Download PowerPoint Presentation - What Causes XP?

Xeroderma Pigmentosum
Nov 21st 2005
Diana Mok
Kaitlin Myers
Thao Nguyen T. Nguyen
Introduction
First described in 1874 by Hebra and
Kaposi
1882: the term XP is first used
Rare disorder transmitted in an autosomal
recessive manner
Characterized
by
photosensitivity,
pigmentary changes, premature skin aging,
and malignant tumor development.
Incidence: + 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)
Cases reported in all races
Sex: equal incidence
Age: Usually detected at 1 or 2 years
Symptoms
Unusually severe sunburn after a short
sun exposure
Freckles at early age
Continued sun exposure leads to
changes: irregular dark spots, thin skin,
excessive dryness, rough-surfaced growths,
skin cancer
Normally begins during infancy
almost always before 20 years of age
and
Eyes: sensitive to the sun, easily irritated,
bloodshot and clouded; noncanerous or
cancerous growths on the eyes may occur
Skin 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.
20% XP patients may suffer from nerverelated
problems:
deafness,
poor
coordination,
spastic
muscles,
or
developmental delay
Some may be very short and may not
develop normal sexual characteristics
Neurological problems: worsen over time if
present
Diagnosis
Measuring the DNA repair factor from skin
or blood samples
Cellular hypersensitivity to UV radiation
and chromosomal breakage studies
Complementation studies
Gene sequencing
Antenatal diagnosis: amniocentesis,
chorionic villi sampling
What Causes XP?
 Defect in nucleotide excision repair (NER)
 2 types of NER:
~Global Genome (GG-NER)
~Transcription coupled (TC-NER)
 Defected, unable to repair DNA damaged by
UV radiation
Where Does XP Occur?
 7 repair genes:
~XPA-9q22.3
~XPB-2q21
~XPC-3p25
~XPD-19q13.2-q13.3
~XPE-11p12-p11
~XPF-16p13.3-p13.2
~XPG-13q33
• All play key roles in GG-NER &TC-NER
Normal DNA Repair Process
When DNA is damaged, both NERs
have a damage sensing phase.
Detection in GG-NER is done by the
product of the XPC gene.
XPA gene product can also detect DNA
damage.
After detection, open complex formed.
XPG gene required.
Products of XPB & XPD part of 9-subunit
protein complex (TFIIH) needed for
complex formation as well.
Damaged DNA removed.
XPG & XPF gene encode
endonucleases.
XPF gene product also functions as an
endonuclease.
Gap filled with new DNA by action
polymerase.
How Bad is It?
 Replication error not in NER but after the post
replication repair.
 XPA-XPG corresponds to defects in gene
process.
 XPA-common
XPE-rare
• Disease Severity:
XPF-mild
XPG-severe
 UV-B radiation causes immunosuppressive
effects that may be pathogenesis of XP.
 XP patient’s skin have depletion of
Langerhans cells due to UV radiation.
 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
Sunscreens and other sun avoidance
methods
(protective
clothing,
hats,
eyewear)
Oral retinoids => dose-related irreversible
calcification of ligaments and tendons
Chemical therapy
Repair DNA damage after UV exposure by
delivery of a DNA repair enzyme into the
skin by means of specially engineered
liposomes (under studies)
Complete excision of malignancies
Ophthalmologic and neurologic
consultations recommended
Personal Account
Fatima
 Originally from the
Dominican Republic
 Diagnosed with lightsensitivity as child
 Doctors/family unsure
how to treat her
 Forty radiation
treatments
 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.”
 Never liked the outdoors as a
child
 Fell ill in sunlight
 Parents signed her up for
several outdoor sports to
shake her out of it
 As adult found the XP
website, sent in a letter
 Now learning how to protect
herself, balance her time, and
enjoy her life.
Shelley
 Shelley is ten years old
 Member of the group Children of
the Moon
 Has created her own website
 Has house and car with UVprotected windows
 Goes to school with UV protected
windows
 Likes the Backstreet Boys, her dog,
and Nintendo
The XP Society and Camp Sundown
 Devoted to education awareness, information
exchange, and promoting medical research
 Camp Sundown is for all ages, and provides a place
for those affected to form relationships with others
with XP
Works Cited
 http://xps.org
 www.moonchildren.com
 http://www.emedicine.com/DERM/topic462.htm
 http://www.cc.nih.gov/ccc/patient.education/pepubs/xeroderma.pdf
 http://hometown.aol.com/pelony7/images/small%20of%20sun%20in%20moon.j
pg
 http://www.skipressworld.com/images/daily_2005/04/ski%20press%20%20sunscreen%203.jpg
 http://phobos.ramapo.edu/~pbagga/xp.JPG
 http://www.zdf.de/ZDFde/img/106/0,1886,2396522,00.jpg
 http://www.zdf.de/ZDFde/img/106/0,1886,2396522,00.jpg
 http://www.reactome.org/cgibin/eventbrowser?DB=gk_current&FOCUS_SPECIES=Homo%20sapiens&ID=
17134&