• 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)

• 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

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)

• 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)

• 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.

• 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.

• 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.

• 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.

• 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.

• 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

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.

• 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.