Inborn Errors of Metabolism

IEM Overview - Metabolic Mayhem

• Genetic defects disrupting metabolic pathways, primarily enzyme deficiencies or transport protein defects.
• Presentation varies: acute neonatal crisis (vomiting, lethargy, coma) to chronic, subtle forms (developmental delay, FTT).
• Key red flags: sepsis-like picture with negative cultures, unexplained metabolic acidosis, hypoglycemia, hyperammonemia, or ketosis.
• Broad categories:
  • Small molecule disorders (intoxication type): aminoacidopathies (e.g., PKU), organic acidemias, urea cycle defects.
  • Energy metabolism defects: fatty acid oxidation disorders (FAODs), mitochondrial disorders.
  • Complex molecule disorders (storage): lysosomal storage diseases (LSDs), peroxisomal disorders.

⭐ Most inborn errors of metabolism follow an autosomal recessive inheritance pattern, though X-linked and mitochondrial inheritance also occur (e.g., OTC deficiency is X-linked).

Red Flags & Dx - Spotting the Signs

• Red Flags:

  • Neonate: Sepsis-like, poor feed, lethargy, vomiting.
  • Neuro: Seizures, abnormal tone, developmental delay/regression.
  • Unusual Odors: 📌 Mousy (PKU), maple syrup (MSUD), sweaty feet (IVA).
  • Triggers: Fasting, protein intake.
  • Family Hx: Consanguinity, unexplained neonatal deaths.
  • Systemic: Hepatomegaly, FTT, cardiomyopathy.

• Diagnostic Approach:

⭐ Any neonate with unexplained encephalopathy, sepsis-like illness, or severe metabolic acidosis warrants urgent IEM investigation.

Key IEMs Part 1 - Sugar & Protein Problems

• Carbohydrate Metabolism Disorders:
  • Galactosemia (Classic): GALT def; Jaundice, hepatomegaly, cataracts, E. coli sepsis. Dx: ↑ Gal-1-P (RBCs), urine reducing substances. Tx: Galactose-free diet.
  • Hereditary Fructose Intolerance (HFI): Aldolase B def; Hypoglycemia, vomiting, hepatomegaly after fructose/sucrose. Tx: Fructose/sucrose-free diet.
  • Von Gierke (GSD Type I): Glucose-6-phosphatase def; Severe hypoglycemia, lactic acidosis, hepatomegaly, hyperuricemia.
• Amino Acid Metabolism Disorders:
  • Phenylketonuria (PKU): PAH def; ID, seizures, eczema, musty odor. Dx: ↑ Phe (newborn screen). Tx: Low Phe diet, Tyr supplement.

    ⭐ Untreated maternal PKU: fetal microcephaly, ID, congenital heart defects.

  • Maple Syrup Urine Disease (MSUD): BCKAD def; Maple syrup odor (urine/cerumen), encephalopathy. Dx: ↑ BCAAs (Leu, Ile, Val). Tx: BCAA restriction. 📌 I Love Vermont.
  • Homocystinuria (Classic): CBS def; Marfanoid, ectopia lentis (↓), ID, thrombosis. Tx: B6, Met-restricted diet, Cys supplement. oka

Key IEMs Part 2 - Storage & Waste Woes

• Lysosomal Storage Disorders (LSDs)

  • Enzyme defect → lysosomal substrate accumulation.
  • Gaucher: Glucocerebrosidase ↓; hepatosplenomegaly, bone pain; "crumpled tissue paper" cells.
  • Tay-Sachs: Hexosaminidase A ↓; cherry-red spot, neurodegeneration; onion-skin lysosomes.
  • Niemann-Pick: Sphingomyelinase ↓; cherry-red spot, foam cells.
  • Fabry (XLR): α-galactosidase A ↓; angiokeratomas, neuropathic pain.
  • MPS: Hurler (corneal clouding), Hunter (XLR, no clouding, aggressive). 📌 Hunter Xpects no Clouds.

• Urea Cycle Defects (UCDs)

  • Urea synthesis defect → ↑ NH₃ (hyperammonemia).
  • Neonatal encephalopathy, vomiting, lethargy.
  • OTC deficiency: Most common, X-linked.
  • Labs: ↑ NH₃, respiratory alkalosis.

• Organic Acidemias (OAs)

  • Amino acid/fatty acid metabolism defect → organic acid accumulation.
  • Neonatal ketoacidosis, encephalopathy, distinct urine odors.
  • MSUD: Branched-chain α-ketoacid DH ↓; sweet urine.
  • Labs: ↑ Anion gap metabolic acidosis, ketosis.

⭐ Ornithine Transcarbamylase (OTC) deficiency is the most common urea cycle disorder and is X-linked recessive, presenting with hyperammonemia and respiratory alkalosis without metabolic acidosis initially.

High‑Yield Points - ⚡ Biggest Takeaways

• Most IEMs are autosomal recessive; X-linked examples: Hunter's, Lesch-Nyhan.
• Newborn screening is crucial for PKU, galactosemia, congenital hypothyroidism.
• Suspect IEMs with neonatal distress, seizures, developmental delay, or unusual body/urine odors.
• PKU: mousy odor, requires phenylalanine restriction to prevent intellectual disability.
• Galactosemia: cataracts, hepatomegaly, E. coli sepsis risk; manage with galactose-free diet.
• MSUD: sweet urine odor, neurotoxicity due to impaired branched-chain amino acid metabolism.