xeroderma pigmentosum

Question 1

What is Xeroderma Pigmentosum (XP)?

Answer 1

A rare autosomal recessive disorder characterized by extreme sensitivity to UV light, leading to a high incidence of skin cancers and frequently, neurological abnormalities.

Question 2

What is the fundamental molecular defect in XP?

Answer 2

A defect in Nucleotide Excision Repair (NER), specifically in the pathway that removes bulky DNA lesions like pyrimidine dimers caused by UV radiation.

Question 3

What is the clinical hallmark of XP?

Answer 3

Severe sunburn reaction, freckling on minimal sun exposure, dry skin (xeroderma), and pigmentary changes, leading to skin cancers (BCC, SCC, melanoma) at a very young age.

Question 4

How is XP genetically classified?

Answer 4

Into 7 complementation groups (XP-A through XP-G) based on the defective gene, plus a variant type (XP-V). Each group corresponds to a mutation in a different protein involved in NER.

Question 5

What is the specific defect in the variant form, XP-V?

Answer 5

XP-V is not a classic NER defect. It is caused by a mutation in DNA polymerase η, a transfusion synthesis polymerase that correctly bypasses UV-induced thymine dimers.

Question 6

What is the consequence of the defective NER machinery?

Answer 6

UV-induced DNA damage (like thymine dimers) accumulates and is not repaired. This leads to an increased mutation rate during DNA replication, which ultimately causes skin cancer.

Question 7

Why do some XP patients develop neurological symptoms?

Answer 7

The defective NER proteins are also involved in repairing oxidative DNA damage in neurons. Their deficiency leads to progressive neuronal death, causing symptoms like sensorineural deafness and ataxia.

Question 8

What is the primary medical management for XP?

Answer 8

Rigorous, lifelong protection from UV radiation: avoiding sunlight, using protective clothing, and applying high-SPF sunscreen.

Question 9

Which DNA repair pathway is defective in classic XP groups (A-G)?

Answer 9

The Nucleotide Excision Repair (NER) pathway.

Question 10

What type of DNA lesions does NER primarily target?

Answer 10

Bulky, helix-distorting lesions, such as pyrimidine dimers (from UV) and large chemical adducts.