Inborn Errors of Amino Acid Metabolism

Overview - Metabolic Mayhem Kickoff

• Inborn Errors of Metabolism (IEMs): Congenital metabolic disorders caused by single gene defects leading to enzyme deficiencies and pathway blocks.
• Inheritance: Primarily Autosomal Recessive (AR).

  ⭐ Most inborn errors of amino acid metabolism are autosomal recessive. A key exception is Ornithine Transcarbamylase (OTC) deficiency, which is X-linked.

• Newborn Screening (NBS): Crucial for early detection, enabling prompt treatment to prevent severe, irreversible damage and improve outcomes significantly.

Aromatic AAs - Fragrant Foul-ups

$Phenylalanine \xrightarrow{Phenylalanine\ hydroxylase, BH_4} Tyrosine$

BCAA Disorders - Sweet Urine Woes

• Maple Syrup Urine Disease (MSUD)
  • Enzyme defect: Branched-chain α-ketoacid dehydrogenase (BCKDH) complex.
  • Accumulates: BCAAs (Leucine, Isoleucine, Valine) & their α-ketoacids.
  • 📌 Mnemonic: I Love Vermont (maple syrup) for Isoleucine, Leucine, Valine.
  • Features: Maple syrup/burnt sugar odor (urine, cerumen), neurotoxicity (lethargy, irritability, seizures, coma), poor feeding.
  • 

  • ⭐ Leucine is considered the most neurotoxic of the branched-chain amino acids in MSUD.

Sulfur AA Slip-ups - Homocysteine Havoc

• Homocystinuria (Classical Type):
  • Defective Enzyme: Cystathionine β-synthase (CBS) ↓.
  • Cofactor: Pyridoxal phosphate (Vitamin B6).
  • Accumulated: ↑ Homocysteine, ↑ Methionine.
  • Reaction: $Homocysteine + Serine \xrightarrow{CBS, B6} Cystathionine$.
  • Key Clinical Features: Marfanoid habitus, ectopia lentis (downward & inward), intellectual disability, thromboembolism, osteoporosis. Note B6 responsiveness.
  • 📌 Mnemonic HOMOCY: Homocysteine ↑, Osteoporosis/ Ocular (↓ lens), Marfanoid habitus, Cardiovascular (thromboembolism), kYphosis/ Intellectual disability.

⭐ Unlike Marfan syndrome, lens dislocation in homocystinuria is typically downward and inward (inferonasal).

Urea Cycle - Ammonia Alert!

• Function: Detoxifies ammonia ($NH_3$) from amino acid catabolism into urea for renal excretion.
• Hyperammonemia S/S: Vomiting, lethargy, seizures, coma, cerebral edema. Initial respiratory alkalosis.
• Ornithine Transcarbamylase (OTC) Deficiency: X-linked recessive. ↑ urinary orotic acid.

  ⭐ OTC deficiency is the most common urea cycle disorder; X-linked, presents with hyperammonemia & ↑ urinary orotic acid. 📌 Urea Cycle: Orange Colored Cats Always Ask For Awesome Umbrellas.

Transport Defects - AA Airlift Issues

High‑Yield Points - ⚡ Biggest Takeaways

• PKU: Phenylalanine hydroxylase deficiency; mousy/musty odor, intellectual disability, eczema, fair skin.
• Alkaptonuria: Homogentisate oxidase deficiency; black urine on standing, ochronosis (cartilage, sclera), arthritis.
• MSUD: BCKDC deficiency (branched-chain); maple syrup urine odor, neurotoxicity, poor feeding.
• Homocystinuria (CBS def.): Downward ectopia lentis, thromboembolism, osteoporosis, marfanoid habitus.
• Tyrosinemia Type I: Fumarylacetoacetate hydrolase deficiency; cabbage-like odor, severe liver failure, ↑ AFP.
• Cystinuria: Defective renal COLA transporter (Cystine, Ornithine, Lysine, Arginine); recurrent hexagonal cystine stones.