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Background: Most reported patients carrying GNAO1 mutations showed a severe phenotype characterized by early-onset epileptic encephalopathy and/or chorea., Objective: The aim was to characterize the clinical and genetic features of patients with mild GNAO1-related phenotype with prominent movement disorders., Methods: We included patients diagnosed with GNAO1-related movement disorders of delayed onset (>2 years). Patients experiencing either severe or profound intellectual disability or early-onset epileptic encephalopathy were excluded., Results: Twenty-four patients and 1 asymptomatic subject were included. All patients showed dystonia as prominent movement disorder. Dystonia was focal in 1, segmental in 6, multifocal in 4, and generalized in 13. Six patients showed adolescence or adulthood-onset dystonia. Seven patients presented with parkinsonism and 3 with myoclonus. Dysarthria was observed in 19 patients. Mild and moderate ID were present in 10 and 2 patients, respectively., Conclusion: We highlighted a mild GNAO1-related phenotype, including adolescent-onset dystonia, broadening the clinical spectrum of this condition. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: The group of dystonia genes is expanding, and mutations of these genes have been associated with various combined dystonia syndromes. Among the latter, the cause of some dystonia parkinsonism cases remains unknown., Objective: To report patients with early-onset dystonia parkinsonism as a result of loss-of-function mutations in nuclear receptor subfamily 4 group A member 2., Methods: Phenotypic characterization and exome sequencing were carried out in 2 families., Results: The 2 patients reported here both had a history of mild intellectual disability in childhood and subsequently developed dystonia parkinsonism in early adulthood. Brain magnetic resonance imaging was normal, and DATscan suggested bilateral dopaminergic denervation. Two frameshift mutations in NR4A2 were identified: a de novo insertion (NM_006186.3; c.326dupA) in the first case and another small insertion (NM_006186.3; c.881dupA) in the second., Conclusions: NR4A2 haploinsufficiency mutations have been recently reported in neurodevelopmental phenotypes. Our findings indicate that dystonia and/or parkinsonism may appear years after initial symptoms. Mutations in NR4A2 should be considered in patients with unexplained dystonia parkinsonism. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Introduction: A strategy based on targeted gene panel sequencing identifies possibly pathogenic variants in fewer than 20% of cases in early-onset and familial form of dystonia. By using Whole Exome Sequencing (WES), we aimed to identify the missing genetic causes in dystonic patients without diagnosis despite gene panel sequencing., Material and Methods: WES was applied to DNA samples from 32 patients with early-onset or familial dystonia investigated by sequencing of a 127 movement disorders-associated gene panel. Dystonia was described according to the familial history, body distribution, evolution pattern, age of onset, associated symptoms and associated movement disorders. Rate of diagnoses was evaluated for each clinical feature., Results: We identified causative variants for 11 patients from 9 families in CTNNB1, SUCLG1, NUS1, CNTNAP1, KCNB1, RELN, GNAO1, HIBCH, ADCK3 genes, yielding an overall diagnostic rate of 34.4%. Diagnostic yield was higher in complex dystonia compared to non-complex dystonia (66.7%-5.9%; p < 0.002), especially in patients showing intellectual disability compared to the patients without intellectual disability (87.5%-16.7%; p < 0.002)., Conclusion: Our approach suggests WES as an efficient tool to improve the diagnostic yield after gene panel sequencing in dystonia. Larger study are warranted to confirm a potential genetic overlap between neurodevelopmental diseases and dystonia., Competing Interests: Declaration of competing interest T.W. received grants from the Revue Neurologique, the Fondation Planiol and the APTES organizations and travels funding from LVL medical; C.T. received honoraria from Allergan and Merz; A.M. received travel funding from Abbvie; E.R received research support from Merz-Pharma, Orkyn, Aguettant, Elivie, Ipsen, Fondation Desmarest, AMADYS, Agence Nationale de la Recherche and Fonds de Dotation Brou de Laurière; has served on scientific advisory boards for Orkyn, Aguettant, Merz-Pharma and has received honoraria from Orkyn, Aguettant, Merz-Pharma, and Medday-Pharma; S.B. received honoraria from Aguettant and Orkyn and travel funding from Ellivie, Ipsen and Aguettant; V.L. is member of the scientific board of the AFM-Telethon, and received honoraria from PTC Therapeutics, Sarepta Therapeutics, Biogen France SAS, AveXis Inc; M.A. received honoraria from Teva, Merz, AbbVie, Actelion, Johnson and Johnson, Aguettant, Orkyn, LVL, Elivie.N.D, B.K, C.M., L.C, R.L, L.L-F., A.G., C.L., P.B., O.L-B., M-A.S., M.B., E.O., P.N., D.D., G.R., J.C. declare no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)