Thomas Wirth1, Louise Laure Mariani2,3, Gaber Bergant4, Michel Baulac2,3, Marie-Odile Habert5,6, Nathalie Drouot7, Emmanuelle Ollivier8, Alenka Hodžić4, Gorazd Rudolf4, Patrick Nitschke8, Gabrielle Rudolf1,7,9, Jamel Chelly1,7,10, Christine Tranchant1,7,9, Mathieu Anheim1,7,9, Emmanuel Roze2,3. 1. Département de neurologie, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France. 2. Sorbonne Université, Institut du Cerveau et de la Moelle épinière, Inserm U 1127, CNRS UMR 7225, F-75013, Paris, France. 3. Assistance Publique-Hôpitaux de Paris, Department of Neurology, Hôpital Pitié-Salpêtrière, F-75013, Paris, France. 4. Clinical Institute of Medical Genetics, University Medical Centre Ljubljana, Ljubljana, Slovenia. 5. Sorbonne Université, CNRS, INSERM, Laboratoire d'Imagerie Biomédicale, LIB, F-75006, Paris, France. 6. AP-HP, Hôpital Pitié-Salpêtrière, Médecine Nucléaire, F-75013, Paris, France. 7. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France. 8. Institut IMAGINE, Bioinformatics Platform, Université Paris Descartes, Paris, France. 9. Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France. 10. Laboratoire de Diagnostic Génétique, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Abstract
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.
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.
Authors: Christine Y Kim; Thomas Wirth; Cécile Hubsch; Andrea H Németh; Volkan Okur; Mathieu Anheim; Nathalie Drouot; Christine Tranchant; Gabrielle Rudolf; Jamel Chelly; Katrina Tatton-Brown; Cornelis Blauwendraat; Jean Paul G Vonsattel; Etty Cortes; Roy N Alcalay; Wendy K Chung Journal: Ann Neurol Date: 2020-08-22 Impact factor: 11.274