Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
Department of Neurology, University Hospital Schleswig-Holstein, Campus Lübeck, Germany.
J Neuromuscul Dis. 2021;8(3):341-356. doi: 10.3233/JND-200598.
Parkinson's disease (PD) is a disabling neurological condition characterized by the loss of dopaminergic neurons. Currently, the treatment for PD is symptomatic and compensates for the endogenous loss of dopamine production. In cases where the pharmacological therapy is only partly beneficial or results in major wearing-off complications, surgical interventions such as deep brain stimulation may be an alternative treatment. The disease cause often remains unknown, but in some patients, a monogenic cause can be identified. Mutations in at least six genes, LRRK2, SNCA, and VPS35 (dominant forms) or Parkin/PRKN, PINK1, and DJ1/PARK7 (recessive forms) have been unequivocally linked to PD pathogenesis. We here systematically screened 8,576 publications on these monogenic PD forms. We identified 2,226 mutation carriers from 456 papers. Levodopa was the most widely applied treatment; only 34 patients were indicated to be untreated at the time of reporting. Notably, detailed treatment data was rarely mentioned including response quantification (good, moderate, minimal) in 951 and/or dose in 293 patients only. Based on available data, levodopa showed an overall good outcome, especially in LRRK2, VPS35, Parkin, and PINK1 mutation carriers ("good" response in 94.6-100%). Side effects of levodopa therapy were reported in ∼15-40%of levodopa-treated patients across genes with dyskinesias as the most frequent one. Non-levodopa medication was indicated to be administered to <200 patients with mainly good outcome. Only a few reports were available on outcomes of brain surgery. Here, most mutation carriers showed a good response. Importantly, none of the available treatments is harmful to one genetic form but effective in another one. In the light of different medication schemes, the progressive nature of PD, and side effects, an improvement of therapeutic options for PD is warranted including a treatabolome database to guide clinicians in treatment decisions. Further, novel disease-cause-modifying drugs are needed.
帕金森病（PD）是一种使人丧失能力的神经疾病，其特征是多巴胺能神经元的丧失。目前，PD 的治疗方法是对症治疗，补偿内源性多巴胺产生的损失。在药物治疗仅部分有益或导致严重的药效减退并发症的情况下，手术干预如深部脑刺激可能是一种替代治疗方法。疾病的病因通常仍不清楚，但在一些患者中，可以确定单基因病因。至少有六个基因（LRRK2、SNCA 和 VPS35（显性形式）或 Parkin/PRKN、PINK1 和 DJ1/PARK7（隐性形式）的突变与 PD 的发病机制有明确的联系。我们在这里系统地筛选了这些单基因 PD 形式的 8576 篇文献。我们从 456 篇论文中确定了 2226 名突变携带者。左旋多巴是最广泛应用的治疗方法；在报告时，只有 34 名患者未接受治疗。值得注意的是，很少有详细的治疗数据被提及，包括 951 名患者的反应定量（好、中、差）和/或 293 名患者的剂量。基于现有数据，左旋多巴显示出总体良好的效果，特别是在 LRRK2、VPS35、Parkin 和 PINK1 突变携带者中（“好”反应的比例为 94.6-100%）。在不同基因中，接受左旋多巴治疗的患者中有 15-40%报告了左旋多巴治疗的副作用，其中最常见的是运动障碍。<200 名患者需要使用非左旋多巴药物，主要是效果良好。只有少数关于脑外科手术结果的报告。在这里，大多数突变携带者表现出良好的反应。重要的是，现有的治疗方法对一种遗传形式没有危害，但对另一种遗传形式有效。鉴于不同的治疗方案、PD 的进行性性质和副作用，有必要改善 PD 的治疗选择，包括建立治疗代谢组学数据库，以指导临床医生的治疗决策。此外，还需要新型的疾病原因修饰药物。
