Inherited Disorders – Comprehensive Study Notes

Errors in DNA transcription (making RNA) or translation (making proteins) can introduce changes in the nucleotide sequence ➜ mutations.
- When such mutations are present in gametes (egg or sperm) they can be transmitted to offspring and become part of the population’s gene pool.
Every kingdom of life – plants, animals, fungi, protists, bacteria – exhibits genetic disorders; in humans alone, thousands are cataloged.
Many of these disorders involve a single gene and therefore follow the simple Mendelian inheritance patterns first described in Gregor Mendel’s pea‐plant experiments.
- Traits can be classified as dominant or recessive based on their expression in heterozygotes.

Disorder manifests only in individuals homozygous for the recessive allele.
- Genotype: $aa$ ➜ phenotype shows disorder.
- Heterozygotes ( $Aa$ ) are carriers: no symptoms but can transmit the allele to children.
Severity ranges from mild cosmetic changes to lethal systemic failure.
- Mild example – Albinism: lack of melanin pigment in skin, hair, eyes. Social & UV‐sensitivity consequences rather than life‐threatening.
- Severe example – Cystic Fibrosis (CF):
- Defective chloride‐ion channel ➜ production of excessive, thick mucus in lungs, pancreas, other organs.
- Clinical effects: labored breathing, chronic infections (bacteria thrive in viscous mucus), pancreatic blockage, possible liver disease.
- Life expectancy: modern median ≈ 41 years (improved dramatically from <5 years in mid-20th century due to antibiotics, physiotherapy, and gene‐specific drugs).

Two carrier parents ( $Aa \times Aa$ ):
- Punnett grid produces $AA, Aa, aA, aa$ .
- Genotypic ratio: $1 : 2 : 1$ ( $AA$ normal / $Aa$ or $aA$ carriers / $aa$ affected ).
- Phenotypic ratio: $3 : 1$ ( three children out of four appear normal, one exhibits disease ).
Probability applies independently to each pregnancy – outcomes do not “average” across a family.

Consanguineous mating ("with blood") = reproduction between close relatives (siblings, cousins, etc.).
- Raises chance that both parents carry the same rare recessive allele inherited from a common ancestor.
- Statistically inflates frequency of homozygous recessives in progeny.
Classic case study – The Fugates of Hazard, Kentucky:
- Recessive condition Methemoglobinemia (elevated methemoglobin preventing O₂ binding, turning skin bluish).
- Generations of intermarriage ➜ several visibly blue-tinted descendants (“Blue People of Kentucky”).

Phenylketonuria (PKU)
- Enzyme deficiency prevents conversion of phenylalanine ➜ tyrosine.
- Accumulation damages developing brain ➜ intellectual disabilities if untreated.
- Managed by strict low-phenylalanine diet beginning at birth (newborn screening vital).
Sickle Cell Disease
- Point mutation in β-globin gene produces abnormal hemoglobin (HbS).
- Deoxygenated HbS polymerizes ➜ crescent-shaped red blood cells ➜ vessel blockage, pain crises, organ damage.
- Heterozygote advantage (malaria resistance) links disorder’s prevalence to evolutionary selection.
Tay–Sachs Disease
- Hexosaminidase A enzyme deficiency ➜ lipid (GM₂ ganglioside) buildup in neurons.
- Progressive neurodegeneration, blindness, early childhood death.

Require only one mutated copy to express phenotype.
- A homozygous dominant condition may be more severe or lethal.
Achondroplasia – common form of dwarfism caused by FGFR3 gene mutation.
- Genotypes: $Aa$ ➜ dwarfism, $AA$ ➜ lethal in utero.

Autosomal dominant neurodegenerative disorder.
- Expanded CAG trinucleotide repeat in HTT gene; length correlates with age of onset.
Delayed expression: symptoms emerge at age ≈ $35\text{–}40$ years (motor dysfunction, cognitive decline, psychiatric issues).
- Evolutionary implication: allele persists because carriers typically reproduce before recognizing they are affected.
Ethical & practical issues:
- Predictive genetic testing can inform family planning but raises anxiety and discrimination concerns.
- No cure; treatments manage symptoms.

Genes situated on sex chromosomes are sex-linked.
- Most reside on the X chromosome due to its larger size and gene content.
In males (XY):
- Only one X copy ➜ recessive alleles have no backup; phenotype is expressed.
In females (XX):
- Recessive allele masked if paired with dominant counterpart.
- X-inactivation can create mosaics but usually still protects against full disorder.
Pedigree hallmarks of X-linked recessive traits:
- More affected males than females.
- Affected fathers never transmit to sons (sons receive Y), but all daughters become carriers.
- Carrier mothers transmit to 50 % of sons (affected) and 50 % of daughters (carriers).

Color Blindness (red-green most common): defective opsin proteins in cone photoreceptors.
Duchenne Muscular Dystrophy (DMD): absence of dystrophin protein ➜ progressive muscle wasting, early mortality.
Hemophilia (A & B): clotting factor deficiency ➜ prolonged bleeding.
Male-Pattern Baldness: androgen‐sensitive hair follicle miniaturization; complex but displays X-linked contribution.

Punnett square probabilities:
- $P(aa\,\text{offspring from} \, Aa \times Aa) = \frac{1}{4} = 25\%$ .
- $P(\text{carrier}) = \frac{1}{2} = 50\%$ .
- $P(\text{phenotypically normal}) = \frac{3}{4} = 75\%$ .
CF life expectancy: ↑ from
HD age of onset: typically 35–40 years; CAG repeats >40 guarantee disease.

Mendel’s foundational principles (segregation, independent assortment) allow modern prediction of disease transmission.
Molecular advances (gene sequencing, CRISPR) aim to correct or dampen single-gene disorders, linking lecture to ongoing biotechnology breakthroughs.
Ethical dimensions – reproductive decisions, genetic counseling, societal support – underscore science’s intersection with philosophy and public policy.