XP and NER

Introduction

Many Caucasians value tanned skin, and it is thought as a symbol of high status. However, there are people out there who could never dream of having a golden skin complexion, since the sunlight is fatal to them. These people are actually suffering from xeroderma pigmentosum, or simply called XP; a rare genetic inheritance disease. In this report I would explain what exactly XP is and how can the patients live with the incurable disease.

XP and NER

Discovered in 1874 by Hebra and Kaposi, xeroderma pigmentosum is a disorder due to the mutation of seven genes involved in the NER (nucleotide excision repair) pathway, a mechanism to repair damaged DNA. The damaged DNA usually occurs in the form of a pymiridine dimer. According to Emanuel and Shcienfeld (2007), there are 2 types of NER; ‘global genomic NER' (GGR) and ‘Transcription- Coupled NER' (TCR).

XP is categorised into XP type A (XPA), XP type B (XPB), XP type C (XP C), XP type D (XPD), XP type E (XPE), XP type F (XPF), XP type G (XPG) and XP variant (XPV). Any of these types of XP causes a patient's skin and eyes to become hypersensitive to the UV light.

The solutions

Photoprotection

UV light, which is abundant in the sunlight, is a short wavelength wave which can damage DNA and give rise to cancer. Sufferers could easily develop various types of cancers, including the basal cell carcinoma, squamous cell carcinoma and malignant melanoma once their skin and eyes are exposed to the UV radiation (the risk is 1000~2000-fold higher than normal individuals). When the DNA is struck by UV radiation, adjacent pymiridines (single-ring bases) may be altered structurally and the interaction between the altered pymiridines forms a pymiridine dimer. NER in normal people could effectively excise the dimer to repair the damage, but not the one in the XP patients.

Thus, patients are advisable to spend most of their time indoors, with the windows covered with filters. Apart from that, National Institute of Health (2005) recommends XP patients to put on long-sleeved clothing, a pair of UV-absorbing sunglasses and a hat whenever they are outside during the day.

Moreover, sunscreen cream with SPF 15 and higher should be applied on all exposed skin all the time to minimise the risk of getting sunburns from both recognised and unrecognised sources of UV radiation. According to Wikipedia contributor, a sunscreen contains substances which filter the UV light. The substances are categorised into organic chemical compounds, organic particulates and inorganic particulates. While compounds like oxybenzone can absorb UV light only, inorganic compounds like TiO2 and ZnO can reflect and scatter the radiation. Sunscreens reduce the production of cytokines such as tumour necrosis factor (TNF) which is linked to immunosuppression. (Lim and Draelos, 2008).

Besides that, according to International Research Agency for Cancer (2001), an SPF-15 formulation containing 7.5% ethylhexyl metoxycinamate and 4.5% benzophenone-3 reduces the number of pyrimidine dimers in the skin induced by solar-simulated UVR. Experiments using mice analogous to human skin also showed that several organic sunscreen products lessen UVR-induced DNA damage.

Apart from sunlight, XP patients should not be exposed to any carcinogens. Carcinogen is one of the mutagens that lead to cancer. Carcinogenic substances, like the smoke from tobaccos and charred food, produce free-radicals which could alter the DNA in the body cells. An XP patient should not smoke or live with a smoker, as the chance of getting lung cancer is much higher than the normal people. (276 words)

Regular medical check-up

Even though there is no evidence that neurological problems are associated with UV light exposure, but it has been found that about 20 to 30 percents of the XP patients develop neurologic abnormalities. These neurological complications include mental retardation, speech disorder, high frequency of hearing-loss and de Sanctis-Cacchoine Syndrome. Thus, neurologist's consultation is needed since majority of the genetic disorder patients usually do develop such conditions.

Medical check-up with dermatologist and ophthalmologist helps to slow down the destructive progress of the disease. According to National Institute of Health (2005), patients must attend the check-up at least once in 3 to 6 months so that any newly developed cancer can be detected at the earliest stage. It is then followed by the removing procedure, which depends on the size and the location of the tumour. Smaller tumour can usually be removed using freezing technique, electrical needle and minor surgery, while the extensive one may need skin-grafting surgery.

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Apart from that, according to Diwan (2008), ocular problems occur in nearly 80% of individuals with XP. Therefore, medical check-up allows early detection and treatment on ocular diseases such as conjunctivitis, keratitis and corneal ulcer. Corneal transplant may have to be performed if the patient's vision has become severely impaired. Diwan is an associate professor at Department of Pathology of University of Texas. He contributed articles on treatment and medication for XP to eMedicine website, a renowned online clinical reference.

Benefits and Risks

Photoprotection and regular medical check-up have been proven effective in increasing the life-span of XP patients. According to Ahmad and Hanaoka (2008), by using this method patients with milder condition may survive up to 40 years old. Sunscreens have proven very effective in reducing the incidence of skin cancer in XP individuals. (Kondoh et al,1997 in Sunscreens).

Frequent use of sunscreen and non-exposure to sunlight leads to a question whether they inhibit the production of vitamin D. Some argues that photoprotection causes hearing loss among XP sufferers as hearing impairment is linked to low level of vitamin D. Nevertheless, various researches showed that it was not the case. Sollitto, Kraemer and DiGiovanna (1997) followed eight XP patients who practised rigorous photoprotection for 6 years and they found that the patients' vitamin D level remained normal. Nevertheless, patients are advised to measure their vitamin D levels every three months. Another issue is the systemic toxicity of sunscreens. Toxicity is caused by the penetration of UV filter's micro-fine particles into the skin. However, according to Lim and Draelos (2008), several skin-penetration studies using micro-fine (nano-)TiO2 found that TiO2 does not go deeper than the stratum corneum (the top layer) of the skin.

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Social and economic implications

alone-1.jpg Photoprotection may deny a patient's right to socialise and enjoy outdoor activities. Patients are also forced to lead a nocturnal life, and therefore, chances to get a proper education and a desired job like normal individuals are very slim. Economically, it is such a great loss as their potential and talent cannot be exploited in the work field.

Furthermore, these patients could easily develop psychological problem due to depression, loneliness and the risk of getting cancers. Although XP patients could still go out during the day with ‘UV-safe' attire, the effectiveness of the garments to protect them is still questionable. As stated in Xeroderma Pigmentosum Inc. website, many ‘UV-safe' garments available in the market are designed to protect those with normal skin, not those with mutated DNA-repair genes.

Getting a frequent medical check-up may be a problem for patients from not-so-well-to-do families. Clinical examinations and surgical operations are expensive; and I believe this could burden the family financially. Besides that, they also have to spend a lot on the special garments. As we have discussed earlier, many of the ‘UV-safe' garments out there do not guarantee a ‘UV-zero' protection for the patients. The garments have to be tested to determine the extent of protection they provide. However, the basis of the conclusion to interpret the result (whether they are safe for the XP patients or not) is still unknown.

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The Alternatives

Prenatal screening method

Many scientists agree that xeroderma pigmentosum is passed down in the form of autosomal recessive trait, where the disorder is expressed only when a pair of alleles responsible for XP is in the form of homologous recessive. Therefore, XP can only be inherited if both of the parents are carriers for the defective gene.

Since the mutation occurs on the autosomal chromosomes, the disease is passed down regardless gender. However, the birth of the children with XP can be avoided using prenatal screening method. According to Fullick (2008), prenatal screening is an option for couples who are at a high risk of having children with genetic condition. For genetic disorders like XP, amnionicentesis and chorionic villus sampling are two tests involved in prenatal screening. The tests are carried out during early pregnancy and if the baby is found to be affected by XP, the couples can choose to continue with the pregnancy or to undergo abortion.

Some people argue that adopting prenatal screening is unethical. Even though the disease can be detected during infancy, but according to NORD (2003), there are cases where the symptoms of XP would only show up later during adulthood. At this point, the patient's condition might have become very severe due to lack of photoprotection from the early age.

Protein therapy

This new approach involves the application of genetic engineering, where a DNA repair enzyme called T4 endonuclease V (T4E5) is encapsulated in liposome and used as a topical cream or lotion. A double-blinded study done by Yarosh et al on 30 XP patients reported that the annual rate of actinic keratoses (rough, scaly patches of skin) incident for the group treated with T4E5 is significantly lower, which is 8.2% compare to that for the group treated with the placebo, which is 25.9%. However, the annual rates of new lesions between both of the groups do not show a large difference.

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Another research was carried out by Wolf et al, where the lotion was applied after a controlled UV exposure on 12 XP patients and 15 normal individuals with a history of skin cancer. The biopsy result later showed that the CPDs (a photo-product resulted from DNA being exposed to UV light) had reduced by 15% whereas for the normal individuals, the CPDs had reduced by 10%. Nevertheless, according to Busch, (1997) the lotion is still not proven to be effective since the enzyme would not persist in the skin indefinitely. I found Bush's claim on Xeroderma Pigmentosum Society, Inc. website, an organisation dedicated to XP patients and caregivers worldwide valid. Even so, this information is already outdated. The latest discovery in 2000 by Wolf et al proves that the topical lotion may open new revenues for photoprotection. Unlike other sunscreening agents, the lotion gives immunoprotective effects, where the immune system of the patients is protected sufficiently against the effects of UV light.

The effectiveness of this method is further supported by a recent article published on Medical News Today on 2007. The article reported that a bio-pharmaceutical company, AGI Dermatics has been granted Fast Track designation by the US FDA for T4E5 lotion, under the brand name of Dimericine. Since there is currently no specific drug available to treat XP, the designation may help to shorten the time taken to bring the drug to market in the future.

Conclusion

In short, I personally believe that with today's ever advancing technology, one day people with xeroderma pigmentosum could be cured so that they can live normally under the sun.

References

Ahmad, S.I. and F. Hanaoka. 2008. Molecular Mechanisms of Xeroderma Pigmentosum. 166p. New York: Springer

Busch, D. 1997. Gene therapy and protein therapy. Available from: http://www.xps.org/research_discovery.htm. Accessed on 16th March 2009

DermNET NZ. 2008. Xeroderma pigmentosum. Available from : http://www.dermnetnz.org/systemic/xeroderma-pigmentosum.html. Accessed on 16th March 2009.

Emanuel, P. and Shcienfeld, N. 2007. A review of DNA repair and possible DNA-repair adjuvants and selected natural anti-oxidants. Dermatology Online Journal. [Internet]. 13 (3): 10. Available from: http://dermatology.cdlib.org/133/reviews/DNA/scheinfeld.html. Accessed on 16th March 2009.

Diwan, A. H. 2008. Xeroderma Pigmentosum Treatment & Medication. Available from: http://emedicine.medscape.com/article/1119902-treatment. Accessed on 16th March 2009.

Fullick, A. 2008. Edexcel AS Biology Student's Book. 270p. United Kingdom: Pearson Education Ltd.

IARC Working Group on the Evaluation of Cancer-preventive Agents, Harri Vainio, World Health Organization, Franca Bianchini, International Agency for Research on Cancer. 2001. Sunscreens. 193p. France: IARC

Karp, G. 2002. Cell And Molecular Biology : Concepts and experiments. 785p. New York: John Wiley and Sons, Inc.

Lim, H.W. and Z.D. Draelos. 2008. Clinical Guide to Sunscreens and Photoprotection. 300p. New York: Informa Health Care.
Medical News Today. 2007. Dimericine(R) Receives FDA Fast Track Designation For Treatment Of Photosensitivity In XP Patients. Available from: http://www.medicalnewstoday.com/articles/81602.php. Accessed on 11th April 2009.

National Institutes of Health. 2006. Understanding Xeroderma Pigmentosum. Available from: www.xpfamilysupport.com/docs/UnderstandingXP.pdf. Accessed on 15th March 2009.

National Organisation for Rare Disorder (NORD). 2003. Xeroderma Pigmentosum. Available from: http://www.rarediseases.org/search/rdbdetail_abstract.html?disname=Xeroderma%20Pigmentosum. Accessed on 17th March 2009.

Sollitto, R.B., Kraemer, K.H., and J.J. DiGiovanna. 1997. Normal vitamin D levels can be maintained despite rigorous photoprotection: six years' experience with xeroderma pigmentosum. Journal of the American Academy of Dermatology. 40(3): 497.

Wikipedia contributors. 2009. Nucleotide excision repair. Available from: http://en.wikipedia.org/w/index.php?title=Nucleotide_excision_repair&oldid=277268352. Accessed on 17th March 2009.

Wikipedia contributors. 2009. Sunscreen. Available from: http://en.wikipedia.org/w/index.php?title=Sunscreen&oldid=300484024. Accessed on 17th March 2009.

Wikipedia contributors. 2009. Xeroderma pigmentosum. Available from: http://en.wikipedia.org/w/index.php?title=Xeroderma_pigmentosum&oldid=272404080. Accessed on 25th February 2009.

Wolf, P., and et al. 2000. Topical treatment with lipsomes containing T4 endonuclease V protects human skin in vivo from ultraviolet-induced upregulation of interleukin-10 and tumour necrosis factor-a. J Invest Dermatology. 114: 149-156

Yarosh, D., Klein, J., O'Connor, A., Hawk, J., Rafal, E., and P. Wolf. 2001. Effect of topically applied T4 endonuclease V in liposomes on skin cancer in xeroderma pigmentosum: a randomised study. Lancet. 357(9260): 926-9.

Xeroderma Pigmentosum Society, Inc. 2005. XP Society Position on ultraviolet radiation and protection. Available from: http://www.xps.org/protection.htm. Accessed on 10th March 2009.

 

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