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Inborn errors of metabolism (IEMs) are genetic disorders caused by mutations that impair the function of enzymes or transport proteins in metabolic pathways. This leads to the accumulation of toxic substances or deficiency of necessary metabolic products, disrupting normal physiology

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Although individually rare, the combined incidence of IEMs is estimated at 1 in 1,500 to 1 in 2,500 live births. With expanded newborn screening, more cases are now detected in asymptomatic stages (Sources: 2, 4, 5).

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IEMs are commonly classified into three pathophysiologic groups:

Intoxication type: Disorders where toxic metabolites accumulate (e.g., organic acidemias, urea cycle disorders, amino acidopathies)

Energy deficiency type: Disorders affecting energy production (e.g., FAO disorders, mitochondrial disorders, glycogen storage diseases)

Storage/complex molecule disorders: Disorders involving lysosomes/peroxisomes (e.g., Tay-Sachs, Gaucher disease)

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Genetic predisposition

Most IEMs are inherited in an autosomal recessive manner; some are X-linked (e.g., OTC deficiency)

High-risk factors: consanguinity, family history of unexplained neonatal deaths, developmental delays, or metabolic crises

Which are the main autosomal dominant ones

Most IEMs are not autosomal dominant. Dominant inheritance is rare but may include some mitochondrial and peroxisomal disorders, depending on the gene involved

Main recessive ones

Autosomal recessive: PKU, MSUD, galactosemia, glycogen storage diseases, organic acidemias, FAO disorders

X-linked recessive: OTC deficiency, Menkes disease, adrenoleukodystrophy

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Heel prick test

When is it done? Between 24–72 hours after birth, ideally after feeding has been established

How is it done? Blood collected on filter paper and analyzed via tandem mass spectrometry

How does it work? Detects elevated or deficient metabolites or enzyme activity

What diseases does it screen? PKU, MSUD, galactosemia, congenital hypothyroidism, MCAD, biotinidase deficiency, severe combined immunodeficiency, cystic fibrosis (Sources: 3, 5)

BH4 test

When/how: Performed in infants with elevated phenylalanine to assess responsiveness to BH4

Purpose: Distinguish classical PKU from BH4-deficient hyperphenylalaninemia

Significance: Guides whether dietary restriction or BH4 therapy is appropriate (Source: 5)

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When suspecting an inborn metabolism disorder:

History and physical exam

Basic labs:

CBC: Anemia, neutropenia (e.g., organic acidemias)

ABG/pH: Acidosis (metabolic), alkalosis (urea cycle disorders)

BUN/Creatinine: Kidney function

Bilirubin, AST/ALT, PT: Liver function

Blood glucose, ketones: Hypoglycemia assessment

Serum ammonia: Key in urea cycle defects

Urine pH and reducing substances (e.g., galactosemia) (Sources: 5, 6)

Secondary tests

Plasma amino acids (PKU, urea cycle)

Acylcarnitine profile (FAO disorders)

Urine organic acids (organic acidemias)

Orotic acid in urine (OTC deficiency)

CSF: lactate, pyruvate, glycine (nonketotic hyperglycinemia)

Genetic testing (exome, gene panels) (Sources: 3, 5, 6)

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Definition: Enzyme deficiencies affecting amino acid metabolism.

Clinical presentation: Developmental delay, seizures, feeding intolerance, specific odors.

Examples & General Treatment:

PKU: Musty body odor, intellectual disability if untreated.

Treatment: Low-phenylalanine diet, BH4 supplementation (if responsive).

MSUD: Poor feeding, lethargy, sweet-smelling urine.

Treatment: BCAA-restricted diet, thiamine, emergency glucose and dialysis during crises.

Tyrosinemia Type I: Liver failure, renal dysfunction, cabbage-like odor.

Treatment: NTBC (nitisinone), tyrosine/phenylalanine restriction, possible liver transplant.

Homocystinuria: Marfanoid features, lens dislocation, thromboembolism.

Treatment: B6, folate, B12, betaine, low-methionine diet.

Alkaptonuria: Dark urine, arthritis.

Treatment: Symptomatic, nitisinone under study.

Nonketotic Hyperglycinemia: Neonatal seizures, hypotonia, apnea.

Treatment: Sodium benzoate, dextromethorphan.

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Definition: Disorders involving accumulation of toxic organic acids due to defective metabolism of amino acids or fatty acids.

Clinical presentation: Poor feeding, vomiting, lethargy, seizures, hypotonia, metabolic acidosis with increased anion gap, neutropenia, thrombocytopenia, hyperammonemia.

Examples & General Treatment:

Propionic Acidemia: Episodes of metabolic decompensation after protein intake or illness.

Treatment: Low-protein diet, biotin, carnitine, antibiotics (reduce gut flora), glucose for catabolism suppression.

Methylmalonic Acidemia: Similar to propionic acidemia, may be responsive to B12.

Treatment: Hydroxocobalamin, dietary restriction, carnitine, dialysis during crises.

Isovaleric Acidemia: Acute encephalopathy, "sweaty feet" odor.

Treatment: Glycine and carnitine supplementation, leucine restriction.

Glutaric Acidemia Type I: Macrocephaly, dystonia, subdural hemorrhage mimicking abuse.

Treatment: Protein restriction, carnitine, emergency treatment during illness.

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Fatty Acid Oxidation Disorders (FAODs)

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Fatty Acid Oxidation Disorders (FAODs)

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Definition: Defects in mitochondrial beta-oxidation of fatty acids.

Clinical presentation: Hypoketotic hypoglycemia, sudden death, hepatomegaly, cardiomyopathy.

Examples & General Treatment:

MCAD Deficiency: Presents with lethargy and seizures during fasting or illness.

Treatment: Avoid fasting, emergency glucose, carnitine.

VLCAD/LCHAD Deficiencies: Cardiomyopathy, rhabdomyolysis, liver dysfunction.

Treatment: High-carbohydrate diet, MCT oil, avoid fasting.

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Definition: Deficiencies in enzymes of the urea cycle leading to ammonia accumulation.

Clinical presentation: Lethargy, vomiting, coma, respiratory alkalosis, seizures in the neonatal period.

Examples & General Treatment:

OTC Deficiency: X-linked, high orotic acid in urine, male neonates severely affected.

CPS1 Deficiency: No orotic acid, severe hyperammonemia.

Citrullinemia: Elevated citrulline levels.

Argininosuccinic Aciduria: Developmental delay, hepatomegaly.

Argininemia: Progressive spasticity.

General Treatment: Low-protein diet, nitrogen-scavenging drugs (sodium benzoate, phenylbutyrate), arginine supplementation, hemodialysis for acute crises.

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Definition: Enzyme deficiencies affecting metabolism of sugars or glycogen.

Clinical presentation:

Galactosemia: Jaundice, hepatomegaly, E. coli sepsis, cataracts.

Treatment: Lifelong lactose/galactose restriction.

Hereditary Fructose Intolerance: Vomiting, hypoglycemia after fructose ingestion.

Treatment: Avoidance of fructose, sucrose, sorbitol.

Glycogen Storage Diseases:

Type I (Von Gierke): Hypoglycemia, lactic acidosis, doll-like face.

Treatment: Frequent cornstarch feeds, GNG support.

Type II (Pompe): Cardiomegaly, muscle weakness.

Treatment: Enzyme replacement therapy.

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History Taking

Focus Areas:

Previous metabolic decompensations

Known family history of IEM or similar symptoms

Triggers of previous illness or hospitalizations

Detailed perinatal and maternal history:

Decreased fetal movement (e.g., GSD IV, Zellweger)

Abnormal serum markers (e.g., low estriol in Smith-Lemli-Opitz)

HELLP/AFLP syndromes (linked to FAODs)

Nonimmune hydrops fetalis (seen in several IEM)

Common Symptom Triggers: Trigger

Infection, fasting, illness:

FAODs, urea cycle defects, organic acidemias

Protein ingestion:

UCDs, organic acidemias, amino acidopathies

Carbohydrate ingestion:

Galactosemia, hereditary fructose intolerance

Complementary foods:

MSUD, carbohydrate disorders

Drugs:

Porphyria, G6PD deficiency

Anesthesia/surgery

Homocystinuria (thromboembolic events)

Symptoms: Possible IEM

-Lethargy after feeding or fasting: FAODs, urea cycle defects

-Recurrent vomiting: Organic acidemias, MSUD

-Developmental delay/regression: PKU, lysosomal storage disorders

-Morning lethargy: GSDs, gluconeogenesis disorders

-Abdominal pain: Fabry, porphyrias

Photophobia, Cystinosis, tyrosinemia type II

-Muscle cramps after exercise: FAODs, GSDs, MAD deficiency

-Poor feeding/growth: Mitochondrial, urea cycle, amino acidopathies

-Protein or sugar aversion: PKU, galactosemia, fructose intolerance

Family History

Gather a three-generation pedigree, looking for:

Consanguinity (many IEM are autosomal recessive)

Recurrent unexplained infant deaths

Neurologic, liver, or cardiac disease

Males with early death (X-linked IEMs like OTC, Hunter syndrome)

Mitochondrial patterns (maternal inheritance, e.g., MELAS, NARP)

While newborn screening is valuable, clinical suspicion is important for IEM diagnosis: detailed history, awareness of symptom triggers, referral to specialists.

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IEMs are inherited disorders of metabolism causing toxic accumulation or energy failure.

They present acutely in neonates or chronically in older children with varied symptoms.

Early recognition, lab analysis, and specialized metabolic testing are essential.

Treatments are often lifelong and include dietary modifications, cofactor supplementation, ammonia detoxification, enzyme replacement, or organ transplant.

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Newborn Reflexes Assessment (Infant) Nursing Pediatric NCLEX Review

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IEMs should be considered in critically ill newborns or children with:

Seizures

Neurodegeneration

Developmental delay

Failure to thrive

Hypoglycemia

Acidosis

Liver disease

Cardiomyopathy

Reye-like syndrome

Unexplained symptoms, especially when linked to dietary changes, regression, or family history of consanguinity or unexplained deaths

Key Physical Signs:

Abnormal hair, eye changes (e.g., cherry-red spots), hepatosplenomegaly, coarse features, skeletal deformities, neurologic regression, unusual tone, microcephaly, rash, or signs mimicking trauma or poisoning