Xeroderma pigmentosum (XP) is a rare genetic disorder that prevents the skin from repairing damage caused by ultraviolet (UV) light exposure.
As a result, patients with XP are prone to developing skin cancers, often during childhood. These individuals must take measures to protect themselves from sunlight, such as wearing special clothing, sunglasses, and sunscreen. However, some patients also experience neurodegenerative conditions like hearing loss, cognitive decline, coordination problems, and seizures. Understanding the underlying causes of these conditions and identifying patients at risk is a key focus for XP researchers.
Dr. Sophie Momen, a consultant dermatologist at Guy’s and St Thomas’ NHS Foundation Trust in London and a researcher at the University of Cambridge, will present her team’s work on developing an early detection algorithm to predict which XP patients may develop neurodegeneration at the annual conference of the European Society of Human Genetics. Due to the rarity of XP and the difficulty of studying the brain in live patients, there has been limited research in this area.
The researchers collected blood samples from XP patients with and without neurodegeneration, as well as from unaffected family members, and converted these samples into pluripotent stem cells. They specifically focused on stem cells that can differentiate into brain cells or neurons. By conducting various experiments on these neurons using multi-omic technologies, the researchers aimed to understand the factors contributing to neurodegeneration in some XP patients but not others. Based on their findings, they developed an algorithm that could be useful in slowing down or preventing the onset of neurodegeneration. The research also identified potential drug targets for future treatments.
The researchers benefited from having access to a large group of XP patients from the national clinic at Guy’s and St Thomas’. This centralized clinic allowed for long-term follow-up and in-depth investigations. It was the first time that such a comprehensive characterization of XP patients and their neurons had been conducted.
Since the establishment of the clinic in 2010, UK patients have received extensive education about photoprotection and early detection of skin cancers, resulting in longer lifespans. None of the patients under the care of the clinic have died from skin cancer. It is important to note that not all XP patients develop neurodegeneration; some primarily experience skin cancers and can take precautionary measures at an early stage.
The results of the study may also contribute to understanding why certain individuals without XP develop neurodegenerative conditions as they age. Studying XP patients has provided insights into why some people develop skin cancers after UV exposure. The findings can now be extrapolated to the understanding of how the faulty DNA repair pathway involved in XP is connected to brain health and the development of neurodegeneration in the general population.
Further validation studies are needed to confirm the accuracy of the early detection algorithm before it can be implemented in clinical practice as a predictive tool. Additionally, clinical trials will be necessary to explore potential medications that could halt or delay neurodegeneration in at-risk patients.
Dr. Momen expresses surprise at the clarity with which the neurons derived from XP patients with and without neurodegeneration could be characterized. The use of proteomics allowed for clear differentiation between the two groups. These results are encouraging and represent progress towards finding effective treatments for this distressing condition.
Professor Alexandre Reymond, the conference chair, emphasizes the importance of personalizing treatments to create a more effective healthcare system. Achieving this goal requires innovative approaches to identify individuals in the population who are at higher risk.