Loss‐of‐Function Mutations in NR4A2 Cause Dopa‐Responsive Dystonia Parkinsonism

• Published in: Movement disorders Vol. 35; no. 5; pp. 880 - 885
• Main Authors: Wirth, Thomas, Mariani, Louise Laure, Bergant, Gaber, Baulac, Michel, Habert, Marie‐Odile, Drouot, Nathalie, Ollivier, Emmanuelle, Hodžić, Alenka, Rudolf, Gorazd, Nitschke, Patrick, Rudolf, Gabrielle, Chelly, Jamel, Tranchant, Christine, Anheim, Mathieu, Roze, Emmanuel
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.05.2020; Wiley Subscription Services, Inc; Wiley
• Subjects: Adult; Basal ganglia; Brain diseases; Central nervous system diseases; Child; Children; Denervation; developmental delay; Dihydroxyphenylalanine; Dopamine receptors; Dystonia; Dystonic Disorders - genetics; Frameshift mutation; Genetics; Haploinsufficiency; Humans; Intellectual disabilities; Life Sciences; Magnetic resonance imaging; Movement disorders; Mutation; Mutation - genetics; Neuroimaging; next generation sequencing; NR4A2; Nuclear Receptor Subfamily 4, Group A, Member 2 - genetics; Parkinsonian Disorders - diagnostic imaging; Parkinsonian Disorders - genetics; parkinsonism; Phenotypes; NR4A2; developmental delay; parkinsonism; dystonia; next generation sequencing; Sciences du Vivant [q-bio]/Génétique
• ISSN: 0885-3185; 1531-8257; 1531-8257
• DOI: 10.1002/mds.27982

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