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Single-Gene (Mendelian) Genetic Disorders

Robbins & Kumar Basic Pathology — Complete MBBS Guide

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1. OVERVIEW & KEY CONCEPTS

• Pleiotropy: One mutation → multiple phenotypic effects (e.g., Marfan syndrome: skeleton + eyes + cardiovascular from a single FBN1 mutation)
• Genetic heterogeneity: Mutations at different loci → same phenotype (e.g., retinitis pigmentosa)
• Modifier genes: Other loci influence severity (important in cystic fibrosis)
• Prenatal screening in high-risk populations (e.g., Ashkenazi Jewish) has reduced incidence of disorders like Tay-Sachs

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2. PREVALENCE TABLE (Selected Disorders)

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3. TRANSMISSION PATTERNS

A. Autosomal Dominant (AD)

• Manifest in heterozygous state
• Both sexes affected and can transmit
• 50% offspring of an affected person are affected
• Key features:
  • New mutations possible → affected child with unaffected parents (siblings unaffected)
  • Reduced penetrance: carries mutant gene but phenotypically normal
  • Variable expressivity: same gene, different severity (e.g., neurofibromatosis 1 — from skin spots to multiple tumors)
  • Delayed onset: symptoms may not appear until adulthood (e.g., Huntington, adult-onset cancer genes)
• Genes involved are usually not enzymes but: regulatory/signaling proteins, structural proteins, receptors/transport proteins (because 50% loss of enzyme activity is compensable)

B. Autosomal Recessive (AR)

• Manifest in homozygous state
• Often involves enzyme deficiencies
• Parents are typically unaffected carriers
• 25% offspring of two carriers are affected
• Often more severe than dominant disorders
• Consanguinity increases risk

C. X-Linked Recessive

• Heterozygous female carriers transmit to sons (50% sons affected)
• Males are hemizygous → fully express the disorder
• Affected male does NOT transmit to sons; all daughters are carriers
• Females rarely express full phenotype (random X inactivation protects most cells)
• Examples: Duchenne muscular dystrophy, hemophilia A & B, G6PD deficiency

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4. DISEASES CAUSED BY MUTATIONS IN STRUCTURAL PROTEIN GENES

4A. Marfan Syndrome

• Inheritance: Autosomal dominant
• Gene: FBN1 at 15q21 (encodes fibrillin-1, an extracellular glycoprotein that is the major component of microfibrils)
• Prevalence: 1 in 5,000; 70–85% familial, rest sporadic de novo mutations
• Pathogenesis:
  • Microfibrils serve as scaffolds for tropoelastin (elastic fibers)
  • Mutant fibrillin acts as dominant negative → impairs microfibril assembly
  • Loss of microfibrils → excessive TGF-β activation (microfibrils normally sequester TGF-β) → vascular smooth muscle damage and ECM degradation
  • Mutations in TGF-β type II receptor → Marfan syndrome type 2 (MFS2)

4B. Ehlers-Danlos Syndromes (EDS)

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5. DISEASES CAUSED BY MUTATIONS IN RECEPTOR/CHANNEL GENES

5A. Familial Hypercholesterolemia (FH)

• Inheritance: Autosomal dominant
• Gene: Loss-of-function mutations in LDL receptor gene (80–85% of cases)
• Prevalence: Heterozygous 1 in 500 (most common Mendelian disorder); prevalence in cardiovascular disease is 20-fold higher

1. Liver secretes VLDL → lipolysis in capillaries → IDL → further metabolism → LDL
2. LDL receptor (binds Apo B-100 and Apo E) on hepatocytes (75% of receptors) mediates LDL uptake
3. Intracellular cholesterol causes: ↓ HMG-CoA reductase (↓ cholesterol synthesis), ↓ LDL receptor synthesis (feedback), ↑ ACAT (cholesterol esterification for storage)

• Receptor mutation → impaired LDL clearance → elevated plasma LDL
• Loss of feedback inhibition → unchecked cholesterol synthesis
• LDL accumulates in macrophages → foam cells → atherosclerosis

1. Receptor not synthesized
2. Failure to transport to Golgi
3. Failure to bind LDL
4. Failure to cluster in coated pits
5. Failure to release LDL in endosomes

5B. Cystic Fibrosis (CF)

• Inheritance: Autosomal recessive (most common life-shortening AR disorder in white populations)
• Gene: CFTR on chromosome 7q31 (encodes the Cystic Fibrosis Transmembrane Regulator, a cAMP-regulated Cl⁻ channel)
• Most common mutation: ΔF508 (deletion of phenylalanine at position 508) → misfolded protein degraded in ER; accounts for ~70% of cases
• Modifier genes: Genes encoding TGF-β, mannose-binding lectin, and other loci modulate disease severity

• CFTR normally secretes Cl⁻ into airway lumen → draws water → thin, watery mucus
• In CF: Cl⁻ secretion blocked → Na⁺ reabsorption increased → water absorbed from lumen → thick, viscid mucus
• Thick mucus → plugging → obstruction → infection (especially Pseudomonas aeruginosa, Staphylococcus aureus) → chronic inflammation → bronchiectasis

1. No CFTR produced
2. CFTR misfolded → retained in ER (ΔF508)
3. CFTR reaches surface but cannot open
4. CFTR channel conducts Cl⁻ poorly
5. Reduced CFTR production
6. CFTR at surface but unstable

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6. DISEASES CAUSED BY ENZYME MUTATIONS

6A. Phenylketonuria (PKU)

• Inheritance: Autosomal recessive
• Gene: Phenylalanine hydroxylase (PAH)
• Prevalence: 1 in 10,000 (European descent)

• PAH converts phenylalanine → tyrosine using cofactor BH₄ (tetrahydrobiopterin); DHPR regenerates BH₄
• In PKU: PAH absent → hyperphenylalaninemia → shunt pathways produce phenylpyruvate, phenylacetate, phenyllactate (excreted in urine/sweat → "mousy/musty odor")
• Excess phenylalanine → impairs brain development (mechanism: competitive inhibition of amino acid transport, reduced myelin synthesis)
• ↓ Tyrosine → ↓ melanin → fair skin/hair (even in dark-skinned individuals)

• Normal at birth
• Rising plasma phenylalanine within weeks
• Severe intellectual disability (IQ <60) by 6 months
• Seizures, eczema, hypopigmentation
• Musty body odor

• Newborn screening: Guthrie test (heel-prick blood spot) — mandatory in most countries
• Treatment: phenylalanine-restricted diet for life
• BH₄ supplementation (sapropterin) works for some mutations

6B. Galactosemia

• Inheritance: AR
• Enzyme defect: Galactose-1-phosphate uridyltransferase (classic form)
• Galactose-1-phosphate accumulates → toxicity in liver, brain, kidney
• Clinical features: Jaundice, hepatomegaly, cataracts, intellectual disability, increased risk of E. coli sepsis in neonates
• Newborn screening + galactose-free diet prevents complications

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7. LYSOSOMAL STORAGE DISEASES

General Mechanism:

Key Diseases:

7A. Tay-Sachs Disease (GM2 Gangliosidosis)

• Deficient enzyme: Hexosaminidase A (HexA) — α-subunit encoded by HEXA gene
• Accumulated substrate: GM2 ganglioside (in neurons)
• Prevalence: 1 in 3,500 (Ashkenazi Jewish)
• Features:
  • Normal at birth; progressive neurodegeneration from ~6 months
  • Hypotonia → dementia → blindness → paralysis → death by age 2–3
  • Cherry-red spot on macula (ganglion cells of retina replaced by lipid-laden neurons; fovea, which lacks these cells, appears cherry-red against pale surroundings)
  • No organomegaly (unlike Niemann-Pick)
• Diagnosis: HexA activity in leukocytes; carrier screening in Ashkenazi Jews (reduced Tay-Sachs incidence by prenatal screening programs)

7B. Niemann-Pick Disease

7C. Gaucher Disease (Most common lysosomal storage disease)

• Deficient enzyme: Glucocerebrosidase (glucocerebrosidase, encoded by GBA gene)
• Accumulated substrate: Glucocerebroside in mononuclear phagocytes (macrophages in liver, spleen, bone marrow)
• Gaucher cells: Enlarged macrophages with "wrinkled tissue paper" cytoplasm (distended lysosomes)
• Pathology is dual: Storage burden + macrophage activation (high IL-1, IL-6, TNF)

7D. Mucopolysaccharidoses (MPS)

• Deficiency of enzymes degrading glycosaminoglycans (heparan sulfate, dermatan sulfate, etc.) → accumulate in lysosomes
• Hurler syndrome (MPS I): α-L-iduronidase deficiency → coarse facial features, corneal clouding, organomegaly, intellectual disability, cardiac disease, short stature

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8. GLYCOGEN STORAGE DISEASES (Glycogenoses)

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9. SINGLE-GENE DISORDERS WITH ATYPICAL (NON-CLASSICAL) PATTERNS OF INHERITANCE

9A. Triplet Repeat Mutations — Fragile X Syndrome (FXS)

• Gene: FMR1 (Familial Mental Retardation 1) on the X chromosome
• Mutation: Expansion of CGG trinucleotide repeats in the 5' UTR
• Frequency: 1 in 1,550 males; 1 in 8,000 females
• Most common genetic cause of intellectual disability in males; second most common overall cause after Down syndrome

• Severe intellectual disability
• Long face, large mandible, large everted ears, macroorchidism (present in >90% post-pubertal males — most consistent physical finding)
• High arched palate, mitral valve prolapse, hyperextensible joints
• Epilepsy (30%), aggressive behavior (90%), autism spectrum disorder, anxiety/ADHD

1. Carrier males (premutation): Clinically normal but transmit through phenotypically normal daughters to affected grandchildren ("normal transmitting males")
2. Affected females: ~20% of carrier females are affected (much higher than typical X-linked recessive)
3. Anticipation: Disease worsens over successive generations as premutation expands to full mutation during oogenesis (NOT spermatogenesis)
4. FXTAS (Fragile X-associated Tremor/Ataxia Syndrome): Premutation carrier males/females → late-onset cerebellar ataxia and tremor
5. FXPOI (Fragile X-associated Primary Ovarian Insufficiency): Premutation carrier females → premature ovarian failure

9B. Mitochondrial Gene Mutations

• Mitochondria have their own circular DNA (~16,500 bp, 37 genes) encoding 13 proteins of the oxidative phosphorylation chain, 22 tRNAs, 2 rRNAs
• Maternal inheritance: Mitochondria are exclusively maternally inherited (sperm contribute no cytoplasm to the fertilized ovum)
• Heteroplasmy: Cells may have mixtures of mutant and normal mitochondria; disease severity correlates with proportion of mutant mitochondria
• Threshold effect: Minimum number of mutant mitochondria required to impair cell function
• Primarily affect high-energy demanding tissues: CNS, skeletal muscle, cardiac muscle, kidney, liver

9C. Genomic Imprinting — Prader-Willi and Angelman Syndromes

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10. HIGH-YIELD SUMMARY TABLE

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11. EXAM HIGH-YIELD MNEMONICS

• Marfan: MALE = Marfan, Aorta (dissection), Lens (ectopia lentis), Extremities (arachnodactyly)
• CF: "5-7" — CFTR gene on chromosome 7q31, ΔF508 most common mutation
• PKU: Pale, musty smell, Phenylalanine → no tyrosine → no melanin
• Fragile X: FAME = Fragile X, Anticipation, Macroorchidism, Ears (large), premutation in females → expansion in oogenesis
• Gaucher: Gaucher = Glucose-cerebroside in Great big macrophages with "Grinkled tissue paper" look
• Tay-Sachs: Tay = Twice (hexosaminidase A has 2 subunits α and β; Tay-Sachs = α deficient; Sandhoff = both α and β deficient)
• Prader-Willi vs Angelman: "Paternal deletion → Prader-Willi"; "maternal deletion → Angel (from mom)"

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