17.4 Genetics, Inborn Errors & Environmental Toxicology
Key Takeaways
- Inheritance patterns—AD, AR, X-linked, mitochondrial, imprinting, and anticipation—predict pedigree shape and recurrence; trinucleotide repeats expand and worsen across generations.
- Aneuploidies (Down trisomy 21, Edwards 18, Patau 13, Turner 45,X, Klinefelter 47,XXY) and microdeletion syndromes have distinctive multi-organ phenotypes used as vignette fingerprints.
- Inborn errors present as mechanism vignettes: PKU (phenylalanine hydroxylase/BH4), galactosemia (GALT), glycogenoses by organ and enzyme, lysosomal storage by accumulated substrate, urea cycle defects with hyperammonemia ± respiratory alkalosis.
- Heavy metals and gases have signature toxidromes: lead (neuro/anemia/basophilic stippling), mercury (neuro/psychiatric), arsenic (garlic, Mees lines, raindrop skin), iron (corrosive GI then shock/liver), CO (cherry-red, left-shifted O2 curve), cyanide (lactic acidosis, bitter almond).
- Environmental carcinogens and radiation (UV pyrimidine dimers; ionizing double-strand breaks) link exposure history to cancer type and DNA-repair themes.
17.4 Genetics, Inborn Errors & Environmental Toxicology
Quick Answer: Read the pedigree (AD/AR/X-linked/mito/imprinting/anticipation). Match aneuploidy and microdeletion phenotypes. Map metabolic blocks (PKU, galactosemia, glycogen, lysosomal, urea cycle). Recognize metal and gas toxidromes and carcinogen–cancer links.
This section is pure pattern recognition across families, chromosomes, pathways, and exposures—classic multisystem CBSE territory.
Inheritance Patterns
Autosomal dominant (AD): Vertical transmission; often structural proteins or receptors with haploinsufficiency or dominant-negative effects (Marfan/FBN1, achondroplasia/FGFR3, familial hypercholesterolemia/LDLR, Huntington, ADPKD, NF1). May show incomplete penetrance and variable expressivity—normal parent phenotype does not always exclude transmission risk if penetrance is incomplete.
Autosomal recessive (AR): Horizontal pattern (affected siblings, unaffected parents who are carriers). Enzyme deficiencies dominate (most inborn errors, CF, sickle cell, thalassemia major risk). Consanguinity increases risk.
X-linked: No male-to-male transmission. X-linked recessive diseases affect males predominantly (hemophilia A/B, Duchenne/Becker, G6PD, Lesch-Nyhan, Hunter—note Hunter is X-linked lysosomal). Carrier females may show mild findings from skewed inactivation. X-linked dominant disorders (Rett/MECP2 often lethal in males; hypophosphatemic rickets) affect both sexes with no male-to-male transmission.
Mitochondrial: Maternal transmission only (sperm mitochondria discarded). Heteroplasmy causes variable severity. Examples: MELAS, MERRF, Leber hereditary optic neuropathy.
Imprinting: Parent-of-origin epigenetic silencing. Prader-Willi (paternal 15q deletion or maternal uniparental disomy) vs Angelman (maternal UBE3A loss / maternal 15q deletion or paternal UPD)—same region, different parent of origin. Beckwith-Wiedemann and Silver-Russell involve 11p15 imprinting.
Anticipation: Progressive earlier/more severe disease in successive generations from trinucleotide repeat expansion (Huntington CAG, myotonic dystrophy CTG, Fragile X CGG, Friedreich GAA). Fragile X also shows premutation phenotypes (FXTAS, primary ovarian insufficiency).
| Pattern | Key pedigree clue |
|---|---|
| AD | Every generation; male-to-male OK |
| AR | Sibship; skips generations |
| X-linked recessive | Males; no father-to-son |
| Mitochondrial | All children of affected mother; none from affected father |
| Imprinting | Parent-of-origin determines disease |
| Anticipation | Worse/earlier each generation |
Chromosomal Aneuploidy
| Syndrome | Karyotype | High-yield features |
|---|---|---|
| Down | Trisomy 21 (or Robertsonian translocation) | Intellectual disability, single palmar crease, AVSD/VSD, duodenal atresia, Hirschsprung, ALL/AMKL risk, Alzheimer early, Brushfield spots |
| Edwards | Trisomy 18 | Rocker-bottom feet, clenched hands, omphalocele, horseshoe kidney, severe prognosis |
| Patau | Trisomy 13 | Holoprosencephaly, cleft lip/palate, polydactyly, cutis aplasia, severe prognosis |
| Turner | 45,X | Female, short stature, webbed neck, coarctation, bicuspid aortic valve, streak ovaries, horseshoe kidney |
| Klinefelter | 47,XXY | Tall male, hypogonadism, infertility (dysgenesis of seminiferous tubules), gynecomastia, Barr body present |
Advanced maternal age increases meiotic nondisjunction risk for free trisomies. Robertsonian translocation Down can have different recurrence counseling. Mosaicism softens phenotypes.
Microdeletion Syndromes (High-Yield)
| Syndrome | Region / gene | Fingerprint |
|---|---|---|
| DiGeorge / velocardiofacial | 22q11 (TBX1) | CATCH-22: Cardiac (truncus/tet), Abnormal facies, Thymic hypoplasia (T-cell), Cleft, Hypocalcemia (parathyroids) |
| Williams | 7q (elastin) | “Elfin” facies, supravalvular aortic stenosis, hypercalcemia, friendly personality |
| Cri-du-chat | 5p deletion | High-pitched cat-like cry, microcephaly |
| Wolf-Hirschhorn | 4p | “Greek helmet” facies |
| Prader-Willi / Angelman | 15q11–13 | Hypotonia/obesity/hyperphagia vs happy puppet/seizures/inappropriate laughter |
FISH or chromosomal microarray detects many microdeletions missed by standard karyotype.
Inborn Errors: Mechanism Vignettes
PKU: Phenylalanine hydroxylase deficiency (or BH4 cofactor issues) → ↑phenylalanine, ↓tyrosine → intellectual disability if untreated, hypopigmentation, musty odor, eczema. Treat with phenylalanine-restricted diet ± BH4. Maternal PKU teratogenicity if diet relaxed in pregnancy.
Galactosemia (classic GALT): Feeding → liver failure, E. coli sepsis risk, cataracts (galactitol), reducing substances in urine. Eliminate lactose/galactose.
Glycogen storage diseases (examples):
- von Gierke (I, glucose-6-phosphatase): Severe fasting hypoglycemia, lactic acidosis, hepatomegaly, hyperuricemia, hyperlipidemia.
- Pompe (II, lysosomal acid maltase): Cardiomegaly, hypotonia, glycogen in lysosomes.
- Cori (III, debranching): Hepatomegaly, hypoglycemia milder than I; limit dextrin-like residues.
- McArdle (V, muscle phosphorylase): Exercise intolerance, myoglobinuria, second-wind; no rise in lactate with forearm exercise test conceptually.
Lysosomal storage (selected):
| Disease | Enzyme / note | Clue |
|---|---|---|
| Tay-Sachs | Hexosaminidase A | Cherry-red macula, no HSM, onion-skin lysosomes |
| Gaucher | Glucocerebrosidase | HSM, bone crises, lipid-laden macrophages |
| Niemann-Pick | Sphingomyelinase | HSM, cherry-red macula, foam cells |
| Fabry | α-galactosidase A (X-linked) | Angiokeratomas, peripheral neuropathy, renal/cardiac |
| Hunter | Iduronate sulfatase (X-linked) | Mild Hurler-like, no corneal clouding |
| Hurler | α-L-iduronidase | Corneal clouding, gargoyle facies, AR |
Urea cycle defects (e.g., OTC deficiency—X-linked most common): present with hyperammonemia, encephalopathy, respiratory alkalosis early (NH3 stimulates ventilation); amino acid patterns distinguish specific enzyme (OTC: ↑orotic acid, ↓citrulline). Treat by limiting protein, scavenging ammonia, dialysis if severe.
Other classics: maple syrup urine disease (branched-chain α-ketoacid dehydrogenase—sweet urine, neurodegeneration), homocystinuria (cystathionine β-synthase—thrombosis, marfanoid, downward vs upward lens distinction from Marfan), OTC vs orotic aciduria (megaloblastic anemia without hyperammonemia in UMP synthase deficiency).
| Disorder | Core lab / clinical |
|---|---|
| PKU | ↑Phe, musty, MR if untreated |
| Galactosemia | Infant liver failure, cataracts, E. coli |
| von Gierke | Hypoglycemia + lactate + uric acid |
| Pompe | Cardiomegaly, hypotonia |
| OTC deficiency | Hyperammonemia, ↑orotate, X-linked |
Heavy Metal Toxicology
Lead: Inhibits ferrochelatase and ALA dehydratase → anemia with basophilic stippling, ↑zinc protoporphyrin; lead lines in bone/gingiva; wrist/foot drop; abdominal colic; cognitive impairment in children; nephropathy. Sources: paint, batteries, ammunition, contaminated water/soil. Chelation (succimer, EDTA, dimercaprol) when indicated.
Mercury: Organic (methylmercury, Minamata) → neuropsychiatric, ataxia, visual fields; elemental vapor → tremor, erethism; inorganic → nephrotic syndrome/GI. Chelation with dimercaprol/succimer depending on form.
Arsenic: Inhibits pyruvate dehydrogenase (lipoic acid binding); garlic odor; severe GI distress; Mee’s lines on nails; raindrop pigmentation and hyperkeratosis chronic; QT prolongation; associated with squamous cancers of skin/lung and angiosarcoma liver historically. Dimercaprol/succimer.
Iron: Pediatric overdose classic—corrosive GI injury, anion-gap metabolic acidosis, hepatotoxicity, radiopaque pills. Deferoxamine chelation; whole bowel irrigation concepts.
| Metal | Signature |
|---|---|
| Lead | Basophilic stippling, neuropathy, developmental delay |
| Mercury | Neuro/psych, cerebellar, renal (form-dependent) |
| Arsenic | Garlic, Mees lines, pigment changes |
| Iron | Toddler pills, acidosis, shock, liver failure |
Carbon Monoxide and Cyanide
Carbon monoxide: Colorless; binds hemoglobin with >> affinity than O2 → ↓O2 content, left-shifted dissociation curve (impaired unloading); inhibits cytochrome oxidase somewhat. Headache, cherry-red skin/venous blood (unreliable), cherry mucosa, bilateral globus pallidus necrosis severe cases. Pulse oximetry misleading; co-oximetry needed. Treat 100% O2 ± hyperbaric.
Cyanide: From fires (synthetic combustion), nitroprusside excess, industrial. Binds Fe3+ in cytochrome c oxidase → histotoxic hypoxia, severe lactic acidosis, almond odor sometimes. Venous blood may appear bright. Antidotes: hydroxocobalamin, nitrites + thiosulfate historically (induce methemoglobin then rhodanese pathway).
Smoke inhalation can combine CO + cyanide—exam favorite.
Environmental Carcinogens and Radiation Injury
| Exposure | Associated cancers / effects |
|---|---|
| Aflatoxin (Aspergillus on grains) | HCC (TP53 R249S classic teaching) |
| Asbestos | Bronchogenic carcinoma (synergy with smoking), mesothelioma |
| Aromatic amines (aniline dyes) | Bladder transitional cell carcinoma |
| Benzene | Acute leukemia |
| Vinyl chloride | Hepatic angiosarcoma |
| Nickel, chromium, radon, smoking, silica | Lung cancer (varied) |
| HPV | Cervical, anal, oropharyngeal SCC |
| EBV | Burkitt, nasopharyngeal, some Hodgkin/post-transplant lymphomas |
| UV light | Pyrimidine dimers → skin cancers; XP extreme |
| Ionizing radiation | DNA double-strand breaks; leukemia, thyroid, breast, others; fibrosis |
Radiation injury acute: marrow suppression, GI mucosal loss, CNS at very high doses (acute radiation syndrome stages). DNA damage activates p53; surviving cells may carry mutations. Localized radiation causes fibrosis and strictures long-term.
Integration for CBSE Vignettes
Start with the ask: pedigree pattern, chromosome face, metabolic crisis labs, or toxidrome. A floppy infant of advanced maternal age with AVSD → trisomy 21 until proven otherwise. Hypoglycemia + high lactate + big liver → von Gierke. Hyperammonemia in a boy after protein load → OTC. Construction worker with wrist drop and stippling → lead. House fire with lactic acidosis and normal PaO2 → consider cyanide ± CO. Genetics and toxicology reward these compact associations under time pressure.
A pedigree shows disease transmitted only through females, with both sons and daughters of an affected mother at risk, but no transmission from affected fathers. Which inheritance pattern is illustrated?
A newborn develops E. coli sepsis, liver failure, and cataracts after milk feeding. Reducing substances are present in urine. Which enzyme deficiency is most likely?
A toddler ingests many prenatal iron tablets and develops hemorrhagic gastroenteritis, anion-gap metabolic acidosis, and rising liver enzymes. Which antidote is specifically indicated for severe iron toxicity?