Inborn Errors of Metabolism

IEM Overview & Screening - Tiny Troubles

• Definition: Inherited single-gene defects; enzyme/transporter dysfunction disrupts metabolic pathways.
• Classification (Broad):
  • Small molecule (aminoacidopathies, organic acidemias, UCDs, FAODs).
  • Large molecule (LSDs, mitochondrial disorders).
• Clinical Clues (Red Flags):
  • Neonatal: Poor feeding, vomiting, lethargy, seizures.
  • Biochemical: Hypoglycemia, metabolic acidosis (↑AG), hyperammonemia.
  • Organ: Hepatosplenomegaly, cardiomyopathy.
  • Sensory: Cataracts, corneal clouding.
  • Unusual odors (e.g., mousy - PKU).
• Newborn Screening (NBS):
  • Critical for early diagnosis & intervention.
  • Method: Tandem Mass Spectrometry (MS/MS) on dried blood spots.

⭐ Most Inborn Errors of Metabolism (IEMs) are autosomal recessive, though notable exceptions like Ornithine Transcarbamylase (OTC) deficiency (X-linked) and Fabry disease (X-linked) exist.

Carbohydrate Metabolism Disorders - Sugar Storms

• Glycogen Storage Diseases (GSDs):
  • Von Gierke (Type I): Glucose-6-phosphatase def. Severe fasting hypoglycemia, hepatomegaly, lactic acidosis, ↑uric acid.
  • Pompe (Type II): Lysosomal $\alpha$-1,4-glucosidase def. Cardiomegaly, muscle weakness. 📌 Pompe affects Pump (heart).
  • Cori (Type III): Debranching enzyme def. Milder Type I features, muscle involvement.
  • McArdle (Type V): Muscle glycogen phosphorylase def. Exercise intolerance, cramps, myoglobinuria.
• Galactosemia:
  • Classic (GALT def.): Galactose-1-phosphate uridyltransferase def. Jaundice, hepatomegaly, cataracts, E. coli sepsis. Avoid galactose/lactose.
  • GALK def.: Galactokinase def. Cataracts only.
• Hereditary Fructose Intolerance (HFI): Aldolase B def. Hypoglycemia, vomiting, jaundice on fructose/sucrose intake.

⭐ Von Gierke's Disease (GSD Type Ia), a defect in glucose-6-phosphatase, presents with severe fasting hypoglycemia, hepatomegaly, lactic acidosis, and hyperuricemia.

Amino Acid, Organic Acid & Urea Cycle Defects - Protein & Ammonia Perils

• AA Defects:
  • PKU: ↓PAH, ↑Phe. Mousy odor.
  • MSUD: ↓BCKDH, ↑BCAAs. Maple syrup urine.
  • Alkaptonuria: ↓HGD, ↑HGA. Dark urine, ochronosis.
  • Homocystinuria: ↓CBS. ↑HCY. Lens subluxation, thrombosis.
  • Tyrosinemia I: ↓FAH. Cabbage odor. Liver/kidney failure.
• OA Defects: Acidosis, hyperammonemia.
  • Methylmalonic Acidemia (MMA): ↓Methylmalonyl-CoA mutase.
  • Propionic Acidemia (PA): ↓Propionyl-CoA carboxylase.
• UCDs: Hyperammonemia, ↓BUN.
  • OTC Deficiency: X-linked. ↑Orotic acid.

⭐ Phenylketonuria (PKU) is caused by phenylalanine hydroxylase deficiency, leading to accumulation of phenylalanine; a mousy or musty odor of urine/sweat is characteristic if untreated.

Lysosomal & Peroxisomal Storage - Cellular Clutter

• Lysosomal Storage Disorders (LSDs): Defective lysosomal enzymes → substrate accumulation.
  • Tay-Sachs: Hexosaminidase A deficiency → GM2 ganglioside accumulation; cherry-red spot, neurodegeneration. 📌 Tay-SaX lacks heXosaminidase.
  • Niemann-Pick: Sphingomyelinase deficiency → sphingomyelin accumulation; hepatosplenomegaly, cherry-red spot (Type A).
  • Gaucher: Glucocerebrosidase deficiency → glucocerebroside; hepatosplenomegaly, pancytopenia, bone crises. "Crumpled tissue paper" macrophages.
  • Fabry: α-galactosidase A deficiency → globotriaosylceramide (Gb3); X-linked; angiokeratomas, renal failure, neuropathy.
  • Mucopolysaccharidoses (MPS): Defective degradation of glycosaminoglycans (GAGs).
    • Hurler (MPS I): α-L-iduronidase deficiency; coarse facies, corneal clouding.
    • Hunter (MPS II): Iduronate-2-sulfatase deficiency; X-linked; NO corneal clouding. 📌 Hunters see clearly (no corneal clouding) and aim for the X.

• Peroxisomal Disorders: Defective peroxisome biogenesis or enzyme function.
  • Zellweger Syndrome: PEX gene mutations → empty peroxisomes; craniofacial dysmorphism, hypotonia, seizures.
  • X-linked Adrenoleukodystrophy (X-ALD): ABCD1 gene defect → VLCFA accumulation; adrenal insufficiency, neurological decline.

⭐ Gaucher disease, the most common lysosomal storage disorder, is due to glucocerebrosidase deficiency, leading to accumulation of glucocerebroside in macrophages (Gaucher cells).

High‑Yield Points - ⚡ Biggest Takeaways

• Most IEMs are autosomal recessive; notable exceptions: Hunter's (XLR), OTC deficiency (XLR).
• PKU: Phenylalanine hydroxylase deficiency; mousy odor, CNS effects; dietary restriction is key.
• Alkaptonuria: Homogentisate oxidase deficiency; dark urine on standing, ochronosis (dark cartilage).
• MSUD: Branched-chain ketoacid dehydrogenase deficiency; sweet/burnt sugar urine odor, neurotoxicity.
• Galactosemia (Classic): GALT deficiency; neonatal jaundice, cataracts, risk of E. coli sepsis.
• Von Gierke's (GSD I): Glucose-6-phosphatase deficiency; severe fasting hypoglycemia, hepatomegaly, lactic acidosis.