Disorders of aromatic amino acids (PKU, alkaptonuria)

Aromatic Amino Acid Pathway - The Posh Phenylalanine Pipeline

Metabolism of Phenylalanine (Phe) to Tyrosine (Tyr). Defects cause inherited disorders.

• Phenylketonuria (PKU):

  • Defect: Phenylalanine hydroxylase (needs BH4 cofactor).
  • Labs: ↑ Phe, ↓ Tyr. Phenylketones in urine.
  • Features: Musty odor, intellectual disability, seizures, fair skin.
  • Rx: Low Phe diet, avoid aspartame.

• Alkaptonuria (Ochronosis):

  • Defect: Homogentisate oxidase.
  • Labs: ↑ Homogentisic acid.
  • Features: Dark urine, blue-black sclera/cartilage (ochronosis), arthritis.

⭐ Maternal PKU Syndrome: High maternal Phe is a teratogen, causing fetal microcephaly and cardiac defects, even if the fetus is genotypically normal.

Phenylketonuria (PKU) - Can't Process Phenylalanine

• Pathophysiology: Autosomal recessive deficiency of phenylalanine hydroxylase (PAH) or its cofactor tetrahydrobiopterin (BH4).

  • Blocks conversion: $Phenylalanine \rightarrow Tyrosine$.
  • Leads to ↑ phenylalanine and ↓ tyrosine (becomes essential).
  • Excess phenylalanine forms phenylketones, excreted in urine.

• Clinical Features:

  • Normal at birth, symptoms appear after a few months.
  • CNS: Severe intellectual disability, seizures, developmental delay, hyperactivity.
  • Physical: Fair skin, light hair, blue eyes (impaired melanin synthesis). Eczema.
  • Odor: A characteristic mousy or musty odor in urine and sweat.

• Diagnosis & Management:

  • Screening: Universal newborn screening (NBS) via tandem mass spectrometry.
  • Treatment: Lifelong dietary restriction of phenylalanine (avoid aspartame). Tyrosine supplementation is crucial.

⭐ Maternal PKU Syndrome: Elevated maternal phenylalanine is a teratogen, causing microcephaly, intellectual disability, and congenital heart defects in the fetus, regardless of the fetal genotype.

📌 P-K-U: Phenylalanine high, Kids with Unusual odor & fair skin.

Alkaptonuria - Black Urine Disease

• Pathophysiology: Autosomal recessive deficiency of homogentisate 1,2-dioxygenase (HGD), an enzyme in the degradative pathway of tyrosine and phenylalanine.
• Metabolic Defect: Blocks the conversion of homogentisic acid to maleylacetoacetic acid.
  • Leads to ↑ accumulation of homogentisic acid (HGA).
• Clinical Triad:
  • Homogentisic aciduria: Urine turns black when left standing or alkalinized due to HGA oxidation.
  • Ochronosis: Blue-black pigment deposition in connective tissues (e.g., sclerae, ear cartilage, tendons).
  • Ochronotic arthropathy: Debilitating arthritis, especially affecting the spine and large joints, presenting in adulthood.
• Diagnosis: Elevated HGA in urine.

⭐ High-Yield: The degenerative arthropathy in alkaptonuria can mimic seronegative spondyloarthropathies, with sacroiliac joint fusion and spinal calcification.

High-Yield Points - ⚡ Biggest Takeaways

• Phenylketonuria (PKU) stems from phenylalanine hydroxylase deficiency, leading to intellectual disability, seizures, and a musty body odor. Tyrosine becomes essential.
• Management is lifelong dietary restriction of phenylalanine; avoid aspartame.
• Maternal PKU can cause fetal microcephaly and congenital heart defects.
• Alkaptonuria is a defect in homogentisate oxidase, causing homogentisic acid to accumulate.
• It classically presents with dark urine, ochronosis (dark pigment), and debilitating arthritis.