A 32-year-old woman presents with progressive neurological deterioration, photosensitivity, and severe sunburn-like skin lesions after minimal sun exposure. Clinical suspicion is raised for a nucleotide excision repair (NER) defect. Which investigation would be most appropriate to confirm the diagnosis of Xeroderma Pigmentosum?

Explanation

## Diagnosis of Xeroderma Pigmentosum (XP) **Key Point:** Xeroderma Pigmentosum is a rare autosomal recessive disorder of nucleotide excision repair (NER) characterized by inability to repair UV-induced DNA damage, particularly thymine dimers. ### Investigation of Choice: Unscheduled DNA Synthesis (UDS) Assay The **unscheduled DNA synthesis assay** is the gold standard functional test for NER defects: 1. **Principle:** Normal cells exhibit rapid DNA repair synthesis (UDS) after UV irradiation, incorporating radioactive nucleotides into newly synthesized repair patches. 2. **In XP patients:** Cultured fibroblasts show **absent or severely reduced UDS** because the NER pathway is defective and cannot initiate repair synthesis. 3. **Sensitivity & Specificity:** This functional assay reliably identifies all complementation groups of XP and distinguishes XP from other photosensitive disorders. 4. **Timing:** Results available within days; more practical than genetic sequencing for rapid diagnosis. **High-Yield:** UDS assay is the **first-line confirmatory test** recommended by international guidelines (e.g., American Academy of Dermatology) for suspected XP because it directly measures the functional defect. ### Why Other Investigations Are Secondary | Investigation | Limitation | |---|---| | **Direct XPA sequencing** | Identifies only XPA mutations; XP has 8 complementation groups (XPA–XPG, XPV); genetic testing comes after functional confirmation | | **Serum thymine dimers** | Not a standard diagnostic test; thymine dimers are intracellular DNA lesions, not reliably measured in serum | | **Skin biopsy + p53 IHC** | p53 mutations are a consequence of accumulated UV damage, not diagnostic of the primary NER defect; does not confirm XP | **Clinical Pearl:** Complementation analysis (co-culture of patient fibroblasts with known XP cell lines) can further classify the XP group, but UDS is the essential first step. **Mnemonic:** **UDS = Unrepaired DNA Synthesis** — if UDS is absent after UV stress in cultured cells, NER is broken.