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C9orf72 repeat expansions are rarely associated with primary progressive aphasias (PPA). In-depth characterization of the linguistic deficits, and the underlying patterns of grey-matter atrophy in PPA associated with the C9orf72 expansions (PPA-C9orf72) are currently lacking. In this study, we comprehensively analyzed a unique series of 16 patients affected by PPA-C9orf72. Eleven patients were issued from two independent French and Finnish cohorts, and five were identified by means of literature review. Voxel-based morphometry (VBM) studies were performed on three of them. This study depicts the spectrum of C9orf72–related aphasic phenotypes, and illustrates their linguistic presentation. The non-fluent/agrammatic variant was the most frequent phenotype in our series (9/16 patients, 56%), with apraxia of speech being the main defining feature. Left frontal lobe atrophy was present in these subjects, peaking in inferior frontal gyrus. Three patients (19%) showed the semantic variant, with progression of atrophy in temporo-polar regions, later involving orbitofrontal cortex. Anterior temporal lobe dysfunction was also particularly relevant in two patients (12.5%) with mixed forms of PPA. Lastly, two patients (12.5%) had unclassifiable PPA with predominating word-finding difficulties. No PPA-C9orf72 patients in our series fulfilled the criteria of the logopenic variant. Importantly, this study underlines the role of C9orf72 mutation in the disruption of the most anterior parts of the language network, including prefrontal and temporo-polar areas. It provides guidelines for C9orf72 testing in PPA patients, with important clinical impact as gene-specific therapies are upcoming.

Studies of the phenotype and population distribution of rare genetic forms of parkinsonism are required, now that gene-targeting approaches for Parkinson's disease have reached the clinical trial stage. We evaluated the frequencies of PRKN, PINK1, and DJ-1 mutations in a cohort of 1587 cases. Mutations were found in 14.1% of patients: 27.6% were familial and 8% were isolated. PRKN was the gene most frequently mutated in Caucasians whereas PINK1 mutations predominated in Arab-Berber individuals. Patients with PRKN mutations had an earlier age at onset, and less asymmetry, levodopa-induced motor complications, dysautonomia, and dementia than those without mutations. This article is protected by copyright. All rights reserved.

To investigate cognitive inhibition in presymptomaticThirty-eight presymptomaticC9+ individuals younger than 40 years had higher error scores (part B) but equivalent HSCT time to completion (part B-part A) compared to C9- individuals. C9+ individuals older than 40 years had both higher error scores and longer time to completion. HSCT time to completion significantly predicted the proximity to estimated clinical conversion from presymptomatic to symptomatic phase in C9+ individuals (based on the average age at onset of affected relatives in the family). Anatomically, we found that HSCT time to completion was associated with the integrity of the cerebellum.The HSCT represents a good marker of cognitive inhibition impairments in C9+ and of proximity to clinical conversion. This study also highlights the key role of the cerebellum in cognitive inhibition.

Background: Genetic mutations causing autosomal recessive Parkinson's disease account for a significant proportion of patients with early-onset disease. However, no large multicentre studies of known recessive Parkinson's disease-linked genes have been performed, to guide genetic testing according to age at onset, family history, ethnic origin, or phenotype. We aimed to evaluate the relative frequencies of mutations in genes causing recessive Parkinson's disease and their associated phenotypes in a large series of European and North African cases. Methods: Clinical data for 1664 patients were collected between 1990 and 2018 from 511 families with recessive Parkinson's disease and/or with consanguinity, and 1098 isolated cases. All the recessively inherited genes were screened by Sanger and/or targeted next-generation sequencing and gene dosage methods. Clinical features were compared between patients with PRKN and those without mutations, by regression analyses adjusted for sex, age at onset, disease duration and levodopa medication. Findings: Biallelic mutations of genes known to cause recessive Parkinson's disease were found in 246 of the 1609 index cases (15·3%): 150 familial (29·4%) and 96 (8·7%) isolated cases. The most frequently mutated genes were PRKN, in 199 cases (12·4%), PINK1, in 23 (1·8%), and DJ-1, in two (0·16%). We screened 675 index cases by targeted sequencing, and 22 were found to have mutations in genes known to cause atypical parkinsonism (3·3%). PRKN and PINK1 mutation frequencies were higher in early-onset (≤40 years) than late-onset Parkinson's disease. The frequency of PRKN mutations in the 1609 index cases decreased with increasing age at onset, from 38% in cases ≤20 years to 4·4% in those with onset at 41 to 60 years. No mutation of PRKN or another recessive Parkinson's disease gene was found in patients with onset above 60. PRKN mutations were more frequent in Caucasians (13·4%) than in North Africans (7·4%). Conversely, PINK1 mutations were more frequent in North Africans (6·3%) than in Caucasians (0·9%). PRKN patients had an earlier age at onset, lower levels of asymmetry, akinesia, levodopa-induced motor complications, dysautonomia, and dementia than those without mutations. Interpretation: This is a large study providing information about the frequency of recessive Parkinson's disease genes according to age at onset, family history, ethnic origin, and associated phenotype. Its findings will be useful for genetic testing and counselling. Funding Statement: Fondation de France, France-Parkinson Association, la Federation pour la Recherche sur le Cerveau, the French program "Investissements d'avenir", National Institute for Health Research. Declaration of Interests: SL reports grants from Fondation de France, the French program “Investissements d’avenir” (ANR-10-IAIHU-06), both outside the scope of the submitted work. MA reports grants and personal fees from Abbvie, Teva, Aguettant, Actelion Pharmaceuticals, personal fees from Johnson and Johnson, Merz, Orkyn, all outside the scope of the submitted work. ER reports grants, personal fees and non-financial support from Orkyn, Aguettant, Merz pharma, Everpharma, personal fees and non-financial support from Movement Disorders Society, grants and non-financial support from Elivie, non-financial support from Merck, Dystonia Coalition, Dystonia Medical Research Foundation, grants from Ipsen, Fondation Desmarest, Fonds de dotation Brou de Lauriere, Agence Nationale de la Recherche, AMADYS, personal fees from Medday pharma, Retrophin, European Academy of Neurology, International Association of Parkinsonism and related Disorders, all outside the submitted work. CT received fees from ALLERGAN and from MERZ. J-CC reports grants from Sanofi, personal fees from EverPharma, Denali, BrainEver, Theranexus, Air Liquide, all outside the scope of this work. EB reports grants from Medtronic France, Abbvie, UCB, and Aguettant laboratories but no conflict of interest nor financial concerns about the present research paper submitted for publication. AB reports grants from ANR - Agence nationale de recherche, ARNN - Association pour la Recherche en Neuro-imagerie et Neuropsychologie, France Parkinson, AP-HP, FMR - Fondation Maladies Rares (ex GIS), France Parkinson + FRC (Federation pour la Recherche sur le Cerveau), Universite Mohammed V - Rabat, Prix Allianz Institut de France, RDS (Roger de Spoelberch Foundation), FDF -Fondation de France-, all outside the submitted work. All other authors have no competing interests to declare. Ethics Approval Statement: Informed consent was obtained from all participants, and genetic studies were approved by local ethics committees (INSERM, CCPPRB du Groupe Hospitalier Pitie-Salpetriere, Paris, France).