Department of Neurology, Clinical Dementia Center and National Reference Center for CJD Surveillance, University Medical School, Göttingen, Germany.
German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.
Brain. 2022 Apr 18;145(2):700-712. doi: 10.1093/brain/awab350.
Genetic prion diseases are a rare and diverse group of fatal neurodegenerative disorders caused by pathogenic sequence variations in the prion protein gene, PRNP. Data on CSF biomarkers in patients with genetic prion diseases are limited and conflicting results have been reported for unclear reasons. Here, we aimed to analyse the diagnostic accuracy of CSF biomarkers currently used in prion clinical diagnosis in 302 symptomatic genetic prion disease cases from 11 prion diagnostic centres, encompassing a total of 36 different pathogenic sequence variations within the open reading frame of PRNP. CSF samples were assessed for the surrogate markers of neurodegeneration, 14-3-3 protein (14-3-3), total-tau protein (t-tau) and α-synuclein and for prion seeding activity through the real-time quaking-induced conversion assay. Biomarker results were compared with those obtained in healthy and neurological controls. For the most prevalent PRNP pathogenic sequence variations, biomarker accuracy and associations between biomarkers, demographic and genetic determinants were assessed. Additionally, the prognostic value of biomarkers for predicting total disease duration from symptom onset to death was investigated. High sensitivity of the four biomarkers was detected for genetic Creutzfeldt-Jakob disease associated with the E200K and V210I mutations, but low sensitivity was observed for mutations associated with Gerstmann-Sträussler-Scheinker syndrome and fatal familial insomnia. All biomarkers showed good to excellent specificity using the standard cut-offs often used for sporadic Creutzfeldt-Jakob disease. In genetic prion diseases related to octapeptide repeat insertions, the biomarker sensitivity correlated with the number of repeats. New genetic prion disease-specific cut-offs for 14-3-3, t-tau and α-synuclein were calculated. Disease duration in genetic Creutzfeldt-Jakob disease-E200K, Gerstmann-Sträussler-Scheinker-P102L and fatal familial insomnia was highly dependent on PRNP codon 129 MV polymorphism and was significantly associated with biomarker levels. In a large cohort of genetic prion diseases, the simultaneous analysis of CSF prion disease biomarkers allowed the determination of new mutation-specific cut-offs improving the discrimination of genetic prion disease cases and unveiled genetic prion disease-specific associations with disease duration.
遗传性朊病毒病是一组由朊病毒蛋白基因 PRNP 中致病性序列变异引起的罕见且多样的致命神经退行性疾病。由于不明原因，目前遗传性朊病毒病患者的 CSF 生物标志物数据有限，且报告的结果相互矛盾。在这里，我们旨在分析目前用于朊病毒临床诊断的 CSF 生物标志物在 11 个朊病毒诊断中心的 302 例有症状的遗传性朊病毒病病例中的诊断准确性，这些病例总共涵盖了 PRNP 开放阅读框中 36 种不同的致病性序列变异。通过实时震颤诱导转化测定法评估 CSF 样本中神经退行性变的替代标志物 14-3-3 蛋白（14-3-3）、总tau 蛋白（t-tau）和α-突触核蛋白以及朊病毒接种活性。将生物标志物结果与健康和神经对照组的结果进行比较。对于最常见的 PRNP 致病性序列变异，评估了生物标志物的准确性以及生物标志物与人口统计学和遗传决定因素之间的关联。此外，还研究了生物标志物预测从症状发作到死亡的总疾病持续时间的预后价值。与 E200K 和 V210I 突变相关的遗传克雅氏病的四种生物标志物具有很高的敏感性，但与格斯特曼-施特劳斯勒-谢因克综合征和致命家族性失眠症相关的突变的敏感性较低。使用通常用于散发性克雅氏病的标准截止值，所有生物标志物均显示出良好至极好的特异性。在与八肽重复插入相关的遗传性朊病毒病中，生物标志物的敏感性与重复次数相关。计算了新的遗传朊病毒病特异性 14-3-3、t-tau 和α-突触核蛋白的截止值。遗传克雅氏病-E200K、格斯特曼-施特劳斯勒-谢因克-P102L 和致命家族性失眠症的疾病持续时间高度依赖于 PRNP 密码子 129 MV 多态性，并且与生物标志物水平显著相关。在遗传性朊病毒病的大队列中，CSF 朊病毒病生物标志物的同时分析允许确定新的突变特异性截止值，从而提高遗传朊病毒病病例的区分能力，并揭示了与疾病持续时间相关的遗传朊病毒病特异性关联。
