Kleinz Teresa, Cavallieri Francesco, Borsche Max, Toschi Giulia, Valzania Franco, Fioravanti Valentina, Valente Enza Maria, Mitrotti Pierfrancesco, Avenali Micol, Zittel Simone, Born Rommi, Matarazzo Michele, Di Fonzo Alessio, Monfrini Edoardo, Radefeldt Mandy, Santinelli Letizia, Griebner Norman, Shambetova Cholpon, Brand Max, Gabbert Carolin, Blauwendraat Cornelis, Trinh Joanne, Beetz Christian, Bauer Peter, Brüggemann Norbert, Klein Christine
medRxiv. 2025 Jun 3:2025.06.03.25328628. doi: 10.1101/2025.06.03.25328628.
The p.Ser71Arg variant is a novel cause of monogenic Parkinson's disease (PD), for which detailed phenotypic information is currently scarce.
To clinically and biologically characterize individuals with PARK- to gain insights into genotype-phenotype relationships, disease severity, and underlying pathology.
We conducted a literature review following the MDSGene database protocol, alongside detailed phenotyping of 11 PARK- patients and one prodromal individual from the Rostock International PD (ROPAD) study. In addition to comprehensive scale-based assessments, including olfactory testing, we obtained neuroimaging data and various biomaterials, and performed α-synuclein seeding assays (SAA) in cerebrospinal fluid in a subset.
83 patients (74 from the literature) were included in the analysis. The median age at onset was 54 (IQR: 46-61) years. Typical Parkinsonism with a favorable dopaminergic response was observed in all patients. In our cohort, the mean MDS-UPDRS III score was 38.5±21.8 points. Autonomic symptoms were present in all individuals, and 10/11 patients had hyposmia. Several non-motor symptoms were reported for the first time in PARK- . Misfolded α-synuclein was identified in 2/2 patients, but not in the prodromal individual. 123I-FP-CIT imaging was available for eight patients, revealing neurodegeneration in all of them.
While PARK- is clinically and likely pathologically similar to idiopathic PD, our study underscores the importance of carefully assessing non-motor symptoms in this newly described form of PD. According to SynNeurGe criteria, PARK- is classified as S (evidence of synucleinopathy), N (neurodegeneration supported by imaging data), and G (presence of a genetic variant).
p.Ser71Arg变异是单基因帕金森病（PD）的一种新病因，目前关于其详细表型信息稀缺。
对携带PARK-的个体进行临床和生物学特征分析，以深入了解基因型-表型关系、疾病严重程度及潜在病理机制。
我们按照MDSGene数据库方案进行文献综述，并对罗斯托克国际帕金森病（ROPAD）研究中的11例携带PARK-的患者和1例前驱个体进行详细表型分析。除了基于综合量表的评估（包括嗅觉测试）外，我们还获取了神经影像学数据和各种生物材料，并对一部分患者的脑脊液进行了α-突触核蛋白种子检测（SAA）。
83例患者（74例来自文献）纳入分析。发病年龄中位数为54岁（四分位间距：46 - 61岁）。所有患者均观察到典型帕金森综合征且对多巴胺能治疗反应良好。在我们的队列中，平均MDS-UPDRS III评分为38.5±21.8分。所有个体均存在自主神经症状，11例患者中有10例嗅觉减退。首次在携带PARK-的患者中报告了几种非运动症状。2例患者检测到错误折叠的α-突触核蛋白，但前驱个体未检测到。8例患者有123I-FP-CIT成像结果，均显示神经退行性变。
虽然携带PARK-的患者在临床和可能的病理方面与特发性PD相似，但我们的研究强调了在这种新描述的PD形式中仔细评估非运动症状的重要性。根据SynNeurGe标准，携带PARK-的患者被分类为S（突触核蛋白病证据）、N（影像学数据支持神经退行性变）和G（存在基因变异）。
