Single Gene Disorders

Inheritance Patterns - Gene Game Rules

• Autosomal Dominant (AD):
  • One mutant allele. Vertical transmission.
  • Male-to-male transmission.
  • Risk: 50% (one affected parent).
• Autosomal Recessive (AR):
  • Two mutant alleles. Horizontal transmission (skips generations).
  • Consanguinity ↑ risk.
  • Risk: 25% (both parents carriers).
• X-linked Recessive (XR):
  • Males > females. No male-to-male.
  • Affected father → all daughters carriers.
  • Carrier mother → 50% sons affected.
• X-linked Dominant (XD):
  • No male-to-male.
  • Affected father → ALL daughters affected, NO sons.
  • Affected mother (hetero) → 50% offspring affected.
• Mitochondrial:
  • Maternal inheritance ONLY.
  • Affected mother → ALL offspring affected.
  • Affected father → NO offspring.

⭐ Penetrance: % of individuals with genotype expressing phenotype. Expressivity: Variation in phenotypic severity for a given genotype.

Amino Acidopathies - Protein Problems

• Inherited enzyme defects in amino acid (AA) metabolism, leading to AA or toxic byproduct accumulation.
• Phenylketonuria (PKU):
  • Defect: Phenylalanine hydroxylase (PAH).
  • Features: Mousy/musty odor, intellectual disability (ID), eczema, fair skin/hair.
  • Screening: Guthrie test (↑Phe).
• Alkaptonuria (Ochronosis):
  • Defect: Homogentisate oxidase.
  • Features: Dark urine on standing, ochronotic pigment (cartilage, sclera), arthritis.
• Maple Syrup Urine Disease (MSUD):
  • Defect: Branched-chain α-ketoacid dehydrogenase complex.
  • Features: Maple syrup/burnt sugar odor (urine, sweat), neurotoxicity, poor feeding.
  • 📌 "I Love Vermont" (Isoleucine, Leucine, Valine affected).
• Homocystinuria:
  • Defect: Cystathionine β-synthase (commonest).
  • Features: Marfanoid habitus, ectopia lentis (downward & inward), thromboembolism, ID.
• Tyrosinemia Type I:
  • Defect: Fumarylacetoacetate hydrolase.
  • Features: Cabbage-like odor, liver failure, renal tubular acidosis (Fanconi syndrome).

⭐ PKU: Autosomal recessive. Early dietary phenylalanine restriction is key to prevent irreversible intellectual disability. Maternal PKU requires strict control before/during pregnancy to prevent fetal damage (microcephaly, ID).

Carbohydrate Metabolism Disorders - Sweet Sicknesses

• Galactosemia (Classic): GALT def. → ↑Gal-1-P, galactitol.
  • Neonatal jaundice, hepatomegaly, cataracts, E. coli sepsis. Urine: reducing substances.
  • Tx: Galactose-free diet.
• Hereditary Fructose Intolerance (HFI): Aldolase B def. → ↑Fructose-1-P.
  • Hypoglycemia, vomiting, jaundice post fructose/sucrose. Aversion to sweets.
  • Tx: Avoid fructose, sucrose, sorbitol.
• Essential Fructosuria: Fructokinase def. Benign. Fructosuria.
• Glycogen Storage Diseases (GSDs):
  • Type I (Von Gierke): Glucose-6-Phosphatase def. Severe fasting hypoglycemia, ↑lactate, hepatomegaly.
  • Type II (Pompe): Lysosomal α-1,4-glucosidase (Acid Maltase) def. Cardiomegaly, muscle weakness. 📌 Pompe Pumps (Heart).
  • Type V (McArdle): Muscle Glycogen Phosphorylase def. Exercise intolerance, cramps, myoglobinuria.

⭐ Classic galactosemia presents with failure to thrive, liver damage, and cataracts if milk feeding is continued; E. coli sepsis is a common neonatal complication.

Lysosomal Storage & Porphyrias - Cellular Clutter

Error generating content for this concept group: No object generated: the tool was not called.

High‑Yield Points - ⚡ Biggest Takeaways

• Autosomal dominant (AD): Vertical transmission, 50% risk to offspring; e.g., Marfan syndrome, Huntington disease.
• Autosomal recessive (AR): Horizontal transmission, 25% risk, often enzyme deficiencies; e.g., Cystic fibrosis, PKU.
• X-linked recessive (XLR): Affects mainly males, carrier females, no male-to-male transmission; e.g., DMD, Hemophilia A.
• X-linked dominant (XLD): Affected fathers transmit to all daughters; e.g., Rett syndrome, Alport syndrome (classic XLD form).
• Mitochondrial inheritance: Maternal transmission to all offspring; e.g., LHON, MELAS.
• Variable expressivity and incomplete penetrance modify Mendelian patterns.
• New mutations are common in severe AD disorders like Achondroplasia or Osteogenesis Imperfecta type II.