A Rare Autosomal Recessive Disease Biology Essay

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Xeroderma Pigmentosum is a rare autosomal recessive disease affecting about 1 in 250,000 people in Europe which greatly reduces the quality of life of its sufferer. XP patients have a much greater chance of developing skin neoplasms, internal organs neoplasms or even neurological disorder due to a defective Nucleotide Excision Repair (NER) pathway. In this report, I found out that most experts in this field do believe that reactive oxygen species which can cause DNA lesions that can only be repaired by the NER pathway is the main cause of the neurological disorder in XP patients. However, modern technology can not yet prove this is the case. The treatments for XP are mainly preventive rather than interventionist. However, more new treatments have been proved to be effective in helping XP patients with the aid of modern technology. The bacterial enzyme T4 Endonuclease V has recently been put in use for treating XP and gene replacement therapy might be a possible treatment for the future.

The aim of this article is to gain a general overview of Xeroderma Pigmentosum (XP), to understand the possible causes of neurological disorder in XP patients as well as the current and possible treatments for XP.

To achieve my aim, I have first researched using various textbooks to understand DNA repair and damage. After that, I set my focus on Xeroderma Pigmentosum and used two online databases "Medline" and "PubMed" to look for review articles on XP in order to have a basic understanding of XP. I used two keywords "Xeroderma Pigmentosum" and "Neoplasm" to achieve the goal (Table 1). After having some basic knowledge of XP, I found that the neurodegeneration and the current treatments for XP are quite interesting so I decided to set my aim of these two topics. By searching for "Xeroderma Pigmentosum" and "Neurodegeneration" on "Medline", I was able to look for some useful articles on my first aim (Table 2). I also searched for "Xeroderma Pigmentosum" and "Gene Therapy" for my second aim (Table 3).

Cancer which can be considered as an uncontrolled growth and spread of cells is one of the top three causes of mortality in the world.(1) With the WHO predicting that it is going to be the top killer by 2010(2), it is vital for the public and medical professions to understand its aeitiology and pathogenesis in order to fight against it.

Generally, the incidence of cancer is increased with aging as the chances of DNA mutation increases with age for lots of different reasons and we now understand that our DNA needs at least 5-6 mutations in order for cancer to develop(3). However, there are some other risk factors which might increase the susceptibility such as smoking, alcohol, radiation and so on. One of the most interesting factors is probably the cancer-prone DNA repair deficiency syndrome, for example Xeroderma Pigmentosum, Cockayne's Syndrome, Werner Syndrome. Patients with these syndromes are characterised by not being able to repair the DNA damage precedes the mutation and thus enhance the chances of getting cancer(4). The aim of this article is to discuss the genetic disorder Xeroderma Pigmentosum (XP). To understand this disorder, we have to first look into the types of DNA damages, their causes and their specific repair mechanism.

DNA damage

Mutation happens for lots of different reasons. It can occur spontaneously or naturally, for example DNA strand looped out during replication, hence causes a deletion of base. The other main types of spontaneous mutation are Depurination (Fig.1) i.e. detachment of Adenosine or Guanine from its deoxyribose sugar due to the hydrolysis of water and deamination (Fig.2) i.e. oxidation of bases by an oxidising agent e.g. nitrous acid. Spontaneous mutation occurs at a rate varies between and 4Ã- per gene per generation.(5-7)

Fig.1-Example of depurination(8)

F.g.2-Examples of deamination(9)

Another type of mutations could be elicited by the exposure of organisms to substantial mutagens, like chemicals or radiation.(7) The focus of this report is mainly on radiation.

Radiation is probably the most well-known type of mutagen and there are three different types of radiation, each of which has its specific effects. The first type is ionising radiation which generates reactive oxygen species (ROS) e.g. H2O2, OH· when passing through cells. These oxygen species oxidise DNA bases and thus causes base mispairing. The second type of radiation is the ultraviolet light. It has a wavelength ~ 260nm and is greatly absorbed by the bases. The absorbed energy causes the fusion of adjacent pyrimidine dimers on the same DNA strand and will mainly affect thymine (Fig.3). The results of this type of mutation are stoppage of DNA replication and transcription, which affects the normal function of cells significantly. Ionising radiation such as X-Rays can have a direct effect on DNA strand as well. It reacts directly with deoxyribose backbone and causes double-strand breaks in the DNA and may in turn completely stop DNA replication because of the significant damage induced.(6-7)

Fig.3-Production of thymine- thymine dimers by UV light(10)

The Cell Cycle

Fig.4-Simplified diagram of the cell cycle(11)

There are 4 main stages in the cell cycle, G1 (Gap 1), S (Synthesis), G2 (Gap 2) and M (Mitosis) and the duration for each cell cycle is around 24 hours. As from the diagram, each stage has its particular functions. There are two important checkpoints between G1 and S phase and G2 and M phase and they are called G1-to-S checkpoint and G2-to-M checkpoint respectively. These checkpoints are important as they detect the existing DNA damage and generate signals for DNA repair. If the DNA damage is too severe and beyond repair, tumour suppressor like p53 will come into action. This prevents the mutated cell from dividing and developing into cancer cells and the cell either goes into apoptosis or senescence.(5, 7)

DNA Repair

As previously mentioned, each type of mutation has its own specific repair mechanism and this paper is to focus on nucleotide excision repair (NER) (Fig.5), which is the only relevant mechanism to XP. NER helps repairing pyrimidine dimers and bulky DNA adduct to bases. This repair system works by detecting distortion to the double helix shape of the polynucleotide strand such as thymine-thymine dimers. This distortion triggers a series of events to restore the stability of the DNA. Firstly, XPC is the protein responsible for recognising the distortions. Then XPA and XPD generate a bubble (Fig.5) - a ring-like structure formed by unwinds of DNA double-strand around the damaged site. The bubble creates two cleavage sites for ERCC1-XPF (5'side) and XPG (3'side) to act on. The cleavage sites are exactly 24 nucleotides away from the lesion on the 5'side and 5 nucleotides from the 3'end. Finally, DNA helicase releases the fragment that has been cut out, and once again DNA polymerases and ligase fill in the gap and repair the lesion. It is important to understand this repair mechanism as several genetic disorders like Xeroderma Pigmentosum, Cockayne's syndrome and trichothiodystrophy are connected with defects in the nucleotide excision repair.(6-7, 12)

Bubble mentioned above

Fig.5-Simplified diagram of NER(13)

Brief introduction of XP

XP was first described by two dermatologists in Vienna, Ferdinand Ritter von Hebra and Moritz Kapozi in the year 1870. The term "xeroderma" denotes "parchment skin" while "pigmentosum" was added later to indicate and emphasize the characterised pigmentation abnormalities(14-15). At that time, no one knows exactly what causes XP and the link between XP and defective NER was established by Cleaver in 1968(14, 16). Researchers have identified that there are 8 complementation groups of XP and they are XP-A-G and XP variant group. XPA-G are known as the classical forms of XP while the XP-V which is not associated with a defective NER, constituting 20% of the cases of XP. Instead of having a defective NER pathway, XP-V patients have gene coded for a defective form of DNA polymerase, causing a thymine-thymine dimers bypass during replication. Each complementation group represents a mutated form of a specific gene, i.e. complementation group A means the patient has a mutated version of the XP-A gene, etc.(14, 17)

Patients with XP have a high photosensitivity to UV radiation as their cells have a defective nucleotide excision repair pathway. As a result, those cells exposed to UV radiation will have a high mutation rate and causes a high occurrence of skin cancer as well as affecting ocular tissues. XP can also cause neurodegeneration or neurological diseases and it would be discussed later.(14-15)

Fig.6-Images of XP patients(18)

Prevalence of XP

XP is a rare autosomal recessive disease, which means that the disease will only be developed in patients with two mutated form of XP genes, XP will not develop in patients with a normal and a mutated gene as the mutated gene is recessive and wouldn't be expressed but he/she would be a carrier of XP. XP has a dispersed worldwide distribution, varying from 1 in 40,000 in Japan and 1 in 250,000 in Europe and USA. Symptoms of XP can start as early as first exposure to sunlight but the average age of onset of symptoms is around 2 years. There is also a greater than 1000-fold increased risk of skin cancers development connected with XP and the average age of onset of the foremost skin cancer or neoplasm is 8 years, around 50 years earlier comparing with the public. The life spans of XP patients are reduced by around 30 years as many of them die of neoplasia. As mentioned before, NER also removes bulky DNA adduct to bases, such lesions are induced chemically by chemicals like alkylating agent rather than UV radiation. This explains why XP patients also have a 10 to 20- fold higher risk of forming internal neoplasms below the age of 20.(7, 12, 14, 17)

Neurodegeneration of XP

It is quite easy and straight forward to understand why XP patients are prone to skin cancers and even internal organs neoplasms. However, there is one interesting clinical feature that is still unexplained and remains puzzling and this is the neurodegeneration of XP patients, which is affecting approximately 20% of the XP patients. Since UV radiation cannot penetrate through our skull, thymine-thymine dimers would not be the type of mutation occurring in the neurological tissues e.g. brain tissues, neurons and so on. Thus, damages in the neurological tissues are more likely to be caused by chemicals like alkylating agents, ROS which damages DNA by oxidising DNA bases or adding bulky adducts to it and are also repaired by the NER pathway(14, 19). The following section will discuss some of the symptoms as well as possible causes of this interesting feature.

The first symptom of the XP neurological disorder is reduced tendon reflexes, possibly as a result of peripheral nervous system and ataxia degeneration. With the progression of the disease, the patient will also develop hearing loss and other motor anomalies and become wheelchair bound eventually. Dementia and progressive cognitive decline are also the possible outcomes of the XP neurological disorder.(19)

There are several candidates for the causes of neurodegeneration in XP patients but there are yet to be a confirmation of the ultimate cause of those symptoms. ROS is a possible cause for neurodegeneration in XP patients. These species react with our DNA bases or deoxyribose sugar and generate some form of lesions which should be repaired by our NER pathway, for example, hydroxyl radical, a ROS which reacts with deoxyribose sugar and produces a lesion called cyclopurine-deoxynucleosides (Fig.7). This type of lesion can only be repaired by NER and will accumulate in our cells if not repaired.(19)

Fig.7-Formation of cyclopurine-deoxynucleosides(19)

Aldehydes and thymine glycol are some other possible reagents that might cause neurodegeneration in XP patients. Aldehydes react with DNA, forming a DNA lesion called Propano-deoxyguanosine lesion (PdG) which might block transcription by RNA polymerase. Thymine glycol causes oxidative damage to the DNA and produces "Nonbulky" oxidatively-induced lesion, which could be repaired by the NER pathway as well.(19-20)

It is important to understand the fundamental cause of neurodegeneration in XP patients, by doing so; we can develop a possible treatment, not only for reducing the incidences of neurological disorder in XP patients, but for improving the patient's quality of life as well. For example if H2O2 is the cause of the neurodegeneration, we can develop a pathway which reduces the level of H2O2 in patient's body and reduces the level of H2O2 in their cells.(19)

Diagnosis for XP

XP can be diagnosed in different ways. Diagnosis can be made clinically by examining eye, skin and nervous system, a detailed family history could also aid in the diagnosis. As XP cells have a defective NER, a functional test for DNA repair on living cells may also be used for diagnosis. Nowadays, genetic testing of XPA and XPC genes is available clinically but the testing for the other genes is only available on a research basis.(21)

Treatment for XP

At the moment, there is no cure for XP. Primary care for XP is probably more important than secondary care in terms of prevention and regulation of the disease. Once the patient is diagnosed with XP, he/she should avoid exposure to sunlight and other mutagens like cigarette smoke or alcohol immediately. XP patients should also wear protective clothing like UV suits, sunglasses and gloves in order to get minimum exposure to UV radiation, reducing the chances of getting further DNA damage. UV radiation levels should also be measured routinely at in-door environment for safety reasons. XP patients should also consume sufficient vitamin D in their diet to compensate for the insufficient production of vitamin D by their body.(21)

As the disease progresses, XP patients might develop small lesions in the skin which could be treated using liquid nitrogen or topical 5-fluorouracil. Skin cancers, neoplasms of the eyelids, conjunctiva and cornea developed could be removed surgically. In patients with multiple skin cancers, high-dose oral isotretinoin may be used to prevent the formation of new neoplasms. X-radiation therapy can also be used to treat cancer with close monitoring as most XP patients are not hypersensitive to therapeutic X-rays.(21)

Gene replacement therapy, i.e. replacing the mutated gene by insertion of a normal set of gene might also be a possible treatment in the future but very few research groups are working on that(22). In 2001, a study showed that the insertion of the bacterial DNA repair enzyme T4 Endonuclease V (also known as denV T4 endonuclease, an enzyme which removes the glycosyl bond of the pyrimidine dimer(23)) in liposomes into XP patients can actually increases the rate of repair of UV induced lesion, lowering the chances of new skin neoplasms development and it is now one of the treatments of XP. (21, 24)

A research on gene replacement therapy published in 2003 was supportive for the XP patients(25). The result was quite promising as the researchers successfully restore the DNA repair capacity of XP cells after the insertion of gene(25). Although the efficacy of the treatment is high, its reliability is relatively low and there are definitely some limitations in the study. Firstly, it was an in vitro experiment; results shown in test tube would not be necessarily the same as in mammals or humans. Secondly, the research only focused on the XP-C cells so it is still unsure whether gene replacement therapy would work on other XP genes. Thirdly, the research was only done on cells from 2 patients; a larger sample size, preferably samples from different ethnicity or a more comprehensive study is needed to confirm the effectiveness in clinical practice.

The bacterial enzyme T4 Endonuclease V was proved to be a quite effective treatment for XP as mentioned previously. The study that I looked into was a randomised study and involves 30 patients, with 20 in the intervention group and 10 in the placebo group(24).

Overall, the study is quite reliable as it was a randomised double-blind study which minimise the bias that might affect the final outcomes of the study. However, some issues do present in the trial and should be addressed for future research. Firstly, the sample size is relatively small; a larger sample size is needed to confirm the effectiveness of the bacterial enzyme. Secondly, the ratio of patients in the two study groups varies, which might affect the statistical outcome significantly, especially for a small-sized study.

Conclusions, limitations and further study

To conclude, with the progression of technology and more time and resources spent on XP, we have now got much more understanding of XP, comparing with the first discovery of the disease. However, we shouldn't be satisfied with it and stop here as there is still a long way to go to get a full understanding of this genetic disorder.

From my research, I found out that majority of the researchers favour ROS as the underlying cause of the neurodegeneration in XP patients. Firstly, our nervous system has a high demand for oxygen and ROS produced during respiration could potentially accumulate in our nervous system, causing damages to our DNA. Secondly, ROS causes DNA lesion that might only be repaired by the NER pathway. Thirdly, ROS can generate lesions that could block the RNA transcription, contributing to the loss of proteins and eventually cell death(19). All of these evidences suggested that ROS are possible causes of the neurological disorder in XP. At the moment, the resources are not available to prove that it is the case and there might be some other DNA damages that cause neurodegeneration which have not been discovered yet. However, I am sure with all the hard-work, and the advancement of technology, this mystery would soon be solved.

In my opinion, with the lack of treatment for XP at the moment, preventive measures would be the most important things. As a result, diagnosis of XP should be made as quickly as possible. Genetic screening for new born baby might be a method for early diagnosis of XP. However, XP is a rare genetic disorder which is not so cost-effective for genetic testing as it is still relatively costly to diagnose XP in a molecular level and we should probably look for a cheaper alternatives and an easier way for diagnosis of XP.

As for the future treatment, as I have previously mentioned, understanding the underlying cause of neurodegeneration is important for reducing the incidences of neurological disorder in XP patients and would improve the patient's quality of life. My opinion on gene replacement therapy is that it is viable as the technology is available but not practical yet. First of all, although our skins are quite easy to reach, we should bear in mind that the skin has got a large surface area and would be quite difficult to insert replacement genes into the majority of the skin cells. We have now developed a method of inserting genes by genetically modified retrovirus, which could deliver genes into our cells quite easily. However, the technology for this is still premature and it is quite hard to monitor the viruses and might generate side effects like escape of viruses to the nature, mutation of the viruses and so on. I think that the information on gene replacement therapy for XP patients is quite limited; a lot more need to be done to address this issue. Finally, I do believe that with the advance of technology and as our knowledge of gene therapy progresses, a cure for XP should soon be found.

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