Uncovering Early Intervention Strategies for Brain Degeneration in “Children of the Night”

Xeroderma pigmentosum (XP), a severe genetic disorder, prevents the body from repairing skin damage inflicted by ultraviolet (UV) light, resulting in skin cancers and possibly neurodegenerative disorders such as hearing impairment and seizures.

An early detection algorithm to anticipate neurodegeneration in individuals with Xeroderma pigmentosum (XP), a genetic disorder triggering UV light-induced skin damage and potential neurological problems, has been developed by researchers. Employing pluripotent stem cells sourced from blood samples, they pinpointed differences in neuron features in XP patients, thereby identifying potential future drug targets to alleviate neurodegeneration.

Xeroderma pigmentosum (XP) is an uncommon and debilitating genetic disorder typified by the inability to repair skin damage caused by ultraviolet (UV) light. Consequently, XP patients develop skin cancers, generally during their childhood. Post-diagnosis, they can be shielded by avoiding sunlight (hence occasionally referred to as ‘children of the night’), donning specialized clothing and sunglasses, and applying sunscreen. However, some also develop neurodegenerative disorders like hearing loss, intellectual function loss, poor coordination, and seizures. XP researchers are prioritizing understanding why this happens and identifying patients who are likely to develop such conditions.

Dr. Sophie Momen, a consultant dermatologist at Guy’s and St Thomas’ NHS Foundation Trust, London, UK, and a researcher in Professor Serena Nik-Zainal’s lab at the University of Cambridge, is set to reveal her team’s work on the development of an early detection algorithm at the annual conference of the European Society of Human Genetics today (Monday). The algorithm predicts patients that might develop such neurodegeneration. XP, being a rare condition that affects one in a million people and considering the challenges of conducting research on the brain—an inaccessible organ in living patients—there has been scarce research in this field until now.

The research team converted blood samples from XP patients with and without neurodegeneration and from family members without XP into pluripotent stem cells (cells that can be directed to differentiate into various cell types). Consequently, the researchers could identify the stem cells that would evolve into brain cells (neurons). Dr. Momen said, “We conducted multiple experiments on these neurons using multi-omic[1] technologies to comprehend why certain XP patients developed neurodegeneration and others did not. This led us to develop our algorithm. This will be beneficial if we can offer something to patients to slow down or halt the onset of neurodegeneration. Our research has exposed possible drug targets, which may achieve just that in the future.”

The researchers were privileged, they note, to have access to a large patient group from the national XP clinic at Guy’s and St Thomas’, where all UK-resident patients with the condition receive care from the same clinical team. “Such a clinic allows patients with rare diseases to receive long-term follow-ups in one location, enabling investigations like ours,” Dr. Momen explains. “This is the first time that such a large number of XP patients have been studied, and their neurons characterized in such detail.”

Since the clinic’s inception in 2010, UK patients have been well-informed about photoprotection and early detection of skin cancers, resulting in extended lifespans. Dr. Momen states, “None of our patients has succumbed to skin cancer. It is often said that XP patients typically die in their 20s and 30s due to skin cancers or neurodegeneration, but this is not always true. Some XP patients primarily develop skin cancers, against which they can take protective measures early on and do not develop neurodegeneration.”

The results might also be valuable in understanding why otherwise healthy individuals develop neurodegeneration with age. Recent years have seen the study of XP patients aid scientists in understanding why some healthy people develop skin cancers after UV light exposure. “We can now extend the findings of our study to comprehend why the faulty DNA repair pathway involved in XP is crucial for brain health. This may help us understand why some people develop neurodegeneration as they age.”

Before the early detection algorithm can be utilized as a predictive tool in clinical practice, further validation studies are required. Clinical trials will also be needed to ascertain if any medications might be effective in halting or delaying neurodegeneration in identified at-risk patients.

Dr. Momen says, “I didn’t expect that we could so clearly characterize the neurons derived from patients with and without neurodegeneration. When we applied proteomics, the results clearly indicated whether patients had neurodegeneration or not. This is very encouraging and, we hope, a step further towards the effective treatment of this distressing condition.”

Professor Alexandre Reymond, the conference chair, said: “Our ability to personalize treatments will translate into a more efficient health system. To achieve this goal, we need new methods to identify those in the population who are at higher risk.”

Notes

Multiomics is a biological analysis approach that integrates various ‘ome’ datasets, for instance, genome, proteome, transcriptome, epigenome, metabolome, and microbiome.

Abstract no. 3869 Functional multi-omic studies reveal ER stress and proteasomal dysfunction in early-onset neurodegeneration in XP

The Wellcome Trust and Cancer Research UK funded the research.

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More about Xeroderma pigmentosum neurodegeneration

• Xeroderma pigmentosum
• Neurodegeneration
• Pluripotent stem cells
• Guy’s and St Thomas’ NHS Foundation Trust
• European Society of Human Genetics
• Multi-omics technologies
• Proteomics