Phenylketonuria and Alkaptonuria

Phenylketonuria - Phenylalanine's Pesky Problem

• Definition: Autosomal recessive inborn error of metabolism causing impaired conversion of Phenylalanine to Tyrosine.
• Enzyme Defect: Phenylalanine hydroxylase (PAH).
  • Cofactor: Tetrahydrobiopterin (BH4).
• Affected Pathway: $Phenylalanine \rightarrow Tyrosine$ (block).
• Clinical Features:
  • Intellectual disability (if untreated).
  • Seizures.
  • Eczema.
  • Hypopigmentation (fair skin, hair, blue eyes).
  • Musty or mousy body/urine odor (due to phenylacetic acid).
  • 📌 PKU: Phenylalanine Kills Understanding (intellectual disability).
• Diagnosis:
  • Newborn screening: Guthrie test (historical), Tandem mass spectrometry (current standard).
  • Labs: ↑ Phenylalanine, ↓ Tyrosine in blood.
• Management:
  • Diet: Lifelong low Phenylalanine diet.
  • Supplementation: Tyrosine.
  • BH4 (Sapropterin) for BH4-responsive PKU.
  • Enzyme therapy: Pegvaliase (adults).
  • Target blood Phenylalanine: 120-360 µmol/L (or 2-6 mg/dL).

⭐ Maternal PKU syndrome: If maternal phenylalanine levels are not strictly controlled before and during pregnancy, it can lead to congenital heart defects, microcephaly, and intellectual disability in the offspring (even if the fetus is heterozygous for PKU).

Alkaptonuria - The Black Urine Blues

• Autosomal recessive disorder affecting the tyrosine degradation pathway.
• Enzyme Deficiency: Homogentisate 1,2-dioxygenase (HGD).
• Pathophysiology: Defective HGD blocks the conversion $Homogentisic sic ightarrow Maleylacetoacetic sic$, leading to accumulation of Homogentisic Acid (HGA).
• Clinical Features:
  • Homogentisic aciduria: Urine darkens to black upon standing or alkalinization.
  • Ochronosis: Bluish-black pigmentation in connective tissues (sclera, ear cartilage, joints) appearing in adulthood.
  • Ochronotic arthropathy: Debilitating arthritis, especially affecting spine and large joints; may lead to joint replacements.
  • Cardiovascular: Aortic/mitral valve calcification and stenosis possible.
• Diagnosis:
  • Urine turns black on exposure to air/alkali.
  • Detection of HGA in urine (e.g., via GC-MS).
• Management:
  • Mainly symptomatic: Analgesics (NSAIDs), physiotherapy, joint replacement for severe arthropathy.
  • Dietary restriction of phenylalanine and tyrosine: Limited clinical benefit.
  • Nitisinone: Inhibits 4-hydroxyphenylpyruvate dioxygenase, reducing HGA production (off-label use, shows promise).
• 📌 Mnemonic: Alkaptonuria: Black (urine, ochronosis), Aching (arthritis), Autosomal recessive.

⭐ Ochronosis, the characteristic pigmentation in Alkaptonuria, is due to the deposition of a melanin-like polymer derived from homogentisic acid in connective tissues.

PKU vs Alkaptonuria - Metabolic Misfits Compared

High‑Yield Points - ⚡ Biggest Takeaways

• Phenylketonuria (PKU): Caused by phenylalanine hydroxylase (PAH) deficiency; leads to intellectual disability, musty odor, hypopigmentation.
• PKU Diagnosis & Management: ↑ Phenylalanine, ↓ Tyrosine; Guthrie test; low phenylalanine diet.
• Alkaptonuria: Due to homogentisate oxidase deficiency; causes dark urine on standing, ochronosis, and arthritis.
• Both are autosomal recessive inborn errors of metabolism.
• Maternal PKU requires strict dietary control to prevent fetal complications.
• Tyrosine becomes an essential amino acid in PKU; BH4 (sapropterin) can be used in some PKU cases.