Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France; Hospital Garcia de Orta, Almada, Portugal; Centre de Référence des Démences Rares ou Précoces, IM2A, Département de Neurologie, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France.
Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France; Centre de Référence des Démences Rares ou Précoces, IM2A, Département de Neurologie, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France; Aramis Project Team, Inria Research Center of Paris, Paris, France.
Parkinsonism Relat Disord. 2020 Nov;80:73-81. doi: 10.1016/j.parkreldis.2020.09.019. Epub 2020 Sep 15.
A phenotype of isolated parkinsonism mimicking Idiopathic Parkinson's Disease (IPD) is a rare clinical presentation of GRN and C9orf72 mutations, the major genetic causes of frontotemporal dementia (FTD). It still remains controversial if this association is fortuitous or not, and which clinical clues could reliably suggest a genetic FTD etiology in IPD patients. This study aims to describe the clinical characteristics of FTD mutation carriers presenting with IPD phenotype, provide neuropathological evidence of the mutation's causality, and specifically address their "red flags" according to current IPD criteria.
Seven GRN and C9orf72 carriers with isolated parkinsonism at onset, and three patients from the literature were included in this study. To allow better delineation of their phenotype, the presence of supportive, exclusion and "red flag" features from MDS criteria were analyzed for each case.
Amongst the ten patients (5 GRN, 5 C9orf72), seven fulfilled probable IPD criteria during all the disease course, while behavioral/language or motoneuron dysfunctions occurred later in three. Disease duration was longer and dopa-responsiveness was more sustained in C9orf72 than in GRN carriers. Subtle motor features, cognitive/behavioral changes, family history of dementia/ALS were suggestive clues for a genetic diagnosis. Importantly, neuropathological examination in one patient revealed typical TDP-43-inclusions without alpha-synucleinopathy, thus demonstrating the causal link between FTD mutations, TDP-43-pathology and PD phenotype.
We showed that, altogether, family history of early-onset dementia/ALS, the presence of cognitive/behavioral dysfunction and subtle motor characteristics are atypical features frequently present in the parkinsonian presentations of GRN and C9orf72 mutations.
一种类似于特发性帕金森病（IPD）的孤立性帕金森综合征表型是 GRN 和 C9orf72 突变的罕见临床表现，这是额颞叶痴呆（FTD）的主要遗传原因。这种关联是否偶然，以及哪些临床线索可以可靠地提示 IPD 患者存在遗传 FTD 病因，目前仍存在争议。本研究旨在描述以 IPD 表型起病的 FTD 突变携带者的临床特征，提供突变因果关系的神经病理学证据，并根据当前 IPD 标准特别解决他们的“警示特征”。
本研究纳入了 7 名以孤立性帕金森病起病且携带 GRN 突变和 3 名携带 C9orf72 突变的患者，以及 3 名来自文献的患者。为了更好地描绘他们的表型，对每个病例进行了 MDS 标准中的支持性、排除性和“警示特征”的分析。
在这 10 名患者（5 名 GRN 突变，5 名 C9orf72 突变）中，有 7 名在整个疾病过程中均符合可能的 IPD 标准，而有 3 名在行为/语言或运动神经元功能障碍后才符合。C9orf72 携带者的疾病持续时间更长，多巴胺反应更持久。细微的运动特征、认知/行为改变、痴呆/ALS 的家族史是遗传诊断的提示线索。重要的是，一名患者的神经病理学检查显示出典型的 TDP-43 包涵体，而没有α-突触核蛋白病，从而证明了 FTD 突变、TDP-43 病理学和 PD 表型之间的因果关系。
我们表明，总的来说，家族史中有早发性痴呆/ALS、认知/行为功能障碍和细微的运动特征是 GRN 和 C9orf72 突变引起的帕金森综合征表现中常见的非典型特征。
