PDF(Pubmed)
Abstract：
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.
摘要：
着色性干皮病（XP）是由参与DNA修复系统的八个基因中的任何一个的双等位基因突变产生的。从而定义了八种不同的基因型(XPA，XPB,XPC,XPD,XPE,XPF,XPG和XP变体或XPV）。除了皮肤和眼科特征，一些患者存在XP神经系统疾病。尚不清楚不同的神经系统体征及其进展在各组之间是否有所不同。因此,我们旨在描述XP神经系统疾病及其在异质性UKXP队列中的演变。XP患者在英国国家XP服务机构进行了随访，从2009年到2021年。记录不同事件的发病年龄。小脑共济失调和其他神经系统体征和症状用共济失调评估和评级量表(SARA)进行评级。非共济失调症状清单(INAS)和日常生活活动问卷(ADL)。患者的突变根据其预测的效果获得评分。收集来自可用辅助测试的数据。招募93名XP患者。三十六（38.7％）报告了神经系统症状，尤其是在XPA中，XPD和XPG组，早期发作和晚期发作形式，通常出现在皮肤和眼科症状之后。XPA,与XPC相比，XPD和XPG患者的SARA评分更高，XPE和XPV。随着时间的推移，XPD的SARA总分显着增加(0.91分/年，95%置信区间:0.61,1.21)和XPA(0.63点/年,95%置信区间:0.38,0.89)。反射减退,失足,上运动神经元标志，舞蹈病,肌张力障碍,在XPA中经常发现动眼体征和认知障碍，XPD和XPG。小脑和全球脑萎缩，轴突感觉和感觉运动神经病,和感觉神经性听力损失是患者的常见发现。一些XPC，XPE和XPV病例出现检查和/或辅助检查异常，提示潜在的神经系统受累。更严重的突变与XPA（严重程度评分每增加1个单位0.40分/年）和XPD（每增加1个单位0.60分/年）的SARA总分的更快进展相关，以及XPA的ADL总分（每增加1个单位0.35分/年）。有症状和无症状的神经系统疾病在XP患者中很常见，神经症状可能是残疾的重要原因。通常,神经系统疾病之前将有皮肤和眼科特征，在患有特发性迟发性神经综合征的患者中，应积极搜索这些疾病。评估小脑功能的量表，尤其是走路和说话，残疾可以在一些群体中表现出进展。突变严重程度可用作临床试验中分层目的的预后生物标志物。
