Xeroderma pigmentosum

Xeroderma pigmentosum
Xeroderma pigmentosum
Specialty	Medical genetics

Xeroderma pigmentosum, or XP, is an autosomal recessive genetic disorder of DNA repair in which the ability to repair damage caused by ultraviolet (UV) light is deficient.^[2]^: 574 In extreme cases, all exposure to sunlight must be forbidden, no matter how small; as such, individuals with the disease are often colloquially referred to as Children of the Night.^[3] Multiple basal cell carcinomas (basaliomas) and other skin malignancies frequently occur at a young age in those with XP. In fact, metastatic malignant melanoma and squamous cell carcinoma^[4] are the two most common causes of death in XP victims. This disease involves both sexes and all races, with an incidence of 1:250,000^{[citation needed]} and a gene frequency of 1:200. XP is roughly six times more common in Japanese people^[4] than in other groups.

The most common defect in xeroderma pigmentosum is an autosomal recessive genetic defect in which nucleotide excision repair (NER) enzymes are mutated, leading to a reduction in or elimination of NER.^[5] If left unchecked, damage caused by ultraviolet (UV) light can cause mutations in individual cell's DNA. If tumor suppressor genes (e.g. p53) or proto oncogenes are affected, the result may be cancer. Patients with XP are at a high risk for developing skin cancers, such as basal cell carcinoma, for this reason.

Normally, damage to DNA in epidermal cells occurs during exposure to UV light. The absorption of the high energy light leads to the formation of pyrimidine dimers, namely cyclobutane-pyrimidine dimers and pyrimidine-6-4-pyrimidone photoproducts. In a healthy, normal human being, the damage is first excised by endonucleases. DNA polymerase then repairs the missing sequence, and ligase "seals" the transaction. This process is known as nucleotide excision repair.

Types

There are seven complementation groups, plus one variant form:

Type	Diseases Database	OMIM	Gene	Locus	Also known as/Description
Type A, I, XPA	Template:DiseasesDB2	Template:OMIM2	XPA	9q22.3	Xeroderma pigmentosum group A - the classical form of XP
Type B, II, XPB	Template:DiseasesDB2	Template:OMIM2	XPB	2q21	Xeroderma pigmentosum group B
Type C, III, XPC	Template:DiseasesDB2	Template:OMIM2	XPC	3p25	Xeroderma pigmentosum group C
Type D, IV, XPD	Template:DiseasesDB2	Template:OMIM2 Template:OMIM2	XPD ERCC6	19q13.2-q13.3, 10q11	Xeroderma pigmentosum group D or De Sanctis-Cacchione syndrome (can be considered a subtype of XPD)
Type E, V, XPE	Template:DiseasesDB2	Template:OMIM2	DDB2	11p12-p11	Xeroderma pigmentosum group E
Type F, VI, XPF	Template:DiseasesDB2	Template:OMIM2	ERCC4	16p13.3-p13.13	Xeroderma pigmentosum group F
Type G, VII, XPG	Template:DiseasesDB2	Template:OMIM2 Template:OMIM2	RAD2 ERCC5	13q33	Xeroderma pigmentosum group G and COFS syndrome type 3
Type V, XPV		Template:OMIM2	POLH	6p21.1-p12	Xeroderma pigmentosum variant - these patients suffer from mutation in a gene that codes for a specialized DNA polymerase called polymerase-η (eta). Polymerase-η can replicate over the damage and is needed when cells enter S-phase in the presence of a DNA-replication.

Symptoms

Symptoms include:

Severe sunburn when exposed to only small amounts of sunlight. These often occur during a child's first exposure to sunlight.
Development of many freckles at an early age
Rough-surfaced growths (solar keratoses), and skin cancers
Eyes that are painfully sensitive to the sun and may easily become irritated, bloodshot and clouded
Blistering or freckling on minimum sun exposure
Spidery blood vessels
Limited growth of hair on chest and legs
Scaly skin
Dry skin
Irregular dark spots on the skin
Corneal ulcerations

Treatment

The most obvious, and often important part of treatment, is avoiding exposure to sunlight. Keratoses can also be treated using cryotherapy or fluorouracil.^[6]

Prognosis

Fewer than 40% of individuals with the disease survive beyond the age of 20. Some XP victims with less severe cases do manage to live well into their 40s.

In popular culture

These fictional characters have XP:

Christopher Snow in Dean Koontz's Moonlight Bay Trilogy
Luke in the 2002 novel Going Out by Scarlett Thomas
In the Japanese movie Taiyou no Uta also known as Midnight Sun, the main character (Kaoru Amane)
In the ITV series Ultraviolet, one of the humans is mistaken for a vampire because he avoids sunlight, when in fact he has XP.
In the independent film Dark Side of the Sun (1988) with Brad Pitt as the main character suffering from XP.
In the 2001 film The Others, the two children, Anne and Nicholas, suffer from XP.
In the 2003 novel Second Glance by Jodi Picoult, Ethan Wakeman, the 9-year-old nephew of Ross Wakeman (the main protagonist)
The 2003 Angela Johnson novel, A Cool Moonlight, centers on a girl who has XP and can never be in the sun. The family has gone to drastic measures to help make her life easier, and to make her feel like a normal 8-year-old.
The Spanish film "Eskalofrío" or "Shiver" released in 2008 featured a main character named Santi who is ostracized as he suffers from the condition.
The 2011 film La permission de minuit by French director Delphine Gleize centers on a teenage boy with XP.
The 2012 documentary "Sun Kissed" explores the XP problem on the Navajo Indian Reservation.

References

^ Template:Cite doi/10.1186.2F1757-1626-1-254
^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0.
^ Medical Biochemistry at a Glance. John Wiley & Sons. 28 November 2011. ISBN 1118292405. Retrieved 17 June 2011. Xeroderma pigmentosa is a rare, autosomal recessive disease caused by a defective UV-specific endonuclease. Patients with mutations are unable to repair DNA damage caused by sunlight and have been described as "children of the night."
^ ^a ^b Li, Lei (January 8, 2007). "Chapter 3 Nucleotide Excision Repair". DNA REPAIR, GENETIC INSTABILITY, AND CANCER. World Scientific Publishing. pp. 75–76. ISBN 981-270-014-5.
^ E. C. Friedberg, G. C. Walker, W. Siede, R. D. Wood, R. A. Schultz and T. Ellenberger (2006). DNA repair and mutagenesis. Washington: ASM Press. p. 1118. ISBN 978-1-55581-319-2.{{cite book}}: CS1 maint: multiple names: authors list (link)
^ Template:Cite doi/10.1186.2F1757-1626-1-254

External links

Information

GeneReviews/NCBI/NIH/UW entry on Xeroderma pigmentosum
An article about this disorder from DigiLander.iol.it (in English and Italian)
Cancer.Net Xeroderma Pigmentosum
DermNet systemic/xeroderma-pigmentosum

Charities

Short films

Sloan Science and Film / Short Films / XP by David Barba 10 minutes
Web Site of a Short Film about an Xeroderma pigmentosum (XP) Patient. Film is directed by Kimberly Williams-Paisley

[1] Template:Cite doi/10.1186.2F1757-1626-1-254

[Andrews-2] James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0.

[3] Medical Biochemistry at a Glance. John Wiley & Sons. 28 November 2011. ISBN 1118292405. Retrieved 17 June 2011. Xeroderma pigmentosa is a rare, autosomal recessive disease caused by a defective UV-specific endonuclease. Patients with mutations are unable to repair DNA damage caused by sunlight and have been described as "children of the night."

[Wei-4] Li, Lei (January 8, 2007). "Chapter 3 Nucleotide Excision Repair". DNA REPAIR, GENETIC INSTABILITY, AND CANCER. World Scientific Publishing. pp. 75–76. ISBN 981-270-014-5.

[5] E. C. Friedberg, G. C. Walker, W. Siede, R. D. Wood, R. A. Schultz and T. Ellenberger (2006). DNA repair and mutagenesis. Washington: ASM Press. p. 1118. ISBN 978-1-55581-319-2.{{cite book}}: CS1 maint: multiple names: authors list (link)

[6] Template:Cite doi/10.1186.2F1757-1626-1-254

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