Neurological disease in xeroderma pigmentosum: prospective cohort study of its features and progression.

Xeroderma pigmentosum (XP) results from biallelic mutations in any of eight genes involved in DNA repair systems, thus defining eight different genotypes (XPA, XPB, XPC, XPD, XPE, XPF, XPG and XP variant or XPV). In addition to cutaneous and ophthalmological features, some patients present with XP neurological disease. It is unknown whether the different neurological signs and their progression differ among groups. Therefore, we aim to characterize the XP neurological disease and its evolution in the heterogeneous UK XP cohort. Patients with XP were followed in the UK National XP Service, from 2009 to 2021. Age of onset for different events was recorded. Cerebellar ataxia and additional neurological signs and symptoms were rated with the Scale for the Assessment and Rating of Ataxia (SARA), the Inventory of Non-Ataxia Signs (INAS) and the Activities of Daily Living questionnaire (ADL). Patients' mutations received scores based on their predicted effects. Data from available ancillary tests were collected. Ninety-three XP patients were recruited. Thirty-six (38.7%) reported neurological symptoms, especially in the XPA, XPD and XPG groups, with early-onset and late-onset forms, and typically appearing after cutaneous and ophthalmological symptoms. XPA, XPD and XPG patients showed higher SARA scores compared to XPC, XPE and XPV. SARA total scores significantly increased over time in XPD (0.91 points/year, 95% confidence interval: 0.61, 1.21) and XPA (0.63 points/year, 95% confidence interval: 0.38, 0.89). Hyporeflexia, hypopallesthaesia, upper motor neuron signs, chorea, dystonia, oculomotor signs and cognitive impairment were frequent findings in XPA, XPD and XPG. Cerebellar and global brain atrophy, axonal sensory and sensorimotor neuropathies, and sensorineural hearing loss were common findings in patients. Some XPC, XPE and XPV cases presented with abnormalities on examination and/or ancillary tests, suggesting underlying neurological involvement. More severe mutations were associated with a faster progression in SARA total score in XPA (0.40 points/year per 1-unit increase in severity score) and XPD (0.60 points/year per 1-unit increase), and in ADL total score in XPA (0.35 points/year per 1-unit increase). Symptomatic and asymptomatic forms of neurological disease are frequent in XP patients, and neurological symptoms can be an important cause of disability. Typically, the neurological disease will be preceded by cutaneous and ophthalmological features, and these should be actively searched in patients with idiopathic late-onset neurological syndromes. Scales assessing cerebellar function, especially walking and speech, and disability can show progression in some of the groups. Mutation severity can be used as a prognostic biomarker for stratification purposes in clinical trials.

Ocular surface biopsies of patients with xeroderma pigmentosum in the United Kingdom: a retrospective observational case series.

BACKGROUND/AIMS: To describe the results of all ocular surface biopsies performed on patients with xeroderma pigmentosum (XP) under the care of the UK Nationally Commissioned XP Service as well as the treatment of any subsequent ocular surface conditions diagnosed. METHODS: Retrospective analysis of medical records. All patients with XP seen by the service from 2010 to 2019 were included and those with ocular surface biopsies were identified. Data was collected on demographics, complementation subgroup (A-G and V), biopsy details, histopathological analysis and subsequent management. RESULTS: Of 108 patients seen in our service, 17 underwent at least one ocular surface biopsy. 45 biopsy samples were available from 13 patients of which 65% were performed on patients from complementation subgroup C (XP-C). Biopsies were categorised as either non-mapping (clinically abnormal ocular surface tissue) or mapping (multiple sites including clinically normal tissue). 67 percent of non-mapping biopsies had a mass as their indication and 46% showed ocular surface squamous neoplasia. General non-dysplastic damage was seen in 67% of non-mapping biopsies and melanocytic changes were seen in 25% of non-mapping and 81% of mapping biopsies. 47 percent of biopsy outcomes required no additional treatment but, of those that did, 50% received mitomycin C. CONCLUSIONS: This is the largest reported series of ocular surface biopsies in patients with XP. It identifies a background of ocular surface melanocytic, degenerative and inflammatory changes, with patients with XP-C showing the most severe effects. We highlight challenges faced in interpreting their histopathology and in planning subsequent treatments.