Hemolysis, cardiomyopathy, liver disease, seizures, hypotonia, cataracts.	Do not dismiss as isolated organ disease when clinical course is unexplained or multisystem features appear.

4. First-Hour NICU Algorithm for Suspected IEM

Step	Action	Important Details
1	Stabilize ABCs and stop catabolism.	Airway and ventilation as needed. Establish IV access. Treat shock, hypoglycemia, seizures, temperature instability, and infection while collecting metabolic samples.
2	Temporarily stop potentially harmful substrates.	If severe illness and IEM is plausible, stop enteral protein and lactose/galactose-containing feeds until the metabolic team guides reintroduction. Avoid starting routine PN protein or lipid during initial stabilization unless advised.
3	Provide glucose calories.	Start D10W or higher dextrose concentration to target an adequate GIR, often 6–8 mg/kg/min initially; use central access if high dextrose concentration is required. Insulin may be needed if hyperglycemia prevents sufficient calorie delivery, but only with close monitoring and specialist input.
4	Draw critical labs immediately.	Blood gas, glucose, electrolytes, BUN/creatinine, liver panel, coagulation studies, CBC, ammonia, lactate, beta-hydroxybutyrate/ketones when available, blood culture, and urinalysis/ketones.
5	Send metabolic diagnostic samples before treatment changes when feasible.	Plasma amino acids, acylcarnitine profile/free-total carnitine, urine organic acids, urine orotic acid if hyperammonemia, urine reducing substances/galactose testing if liver disease, and newborn screen if not already obtained.
6	Call metabolic-genetics early.	Call while labs are being drawn, not after send-out results return. Early decisions include ammonia scavengers, arginine/citrulline, carglumic acid, carnitine, vitamin cofactors, dialysis, and transfer.
7	Escalate for hyperammonemia or severe acidosis.	Repeat ammonia and blood gas frequently. Arrange renal replacement therapy early when ammonia is severe, rising, or neurologic status is deteriorating despite medical therapy.

5. Diagnostic Sampling: Do It Before the Metabolic Signature Disappears

Test	Why It Matters	Collection Pearls / Interpretation
Ammonia	Identifies brain-threatening hyperammonemia and guides dialysis/scavenger urgency.	Free-flowing venous or arterial sample, avoid hemolysis, place on ice, send STAT. Repeat if elevated or clinical status changes.
Blood gas + electrolytes + anion gap	Separates respiratory alkalosis, metabolic acidosis, and mixed disorders.	High anion gap → organic acidemia/lactic acidosis; respiratory alkalosis with hyperammonemia → urea-cycle defect.
Glucose + ketones / beta-hydroxybutyrate	Detects hypoglycemia and distinguishes hypoketotic vs. ketotic states.	Hypoketotic hypoglycemia → FAOD or hyperinsulinism; marked ketonuria in a neonate is abnormal and supports organic acidemia or ketolysis defects.
Lactate	Screens for tissue hypoperfusion and primary energy metabolism disorders.	Incorrect sampling can falsely elevate lactate. Persistent true elevation should trigger metabolic/mitochondrial evaluation.
Plasma amino acids	Screens aminoacidopathies and urea-cycle patterns.	Draw at presentation before prolonged protein restriction or scavenger therapy whenever possible. Alloisoleucine supports MSUD; citrulline/arginine patterns help classify UCD.
Acylcarnitine profile + free/total carnitine	Screens FAOD and many organic acidemias.	Obtain even if newborn screen was sent; acute illness may reveal diagnostic intermediates.
Urine organic acids	High-yield screen for organic acidemias, ketolysis defects, and selected mitochondrial clues.	Collect during acute illness; freeze/send promptly according to lab policy.
Urine orotic acid	Helps classify hyperammonemia — elevated in OTC deficiency and some other UCD patterns.	Useful for distinguishing OTC and related defects; interpret with plasma amino acids and genetics.
Liver-focused metabolic tests	Needed when jaundice/coagulopathy/liver failure dominate.	Total/direct bilirubin, AST/ALT/GGT, PT/INR, ferritin, galactosemia testing, succinylacetone, alpha-1 antitrypsin phenotype, bile acids or genetic panels as directed.
CSF studies	Reserved for selected neurologic presentations.	Paired blood/CSF glycine for NKHG, CSF glucose for GLUT1, CSF lactate and amino acids when requested by IMD team.

6. Pattern Recognition: Common Emergency Phenotypes

Pattern	Likely Category	Immediate Treatment Logic
High ammonia + respiratory alkalosis + little/no metabolic acidosis	Urea-cycle disorder	Stop protein, high non-protein calories, metabolic consultation, arginine/citrulline depending on suspected defect, nitrogen scavengers, urgent dialysis if severe or rising.
High ammonia + high-anion-gap acidosis + ketosis/cytopenias	Organic acidemia	Stop protein briefly, high glucose ± insulin, correct acidosis, L-carnitine, vitamin cofactors, consider carglumic acid, treat infection, dialysis if severe hyperammonemia/acidosis persists.
Hypoketotic hypoglycemia ± cardiomyopathy / rhabdomyolysis	Fatty-acid oxidation disorder	Avoid fasting, high glucose infusion, avoid routine lipid boluses/long fasting intervals, treat secondary carnitine deficiency only with metabolic guidance, cardiac monitoring.
Lactic acidosis + hypotonia / cardiomyopathy / liver failure	Mitochondrial/pyruvate/energy disorder	Support perfusion and glucose; avoid prolonged fasting; consider thiamine, biotin, carnitine only with specialist direction; evaluate heart/liver/brain.
Conjugated jaundice + coagulopathy + cataracts / E. coli sepsis	Galactosemia until proven otherwise	Stop lactose/galactose; use appropriate galactose-free formula per local policy; treat sepsis; check GALT/galactose-1-phosphate/urine galactitol as applicable.
Seizures resistant to standard therapy	Vitamin/cofactor, transporter, amino acid, peroxisomal, or mitochondrial disorder	EEG, correct glucose/electrolytes, consider pyridoxine or pyridoxal phosphate trial with monitoring, send paired metabolic studies before or during therapy.
Hydrops / organomegaly / dysmorphism	Complex molecule disorder, chromosomal syndrome, storage disease, peroxisomal or mitochondrial disorder	Stabilize cardiopulmonary status, involve genetics, collect broad metabolic/genomic testing; do not expect newborn screen to exclude these conditions.

7. Hyperammonemia: Emergency Escalation Pathway

Hyperammonemia safety rule

Any encephalopathic neonate needs an ammonia level early.
A substantially elevated ammonia level is a neurologic emergency; the duration of elevation is strongly linked to outcome.
Repeat ammonia often enough to know the direction of travel; do not rely on one value if clinical status is changing.
Prepare for dialysis/hemofiltration early when ammonia is severe, rapidly rising, or not improving with medical therapy.

Drawing it, reading it, and the doses (Baylor Ed. 33)

How to draw it: from a free-flowing vein or artery, on ice, assayed immediately. A struggled-for sample gives a number you cannot act on.
Values below 100 µmol/L are of little significance in newborns and do not explain an encephalopathy — look elsewhere. Ammonia also rises in severe hepatic disease from other causes (neonatal herpes, for example) and in vascular anomalies such as a persistent ductus venosus.
While dialysis is being arranged, a priming infusion of sodium phenylacetate and sodium benzoate, 250 mg/kg of each, with arginine 200–600 mg/kg in 25–35 mL/kg of 10% dextrose over 90 minutes; the same doses then run over the next 24 hours. Surgical placement of an adequately sized dialysis catheter is essential for dialysis to work.
Arginine is widely available where Ammonul is not. Until the specific disorder is known, 600 mg/kg is the recommended dose — it replenishes urea cycle intermediates and replaces the arginine the kidney would normally make, reversing protein catabolism. In argininosuccinate lyase deficiency, arginine alone with protein restriction is effectively curative. It is not indicated in arginase deficiency, which is generally not symptomatic in neonates.
For OTC deficiency, the commonest urea cycle disorder, oral citrulline around 200 mg/kg/day helps lower ammonia.
Organic aciduria — a hyperammonaemic, severely acidotic newborn can be assumed to have one. Give IV L-carnitine 100 mg/kg/day divided three times daily, plus glucose and insulin calories to reverse catabolism, and the vitamin cofactors: thiamine 100 mg, biotin 10 mg, hydroxocobalamin 1 mg. Hyperammonaemia often responds promptly enough to avoid dialysis; carglumic acid helps the hyperammonaemia of organic acidurias specifically.
Before giving 1 mg or more of hydroxocobalamin for a suspected organic aciduria, send a B12 level: maternal deficiency corrects almost immediately with one dose, whereas an inherited disorder of B12 metabolism needs considerably more.
Turnaround to expect: plasma amino acids and urine organic acids within about 24 hours; an acylcarnitine profile 48–72 hours. Treatment starts before any of them return — bicarbonate for acidosis, glucose for hypoglycaemia, cofactors, and nitrogen scavenging or dialysis as indicated.

Ammonia Context	Interpretation	Action
Normal or mildly elevated	Does not exclude IEM, especially organic acidemia, FAOD, mitochondrial disease, or treated/late presentation.	Continue evaluation if clinical pattern fits; repeat if worsening encephalopathy, respiratory alkalosis, or liver failure.
>150 µmol/L in a sick neonate	Concerning for metabolic hyperammonemia, especially if not explained by severe liver failure or sampling artifact.	Call metabolic-genetics immediately; send plasma amino acids, urine orotic acid, urine organic acids, and acylcarnitines; stop protein temporarily; reverse catabolism.
Very high or rising ammonia, coma, seizures, or rapid neurologic decline	Time-critical risk of brain injury.	Begin medical therapy with metabolic team and activate dialysis/renal replacement pathway without delay.

8. Disease-Specific Bedside Notes

Condition / Group	Recognition Clues	Initial NICU Actions Before Final Diagnosis
Classic galactosemia	Persistent jaundice, liver dysfunction, coagulopathy, cataracts, vomiting, poor feeding, E. coli sepsis.	Stop lactose/galactose-containing feeds; send galactosemia testing; treat sepsis and coagulopathy; genetics/metabolic dietitian follow-up.
MSUD (Maple Syrup Urine Disease)	Well interval then poor feeding, encephalopathy, abnormal tone, opisthotonus, maple-syrup odor, ketonuria; ammonia/acidosis may be mild.	Stop protein briefly, high calories, send plasma amino acids/alloisoleucine, avoid excessive free water, discuss dialysis if leucine/encephalopathy severe.
Organic acidemias	High anion gap metabolic acidosis, ketosis, hyperammonemia, cytopenias, vomiting, shock-like presentation.	Glucose calories ± insulin, L-carnitine, cofactors such as biotin/thiamine/hydroxycobalamin when directed, carglumic acid may be considered, dialysis if refractory.
Urea-cycle defects	Hyperammonemic encephalopathy, respiratory alkalosis early, hypotonia, tachypnea, seizures/coma; often little acidosis initially.	Stop protein, high calories, send amino acids/orotic acid, ammonia scavengers and arginine/citrulline per metabolic team, urgent dialysis for severe cases.
Fatty-acid oxidation disorders (FAOD)	Hypoketotic hypoglycemia, liver dysfunction, cardiomyopathy, arrhythmia, rhabdomyolysis; maternal HELLP/acute fatty liver may be a clue.	Avoid fasting; high glucose; cardiac monitoring; send acylcarnitine/free-total carnitine/urine organic acids; disease-specific diet and carnitine only with specialist guidance.
GSD / gluconeogenesis defects	Hypoglycemia, hepatomegaly, lactic acidosis, hyperlipidemia, elevated uric acid/transaminases.	Prevent fasting, glucose infusion, avoid glucagon assumptions without endocrine/metabolic context, plan continuous feeds/cornstarch only with specialist care.
Pyridoxine or pyridoxal phosphate responsive seizures	Early refractory seizures or epileptic encephalopathy; may have abnormal EEG without clear structural cause.	Continuous EEG when possible; correct glucose/electrolytes; trial pyridoxine/pyridoxal phosphate with apnea preparedness and specialist guidance; collect urine/CSF samples when feasible.
Cystic fibrosis / meconium ileus	Elevated IRT or DNA variant(s), meconium ileus, respiratory/GI signs.	Sweat test when age/weight/gestation criteria are feasible; pulmonary/CF center referral; symptomatic infants need evaluation regardless of newborn screen result.

9. Consultation, Transfer, and Communication

Situation	Who to Call	Communication Points
Suspected IEM but stable	Metabolic-genetics service and metabolic dietitian.	Share gestational age, postnatal age, feeding history, illness timeline, family history, ammonia, gas, anion gap, glucose, lactate, ketones, liver/coagulation status, and samples already collected.
Hyperammonemia, coma, seizures, severe acidosis, or shock	Metabolic-genetics, PICU/nephrology/dialysis team, pharmacy, transport, and receiving metabolic center.	Ask early about nitrogen scavengers, arginine/citrulline, carglumic acid, carnitine/cofactors, dialysis catheter size/location, and whether transfer is safer before deterioration.
Positive newborn screen but asymptomatic	Newborn-screen follow-up program and metabolic-genetics team.	Do not reassure solely because baby looks well. Confirm feeding plan, fasting limits, urgent labs, and emergency letter while confirmatory testing is pending.
Family counseling	Metabolic-genetics, social work, interpreter, lactation/dietitian.	Explain that treatment often begins before the exact diagnosis because delay can injure the brain. Avoid blaming feeding choice; emphasize inherited and treatable emergency pathways.

10. Parent-Facing Communication

Suggested language

"Your baby is very sick, and one possible reason is that the body is having trouble processing protein, sugar, fat, or another nutrient. These conditions are rare, but they can become dangerous quickly in newborns."
"We are treating the emergency now while we send special blood and urine tests. Waiting for every result before starting treatment could be harmful."
"Some of the early treatment is temporary: giving sugar calories, pausing certain feeds, treating infection, and sometimes using special medicines or dialysis if ammonia is high."
"A metabolic/genetics specialist is helping guide the safest feeding and medication plan."

11. Source-Comparison Notes

Topic	Baylor 2025–2026	West Midlands 2025–2028	Belize Contribution
Recognition	Broad conceptual framework; IEM can mimic sepsis and nonspecific neonatal illness.	Very practical trigger list by presentation: encephalopathy, acidosis, liver disease, hypoglycemia, hydrops, hypotonia, cataracts, seizures.	Highlights IEM within hypoglycemia, neonatal seizures, NEC differential, and cholestasis workup rather than as a stand-alone chapter.
Initial testing	Acid-base balance, ammonia, lactate, urinalysis, amino acids, acylcarnitines, organic acids, and targeted studies.	Specifies urine freezing, blood spot/acylcarnitines, plasma amino acids, ammonia, lactate, and situation-specific tests.	Supports ammonia/lactate/blood gas/metabolic screen in seizure evaluation and lists IEM causes of persistent hypoglycemia.
Treatment	Begin treatment before diagnosis; glucose, bicarbonate, vitamin cofactors, scavengers/dialysis for hyperammonemia.	Emergency ABC stabilization, stop protein/fat/galactose initially, D10 infusion, infection coverage, seizure control, and IMD-led specific management.	Supports treating reversible metabolic/electrolyte problems first in seizures and avoiding delayed cause-directed care.
Newborn screen	Important but incomplete; state-specific panels; false negatives possible with transfusions or non-panel diseases.	Emphasizes urgent IMD team advice rather than relying on screening alone.	Provides disease examples but not a comprehensive metabolic emergency pathway.

12. Suggested NICU Quality Metrics

Metric	Target
Time from first encephalopathy/hypoglycemia/acidosis trigger to ammonia result	Local benchmark; aim for STAT result workflow and immediate repeat if abnormal.
Percent of suspected IEM cases with plasma amino acids, acylcarnitine profile, and urine organic acids collected before prolonged substrate restriction	Track missed diagnostic windows.
Time from ammonia >150 µmol/L in a sick neonate to metabolic-genetics contact	Immediate escalation.
Availability of metabolic emergency medications (sodium benzoate/phenylacetate or local equivalent, arginine, carglumic acid, L-carnitine, biotin, thiamine, pyridoxine/pyridoxal phosphate as applicable)	Monthly pharmacy check.
Documented parent communication and genetics follow-up after suspected/confirmed IEM	100% before transfer or discharge.

Key References and Source Base

Baylor College of Medicine. Guidelines for Acute Care of the Neonate, Edition 33, 2025–2026. Chapter 7.1: Inborn Errors of Metabolism.
West Midlands Neonatal Operational Delivery Network. Neonatal Guidelines 2025–2028. Inherited Metabolic Disorders guideline.
Belize Ministry of Health. Neonatal Clinical Practice Guidelines 2018–2021. Hypoglycemia, seizure, cholestasis, and metabolic differential sections.
New England Consortium of Metabolic Programs. Acute Illness Materials and Hyperammonemia Protocol. Boston Children's Hospital-based metabolic emergency materials.
HRSA Newborn Screening. Recommended Uniform Screening Panel and condition information pages.
GeneReviews and ACMG ACT Sheets/Algorithms. Disorder-specific confirmatory testing and follow-up after a positive newborn screen. GeneReviews at NCBI.

Implementation note

This chapter provides orientation for bedside stabilization while a metabolic-genetics team leads definitive diagnosis and disease-specific therapy. Specific medication doses (nitrogen scavengers, arginine, carglumic acid, cofactors, carnitine) must be confirmed with pharmacy and a metabolic-genetics specialist. Local dialysis/hemofiltration pathways and transfer protocols vary by institution.

Inborn Errors of Metabolism