Xeroderma Pigmentosum Nov 21 st 2005 Diana Mok

Xeroderma Pigmentosum Nov 21 st 2005 Diana Mok Kaitlin Myers Thao Nguyen T. Nguyen

Introduction üFirst described in 1874 by Hebra and Kaposi ü 1882: the term XP is first used üRare disorder transmitted in an autosomal recessive manner üCharacterized by photosensitivity, pigmentary changes, premature skin aging, and malignant tumor development.

üIncidence: + the US: 1 in 250, 000 (XPC most common) + Europe: 1 in 250, 000 (XPC most common) + Japan: 1 in 40, 000 (XPA most common) üCases reported in all races üSex: equal incidence üAge: Usually detected at 1 or 2 years

Symptoms üUnusually severe sunburn after a short sun exposure üFreckles at early age üContinued sun exposure leads to changes: irregular dark spots, thin skin, excessive dryness, rough-surfaced growths, skin cancer

üNormally begins during infancy and almost always before 20 years of age üEyes: sensitive to the sun, easily irritated, bloodshot and clouded; noncanerous or cancerous growths on the eyes may occur üSkin cancer: first skin cancer may develop before the person is 10, many other skin cancers may continue to form; often on the face and sun-exposed parts of the body.

ü 20% XP patients may suffer from nerverelated problems: deafness, poor coordination, spastic muscles, or developmental delay üSome may be very short and may not develop normal sexual characteristics üNeurological problems: worsen over time if present

Diagnosis üMeasuring the DNA repair factor from skin or blood samples üCellular hypersensitivity to UV radiation and chromosomal breakage studies üComplementation studies üGene sequencing üAntenatal diagnosis: amniocentesis, chorionic villi sampling

What Causes XP? ü Defect in nucleotide excision repair (NER) ü 2 types of NER: ~Global Genome (GG-NER) ~Transcription coupled (TC-NER) ü Defected, unable to repair DNA damaged by UV radiation

Where Does XP Occur? ü 7 repair genes: ~XPA-9 q 22. 3 ~XPB-2 q 21 ~XPC-3 p 25 ~XPD-19 q 13. 2 -q 13. 3 ~XPE-11 p 12 -p 11 ~XPF-16 p 13. 3 -p 13. 2 ~XPG-13 q 33 • All play key roles in GG-NER &TC-NER

Normal DNA Repair Process ü When DNA is damaged, both NERs have a damage sensing phase. ü Detection in GG-NER is done by the product of the XPC gene. ü XPA gene product can also detect DNA damage.

ü After detection, open complex formed. ü XPG gene required. ü Products of XPB & XPD part of 9 -subunit protein complex (TFIIH) needed for complex formation as well. ü Damaged DNA removed.

ü XPG & XPF gene encode endonucleases. ü XPF gene product also functions as an endonuclease. ü Gap filled with new DNA by action polymerase.

How Bad is It? ü Replication error not in NER but after the post replication repair. ü XPA-XPG corresponds to defects in gene process. ü XPA-common XPE-rare • Disease Severity: XPF-mild XPG-severe

ü UV-B radiation causes immunosuppressive effects that may be pathogenesis of XP. ü XP patient’s skin have depletion of Langerhans cells due to UV radiation. ü Defects in cell-mediated immunity reported in XP: ~impaired response to recall antigens ~decreased circulatory T-helper cells to supressor cells ratio ~reduced natural killer cell activity

Treatments üSunscreens and other sun avoidance methods (protective clothing, hats, eyewear) üOral retinoids => dose-related irreversible calcification of ligaments and tendons üChemical therapy

üRepair DNA damage after UV exposure by delivery of a DNA repair enzyme into the skin by means of specially engineered liposomes (under studies) üComplete excision of malignancies üOphthalmologic and neurologic consultations recommended

Personal Account Fatima ü Originally from the Dominican Republic ü Diagnosed with lightsensitivity as child ü Doctors/family unsure how to treat her ü Forty radiation treatments ü Now an active member of the XP society “I’m very grateful to God that I’m still alive. ”

Polly “I can’t find any doctor in this area (West Virginia) who has any concept of what it means to have a light sensitivity disorder. ” ü Never liked the outdoors as a child ü Fell in sunlight ü Parents signed her up for several outdoor sports to shake her out of it ü As adult found the XP website, sent in a letter ü Now learning how to protect herself, balance her time, and enjoy her life.

Shelley ü Shelley is ten years old ü Member of the group Children of the Moon ü Has created her own website ü Has house and car with UVprotected windows ü Goes to school with UV protected windows ü Likes the Backstreet Boys, her dog, and Nintendo

The XP Society and Camp Sundown ü Devoted to education awareness, information exchange, and promoting medical research ü Camp Sundown is for all ages, and provides a place for those affected to form relationships with others with XP

Works Cited ü http: //xps. org ü www. moonchildren. com ü http: //www. emedicine. com/DERM/topic 462. htm ü http: //www. cc. nih. gov/ccc/patient. education/pepubs/xeroderma. pdf ü http: //hometown. aol. com/pelony 7/images/small%20 of%20 sun%20 in%20 moon. j pg ü http: //www. skipressworld. com/images/daily_2005/04/ski%20 press%20%20 sunscreen%203. jpg ü http: //phobos. ramapo. edu/~pbagga/xp. JPG ü http: //www. zdf. de/ZDFde/img/106/0, 1886, 2396522, 00. jpg ü http: //www. reactome. org/cgibin/eventbrowser? DB=gk_current&FOCUS_SPECIES=Homo%20 sapiens&ID= 17134&