Harvey's Garden

Modes of inheritance

5 min read

Mnemonic

Tip

When you see a disease name:

  1. Is it Mitochondrial? (Ragged red fibers, maternal only).
  2. Is it on the X-Linked Mnemonic list? (Fabry, Hunter, Hemophilia, G6PD, etc.).
  3. Is it Structural? Guess AD.
  4. Is it Metabolic/Enzyme? Guess AR.
  5. Is it a Neurocutaneous syndrome or MEN? AD.

1. The “Structural vs. Metabolic” Rule (The Golden Rule)

This is the single most important concept to reduce your memory load.

  • Structural Defects are usually Autosomal Dominant (AD).
    • Logic: If you are building a wall (structure) and half the bricks are crumbling, the wall falls. One bad copy ruins the structure.
    • Examples: Marfan (fibrillin), Ehlers-Danlos (collagen), Osteogenesis Imperfecta (collagen), Hereditary Spherocytosis (spectrin/cytoskeleton), Achondroplasia (bone cartilage).
  • Enzyme/Metabolic Defects are usually Autosomal Recessive (AR).
    • Logic: Enzymes are workers. If you have 50% of your workers (heterozygote), the factory usually still runs fine. You need to lose 100% of workers (homozygote recessive) to get sick.
    • Examples: PKU, Cystic Fibrosis, Tay-Sachs, Glycogen Storage Diseases, Mucopolysaccharidoses (except Hunter).

2. Master the X-Linked Recessive List

Since you can’t memorize all AR or AD diseases, memorize the X-Linked Recessive (XR) list perfectly. If a disease is on the exam and it’s not on your XR list and not Mitochondrial, it is likely Autosomal.

Mnemonic: “Oblivious Female Will Often Give Her Boys Her x-Linked Disorders”

  • Ornithine transcarbamylase deficiency (The only XR Urea Cycle defect)
  • Fabry disease (The only XR Lysosomal Storage disease)
  • Wiskott-Aldrich
  • Ocular albinism
  • G6PD deficiency
  • Hunter Syndrome (Mucopolysaccharidosis II—The Hunter sees the X target)
  • Bruton agammaglobulinemia
  • Hemophilia A & B
  • Lesch-Nyhan
  • Duchenne (and Becker) Muscular Dystrophy

3. The “MEN” are Dominant

All Multiple Endocrine Neoplasia syndromes are Autosomal Dominant.

  • MEN 1, MEN 2A, MEN 2B.
  • Memory Hook: “The MEN are Dominant” (A simple, slightly outdated social heuristic, but it sticks).

4. Neurocutaneous Disorders are Dominant

Almost all the major neurocutaneous disorders (“Phakomatoses”) are Autosomal Dominant.

  • Neurofibromatosis type 1 & 2
  • Tuberous Sclerosis
  • Von Hippel-Lindau
  • Exception: Sturge-Weber (Somatic mosaicism, not inherited).

5. The “Tricky” Exceptions (High-Yield Traps)

The USMLE loves to test exceptions to the rules above. Memorize these specifically:

  1. Familial Hypercholesterolemia (Type IIA): It involves a receptor (LDL receptor), but it is Autosomal Dominant. (Think: The receptor is a structural part of the cell membrane).
  2. Adult Polycystic Kidney Disease (ADPKD): The name says “Adult,” and adults are big/dominant. Infantile PKD is Recessive.
  3. Acute Intermittent Porphyria: Metabolic (heme synthesis), but Autosomal Dominant. (Most other porphyrias are dominant too, except Congenital Erythropoietic Porphyria).
  4. Essential Tremor: Autosomal Dominant.
  5. Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu): Structural blood vessel issue Autosomal Dominant.

6. Mitochondrial = Maternal

If the vignette describes a mother passing it to all her kids, but her son passes it to none, it is Mitochondrial.

  • Buzzwords: “Ragged Red Fibers,” “Lactic Acidosis.”
  • Diseases: MELAS, MERRF, Leber Hereditary Optic Neuropathy.

Autosomal Dominant (AD)

  • Inheritance Pattern
    • Affected individuals in every generation (vertical transmission)
  • Key Features
    • Often structural proteins, receptors, or transcription factors
    • Variable expressivity (severity varies among affected individuals)
    • Incomplete penetrance (not all with mutation show disease)
    • New mutations common (especially if reduced reproductive fitness)
  • Classic Examples
    • Familial hypercholesterolemia (LDL receptor defect)
    • Huntington disease (CAG repeat expansion, chromosome 4)
    • Marfan syndrome (fibrillin-1 defect)
    • Neurofibromatosis type 1 (NF1 gene)
    • Achondroplasia (FGFR3 mutation)
    • ADPKD (PKD1/PKD2)
    • Hereditary spherocytosis (spectrin/ankyrin defects)

Autosomal Recessive (AR)

  • Inheritance Pattern
    • Skips generations (horizontal transmission)
  • Key Features
    • Often enzyme deficiencies
    • Carriers asymptomatic (heterozygotes)
    • More common in isolated populations
  • Classic Examples
    • Cystic fibrosis (CFTR, ΔF508 most common)
    • Sickle cell disease (β-globin mutation)
    • Thalassemias (α or β-globin defects)
    • Phenylketonuria (phenylalanine hydroxylase deficiency)
    • Albinism (tyrosinase deficiency)
    • Glycogen storage diseases (most types)
    • Lysosomal storage diseases (Tay-Sachs, Gaucher, Niemann-Pick)
    • Hemochromatosis (HFE gene, C282Y mutation)

X-Linked Recessive (XLR)

  • Inheritance Pattern
    • Affects mostly males
    • Transmitted through carrier females
    • No male-to-male transmission
    • Affected males have unaffected parents
    • 50% of male offspring of carrier females affected
  • Key Features
    • Males hemizygous (only one X chromosome)
    • Females usually carriers (lyonization may cause mild symptoms)
  • Classic Examples
    • Duchenne/Becker muscular dystrophy (dystrophin gene)
    • Hemophilia A (Factor VIII deficiency)
    • Hemophilia B (Factor IX deficiency)
    • G6PD deficiency
    • Fabry disease (α-galactosidase A deficiency)
    • Hunter syndrome (iduronate sulfatase deficiency)
    • Lesch-Nyhan syndrome (HGPRT deficiency)
    • Bruton agammaglobulinemia (BTK gene)
    • Wiskott-Aldrich syndrome (WAS gene)

X-Linked Dominant (XLD)

  • Inheritance Pattern
    • Affects both sexes, but females > males
    • No male-to-male transmission
    • Affected males have all affected daughters
    • Often lethal in males (in utero)
  • Classic Examples
    • Fragile X syndrome (CGG repeat expansion in FMR1)
    • Vitamin D-resistant rickets (hypophosphatemic rickets)
    • Rett syndrome (MECP2 mutation, lethal in males)
    • Incontinentia pigmenti (NEMO gene, lethal in males)

Mitochondrial Inheritance

  • Inheritance Pattern
    • Maternal inheritance only (mitochondria from oocyte)
    • Affects both sexes equally
    • All offspring of affected mother may be affected
    • Affected fathers do NOT pass to offspring
  • Key Features
    • Heteroplasmy (variable % of mutant mitochondria in cells)
    • Affects high-energy tissues (muscle, brain, heart)
    • Variable expressivity due to heteroplasmy
  • Classic Examples
    • Leber hereditary optic neuropathy (acute vision loss in young males)
    • MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, Stroke-like episodes)
    • MERRF (Myoclonic Epilepsy with Ragged Red Fibers)
    • Kearns-Sayre syndrome (ophthalmoplegia, retinopathy, cardiomyopathy)

Graph View