Metabolic disorders overview

Intro & Classification - Metabolic Mayhem Map

• Inherited Metabolic Disorders (IEMs): Genetically determined biochemical pathway defects, often due to a single enzyme deficiency.
• Presentation varies: acute neonatal crisis, chronic progressive damage, or intermittent symptoms triggered by stressors (e.g., illness, fasting).

⭐ Most IEMs present in neonates after a symptom-free interval, often triggered by protein feeding (aminoacidopathies) or fasting (fatty acid oxidation defects).

Carbohydrate Disorders - Sweet Sicknesses

• Galactosemia (Classic):

  • Deficiency: Galactose-1-phosphate uridyltransferase (GALT).
  • Presentation: Jaundice, hepatomegaly, infantile cataracts, intellectual disability.
  • Triggers: Breast milk, standard infant formula.
  • Lab: ↑ blood galactose, ↑ urine galactitol.
  • 📌 Mnemonic: FAB GUT - Fructose is to Aldolase B as Galactose is to UridylTransferase.

• Hereditary Fructose Intolerance:

  • Deficiency: Aldolase B.
  • Presentation: Hypoglycemia, jaundice, vomiting after consuming fructose or sucrose.
  • Triggers: Fruit, honey, juice.

⭐ Neonatal sepsis with E. coli is a classic presentation of galactosemia.

• Glycogen Storage Diseases (GSDs):
  • Group of disorders affecting glycogen synthesis or breakdown.
  • Example: Von Gierke disease (Type I) → severe fasting hypoglycemia.

Amino Acidopathies - Protein Processing Pains

• General: Inherited defects in amino acid metabolism leading to accumulation of toxic substrates or intermediates. Most are autosomal recessive.

• Phenylketonuria (PKU):

  • Deficiency: Phenylalanine hydroxylase ($PAH$).
  • Features: Musty/mousy body odor, intellectual disability, fair skin.
  • Screen: Newborn screening mandatory in US.

• Maple Syrup Urine Disease (MSUD):

  • Deficiency: Branched-chain α-ketoacid dehydrogenase ($BCKDH$).
  • Features: Sweet-smelling urine, neurotoxicity, poor feeding.

• Alkaptonuria (Ochronosis):

  • Deficiency: Homogentisate oxidase.
  • Features: Urine turns black on standing, dark cartilage/sclerae, arthralgias.

• Homocystinuria:

  • Deficiency: Cystathionine synthase (most common).
  • Features: Marfanoid habitus, ectopia lentis (downward), thrombosis.

⭐ Exam Favorite: Differentiate lens dislocation: Homocystinuria = down and inward vs. Marfan syndrome = up and outward.

Lysosomal & Lipid Storage - Cellular Clutter Crisis

• Pathophysiology: Deficient lysosomal enzymes → accumulation of undigested substrates → cellular dysfunction & organ damage.

⭐ Exam Favorite: Differentiate Tay-Sachs from Niemann-Pick by organomegaly. Both present with a "cherry-red" macula, but only Niemann-Pick causes significant hepatosplenomegaly.

Mitochondrial Myopathies - Powerhouse Problems

• Genetics: Maternal inheritance only (mtDNA).
• Pathognomonic finding: "Ragged red fibers" on muscle biopsy (Gomori trichrome stain) - represent aggregates of abnormal mitochondria.
• Presentation: Variable; often myopathy, lactic acidosis, and CNS dysfunction (encephalopathy, seizures, stroke-like episodes).

⭐ MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes) is a classic syndromic example.

High‑Yield Points - ⚡ Biggest Takeaways

• Most inherited metabolic disorders are autosomal recessive and result from enzyme deficiencies.
• Key X-linked exceptions include Fabry disease, Hunter syndrome, and G6PD deficiency.
• Presentation spans from acute neonatal crisis (vomiting, lethargy) to chronic, progressive symptoms.
• Critical lab findings often include hypoglycemia, hyperammonemia, and metabolic acidosis.
• Newborn screening is vital for early detection of conditions like PKU and galactosemia.
• Management often involves dietary restriction or enzyme replacement therapy.