Inborn Errors

Inborn Errors of Metabolism

Inborn errors of metabolism (IEM) are genetic disorders caused by enzyme deficiencies that disrupt specific metabolic pathways. Most are autosomal recessive. They typically manifest in infancy. Enzyme deficiency → substrate accumulates (toxic) and product is deficient.

General Principles

  • Substrate accumulation → often toxic to brain and liver
  • Deficient product → may need supplementation
  • Alternative pathways often produce abnormal metabolites (diagnostic)
  • Newborn screening (Guthrie test, tandem mass spectrometry) enables early detection

Amino Acid Disorders

  • PKU: Phenylalanine Hydroxylase ± BH4 deficiency. ↑Phe → phenylketones. Fair skin/hair/eyes, mousy odor, severe intellectual disability. Detect by: Guthrie test (bacterial inhibition assay). Treat: Low-Phe diet, BH4 (sapropterin for BH4-responsive PKU), avoid aspartame.
  • MSUD: Branched-chain α-keto acid dehydrogenase (BCKAD) deficiency. ↑Leu, Ile, Val + their keto acids. Maple syrup odor in urine, severe neurological damage. Treat: BCAA-restricted diet, thiamine (B1) in some.
  • Homocystinuria: CBS deficiency (most common), MTHFR deficiency, or cobalamin metabolism defects. ↑Homocysteine → ↓cross-links → lens dislocation (downward), Marfanoid habitus, DVT, intellectual disability. Treat: B6 (CBS responsive), methionine-free diet, betaine, B12, folate.
  • Alkaptonuria: Homogentisate 1,2-dioxygenase deficiency. Homogentisic acid accumulates → dark urine on oxidation, ochronosis (pigment in connective tissue), arthritis in adults. Benign in childhood.

Carbohydrate Disorders

  • Galactosemia (Classic): GALT deficiency. Galactose-1-P accumulates after breast milk feeding → liver jaundice/cirrhosis, cataracts, E. coli sepsis (galactose impairs immune function), intellectual disability. Treat: Eliminate galactose/lactose.
  • HFI (Hereditary Fructose Intolerance): Aldolase B deficiency. Fructose-1-P accumulates → inhibits glycogen phosphorylase + PDC → hypoglycemia + liver damage. Treat: Avoid fructose, sucrose, sorbitol.
  • Glycogen Storage Diseases: (See Glycogen metabolism topic)

Lysosomal Storage Diseases

  • Gaucher's, Niemann-Pick, Tay-Sachs, Fabry's, Krabbe's, Hurler's (MPS I, α-Iduronidase), Hunter's (MPS II, Iduronate sulfatase, X-linked, no corneal clouding)
  • All accumulate undegraded substrate in lysosomes → organomegaly (usually), neurological manifestations
  • Treatment: Enzyme Replacement Therapy (Gaucher's — imiglucerase), Substrate reduction therapy, Bone marrow transplant

Urea Cycle Disorders

  • OTC (Ornithine Transcarbamylase) deficiency: Most common; X-linked (only X-linked urea cycle disorder); hyperammonemia, orotic acid in urine (excess carbamoyl-P diverted to pyrimidine synthesis)
  • CPS-I deficiency: AR; ↑NH₃, NO orotic aciduria
  • ASA (Argininosuccinic Aciduria): ASL deficiency; ↑citrulline + ASA
  • Argininosuccinase deficiency: Brittle hair (trichorrhexis nodosa)

Peroxisomal Disorders

  • Zellweger spectrum: Absent/abnormal peroxisomes → failure to oxidize VLCFA → brain malformation; severe
  • X-linked ALD: Defect in ABCD1 transporter → VLCFA accumulate in brain and adrenal