A 7-month-old boy presents to the family physician with extensive scaliness and pigmentation of sun-exposed skin areas. His mother says that these symptoms were absent until mid-spring and then became significantly worse after their trip to California in the summer. The child was born in December to a consanguineous couple after an uncomplicated pregnancy. He is breastfed and receives mashed potatoes, bananas, and carrots as complementary foods. His weight is 8.5 kg (18.7 lb) and length is 70 cm (2 ft 96 in). The patient’s vital signs are within normal limits for his age. On physical examination, there is freckling, scaling, and erythema on the sunlight-exposed areas of the face, trunk, and upper and lower extremities. No blistering, scarring, hypertrichosis, or alopecia is noted. The rest of the exam is unremarkable. Which process is most likely disrupted in this patient?

Hydroxylation of proline and lysine in the procollagen molecule

Conversion of uroporphyrinogen III to coproporphyrinogen III

While performing a Western blot, a graduate student spilled a small amount of the radiolabeled antibody on her left forearm. Although very little harm was done to the skin, the radiation did cause minor damage to the DNA of the exposed skin by severing covalent bonds between the nitrogenous bases and the deoxyribose sugar, leaving several apurinic/apyrimidinic sites. Damaged cells would most likely repair these sites by which of the following mechanisms?

Nonhomologous end joining repair

Two healthy adults have only one child. He has Friedreich ataxia (FA). They are considering having more children, but are uncertain of their risk of having another child with the condition. What should they do?

See a genetic counselor; risk of having another child with FA is 25%

Proceed with conception; risk of having another child with FA is unpredictable

See a genetic counselor; risk of having another child with FA is 66%

Proceed with conception; risk of having another child with FA is 0%

See a genetic counselor; risk of having another child with FA is 50%

A 54-year-old woman with breast cancer comes to the physician because of redness and pain in the right breast. She has been undergoing ionizing radiation therapy daily for the past 2 weeks as adjuvant treatment for her breast cancer. Physical examination shows erythema, edema, and superficial desquamation of the skin along the right breast at the site of radiation. Sensation to light touch is intact. Which of the following is the primary mechanism of DNA repair responsible for preventing radiation-induced damage to neighboring neurons?

Nonhomologous end joining repair

An investigator studying DNA mutation mechanisms isolates single-stranded DNA from a recombinant bacteriophage and sequences it. The investigator then mixes it with a buffer solution and incubates the resulting mixture at 70°C for 16 hours. Subsequent DNA resequencing shows that 3.7 per 1,000 cytosine residues have mutated to uracil. Which of the following best describes the role of the enzyme that is responsible for the initial step in repairing these types of mutations in living cells?

Connecting the phosphodiester backbone

Cleavage of the phosphodiester bond 3' of damaged site

Release of the damaged nucleotide

Addition of free nucleotides to 3' end

DNA repair deficiency syndromes for USMLE Step 3: High-Yield Biochemistry Lessons

DNA Repair Defects - Glitches in the Code

Ataxia-Telangiectasia: Defect in non-homologous end joining (NHEJ). Presents with cerebellar ataxia, telangiectasias, and immunodeficiency. Due to ATM gene mutation.
Xeroderma Pigmentosum: Faulty nucleotide excision repair (NER). Leads to extreme UV sensitivity, ↑ skin cancers.
Fanconi Anemia: Impaired repair of interstrand crosslinks. Results in pancytopenia, café-au-lait spots, and congenital anomalies.
Lynch Syndrome (HNPCC): Defective mismatch repair (MMR). Associated with high risk for colorectal and endometrial cancers.

⭐ Patients with Xeroderma Pigmentosum cannot repair pyrimidine dimers formed by UV light, leading to a >1000x increased risk of skin cancer.

Common Xeroderma Pigmentosum Symptoms

NER Defects - Sun-Kissed Sufferers

Xeroderma Pigmentosum (XP)
- Defective Nucleotide Excision Repair (NER) pathway, failing to repair UV-induced pyrimidine dimers.
- Presents with extreme photosensitivity, severe sunburn, and premature skin aging.
- Massively ↑ risk of skin cancers (basal cell, squamous cell, melanoma).
- Neurological degeneration in ~30% of cases.
Cockayne Syndrome (CS)
- Defect in transcription-coupled NER.
- Features progeria (premature aging), photosensitivity, and neurodegeneration, but no ↑ cancer risk.
Trichothiodystrophy (TTD)
- Similar NER defect to XP/CS.
- Characterized by brittle, sulfur-deficient hair, short stature, and intellectual disability. Photosensitivity is common, but no ↑ cancer risk.

⭐ Exam Favourite: Patients with Xeroderma Pigmentosum have a >2,000-fold increased risk of developing melanoma and non-melanoma skin cancers before the age of 20.

Mismatch Repair Woes - Lynch's Legacy

DNA Damage, Mismatch Repair, and Microsatellite Instability

Pathophysiology: Autosomal dominant mutation in mismatch repair (MMR) genes, leading to faulty "spell-checking" of newly synthesized DNA.
- Key Genes: MSH2, MLH1, MSH6, PMS2.
Result: Accumulation of mutations, particularly in microsatellites (short tandem repeats), a condition known as Microsatellite Instability (MSI).
Clinical: Also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC). High risk for:
- Colorectal Cancer (often right-sided)
- Endometrial Cancer
- Ovarian Cancer

⭐ Exam Favorite: Endometrial cancer is the most common extracolonic malignancy associated with Lynch syndrome.

📌 Mnemonic (Amsterdam Criteria - "3-2-1 Rule"): At least 3 relatives with a Lynch-associated cancer; spanning 2 generations; 1 of whom was diagnosed before age 50.

DSB Repair Fails - Ataxia & Anemia

Ataxia-Telangiectasia (AR)
- Defect: Mutated ATM gene, crucial for non-homologous end joining (NHEJ).
- Presentation (Triad): Cerebellar Ataxia, oculocutaneous Telangiectasias, recurrent sinopulmonary infections (due to IgA deficiency).
- Labs: ↑ AFP (alpha-fetoprotein), ↓ IgA, lymphopenia.
- Cancer Risk: ↑ lymphoma, leukemia.
Fanconi Anemia (AR)
- Defect: Failure of DNA crosslink repair.
- Presentation: Aplastic anemia (pancytopenia), progressive bone marrow failure.
- Physical Signs: Thumb/radial defects, short stature, café-au-lait spots.
- Cancer Risk: ↑ AML, solid tumors.

⭐ High-Yield: Ataxia-Telangiectasia is the only primary immunodeficiency with elevated AFP, a key diagnostic clue.

Ataxia-telangiectasia: clinical features and genetics

High‑Yield Points - ⚡ Biggest Takeaways

Xeroderma Pigmentosum: Faulty nucleotide excision repair of UV-induced pyrimidine dimers.

Ataxia-Telangiectasia: Defective non-homologous end joining from an ATM gene mutation.

Lynch Syndrome (HNPCC): Impaired mismatch repair (MSH2, MLH1), ↑ risk of colorectal cancer.

Fanconi Anemia: Defective interstrand crosslink repair, leading to aplastic anemia.

Bloom Syndrome: Mutated BLM helicase causing chromosomal instability and cancer predisposition.

Cockayne Syndrome: Defective transcription-coupled NER, causing premature aging.

Continue reading on Oncourse

CONTINUE READING — FREE

or get the app

App Store|Google Play