Fábio Carneiro1, Dario Saracino2, Vincent Huin3, Fabienne Clot4, Cécile Delorme5, Aurélie Méneret6, Stéphane Thobois7, Florence Cormier5, Jean Christophe Corvol8, Timothée Lenglet9, Marie Vidailhet6, Marie-Odile Habert10, Audrey Gabelle11, Émilie Beaufils12, Karl Mondon13, Mélissa Tir14, Daniela Andriuta14, Alexis Brice15, Vincent Deramecourt16, Isabelle Le Ber17. 1. 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. 2. 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. 3. Univ. Lille, Inserm, CHU-Lille, Lille Neuroscience & Cognition, UMR-S1172, Team Alzheimer & Tauopathies, F-59000, Lille, France. 4. Unité Fonctionelle de Neurogénétique Moléculaire et Cellulaire, Sorbonne Université, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France. 5. Département de Neurologie, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France. 6. Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France; Département de Neurologie, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France. 7. Univ. Lyon, Université Claude Bernard Lyon 1, Faculté de Médecine Lyon Sud Charles Mérieux; CNRS, Institut des Sciences Cognitives Marc Jeannerod, UMR 5229, Bron; Hospices Civils de Lyon, Hôpital Neurologique Pierre Wertheimer, Neurologie C, Bron, France. 8. Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France; Département de Neurologie, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France; Centre d'Investigation Clinique Neurosciences, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France. 9. Département de Neurologie, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France; Centre de Référence SLA-IdF, AP-HP - Hôpital Pitié Salpêtrière, Paris, France. 10. Sorbonne Université, CNRS, Inserm, Laboratoire d'Imagerie Biomédicale, LIB, Paris, AP-HP - Hôpital Pitié-Salpêtrière, Médecine Nucléaire, Paris, France. 11. CMRR, Département de Neurologie, CHU de Montpellier, Inserm U1061, Université de Montpellier i-site MUSE, Montpellier, France. 12. Université François Rabelais de Tours, CHRU de Tours, Tours, France; Inserm U1253, IBrain, Tours, France. 13. Université François Rabelais de Tours, CHRU de Tours, Tours, France. 14. Département de Neurologie, Laboratoire de Neurosciences Fonctionnelles et Pathologies (UR UPJV 4559), Université d'Amiens et Université de Picardie Jules Verne, Amiens, France. 15. Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France. 16. Université de Lille, Inserm U1172, CHU Lille, DistAlz, LiCEND, CNR-MAJ, Lille, France. 17. 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; Département de Neurologie, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France; Paris Brain Institute - Institut du Cerveau - ICM, FrontLab, Paris, France. Electronic address: isabelle.leber@upmc.fr.
Abstract
INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Authors: Emma L van der Ende; Jazmyne L Jackson; Marka van Blitterswijk; John C Van Swieten; Adrianna White; Harro Seelaar Journal: J Neurol Neurosurg Psychiatry Date: 2021-01-15 Impact factor: 10.154