Disorders of Amino Acid Metabolism

Phenylketonuria (PKU) - Phenylalanine's Problem

• Autosomal recessive; Phenylalanine Hydroxylase (PAH) enzyme deficiency.
• Pathophysiology: Phenylalanine ($Phe$) accumulates; $Phe \rightarrow Tyrosine$ blocked; ↓Tyrosine.
• Clinical Features:
  • Severe intellectual disability (untreated)
  • Seizures, eczema
  • Mousy/musty odor (phenylacetic acid)
  • Hypopigmentation (fair hair/skin, blue eyes from ↓melanin)
• Diagnosis:
  • Newborn screening (NBS) via Tandem Mass Spectrometry.
  • ↑ Plasma $Phe$ >20 mg/dL (normal <2 mg/dL).
• Treatment:
  • Lifelong low-$Phe$ diet.
  • Tyrosine supplementation.
  • Sapropterin (BH4 cofactor) for responsive cases.
• 📌 Mnemonic: PKU = Pale, Psychomotor delay, Peculiar odor.

⭐ Maternal PKU syndrome can cause microcephaly, congenital heart defects, and intellectual disability in the fetus of an untreated mother whose phenylalanine levels are not controlled before and during pregnancy.

Maple Syrup Urine Disease (MSUD) - Branched-Chain Blues

• Defect: AR; deficient Branched-Chain α-Ketoacid Dehydrogenase (BCKDH).
• Accumulates: BCAAs (Leucine, Isoleucine, Valine) & their α-ketoacids. 📌 I L♥ve Vermont Maple Syrup (Ile, Leu, Val).
• Classic (Neonatal): Poor feeding, vomiting, lethargy, encephalopathy, seizures. Sweet "maple syrup" odor (urine, cerumen).
• Dx: ↑ Plasma BCAAs (esp. Leucine), alloisoleucine (key), ↑ urine ketoacids. Newborn screen.
• Rx: Lifelong BCAA restriction. Thiamine (B1) if responsive. Acute: IV fluids, glucose, insulin; dialysis. Liver transplant.

⭐ The characteristic sweet odor of urine in MSUD, often described as burnt sugar or maple syrup, is primarily due to the accumulation of sotolone, a metabolite of isoleucine.

Homocystinuria & Tyrosinemias - Sulphur & Aromatic Ails

• Homocystinuria (HCU): AR; CBS deficiency common.

  • Features: Marfanoid, intellectual disability, thromboembolism, osteoporosis.
  • Ocular: Lens dislocation (↓ & inwards).
  • Dx: ↑Homocysteine & methionine; +ve cyanide-nitroprusside.
  • Rx: Pyridoxine (B6), ↓methionine diet, betaine.

  ⭐ In classical Homocystinuria (cystathionine β-synthase deficiency), lens dislocation is typically downwards and inwards (inferonasal), a key differentiator from Marfan syndrome where it is upwards and outwards (superotemporal).

• Tyrosinemias: Defect in tyrosine degradation.

  • Type I (Hepatorenal): FAH deficiency.
    • Features: Liver failure, renal tubular acidosis, rickets, neuropathy, ↑AFP (HCC risk). Cabbage-like odor.
    • Dx: ↑Succinylacetone.
    • Rx: Nitisinone, diet (↓Phe, ↓Tyr).
  • Type II (Oculocutaneous): TAT deficiency.
    • Features: Painful palmoplantar hyperkeratosis, corneal plaques.
    • Dx: ↑Tyrosine.
    • Rx: Diet (↓Phe, ↓Tyr).

Alkaptonuria & Urea Cycle Overview - Dark Pigments, Ammonia Alerts

• Alkaptonuria (Ochronosis)

  • AR; Defect: Homogentisate 1,2-dioxygenase.
  • Patho: ↑ HGA (Homogentisic acid) → ochronotic pigment.
  • Clinical: Dark urine, ochronosis (sclera, cartilage), adult arthritis.
  • Rx: Nitisinone, low protein.

  ⭐ Alkaptonuria, caused by homogentisate 1,2-dioxygenase deficiency, leads to ochronosis (bluish-black discoloration of connective tissue) and dark urine upon standing/alkalinization, but typically presents with arthritis in adulthood rather than severe infantile symptoms.

• Urea Cycle Overview

  • Function: Liver detoxifies $NH_3$ (toxic) to urea.
  • Defects (UCDs): Hyperammonemia → neurotoxicity.
    • Symptoms: Vomiting, lethargy, seizures, coma.
  • 📌 Mnemonic (Intermediates): "Ordinarily, Careless Crappers Are Also Frivolous About Urination".

High‑Yield Points - ⚡ Biggest Takeaways

• PKU: Phenylalanine hydroxylase defect; mousy odor, intellectual disability. Guthrie test for screening.
• MSUD: Branched-chain α-ketoacid dehydrogenase defect; maple syrup urine odor, neurotoxicity.
• Alkaptonuria: Homogentisate oxidase defect; dark urine, ochronosis, arthritis.
• Homocystinuria: Cystathionine β-synthase defect; Marfanoid, downward lens dislocation, thrombosis.
• Tyrosinemia Type I: Fumarylacetoacetate hydrolase defect; liver failure, cabbage odor, ↑succinylacetone.
• OTC Deficiency: Most common Urea Cycle Defect; X-linked, hyperammonemia.