CLINICAL/SCIENTIFIC NOTES OPEN ACCESS NR4A2 Mutations Can Cause Intellectual Disability and Language Impairment With Persistent Dystonia-Parkinsonism Silvia Jesús, MD, PhD,* Isabel Hinarejos, MSc,* Fátima Carrillo, MD, PhD, Dolores Martı́nez-Rubio, PhD, Correspondence Dr. Mir Daniel Macı́as-Garcı́a, MD, Ana Sánchez-Monteagudo, PhD, Astrid Adarmes, MD, Vincenzo Lupo, PhD, pmir@us.es Belén Pérez-Dueñas, MD, PhD, Pablo Mir, MD, PhD,* and Carmen Espinós, PhD* or Dr. Espinós cespinos@cipf.es Neurol Genet 2021;7:e543. doi:10.1212/NXG.0000000000000543 The NR4A2/NURR1 gene (MIM*601828) has recently been associated with autosomal-dominant MORE ONLINE early-onset dystonia-parkinsonism with intellectual disability.1 NR4A2 codifies for a nuclear tran- Video scription factor and is expressed mainly in the substantia nigra, ventral tegmental area, and limbic areas.2 To date, 14 different alterations in NR4A2 have been described associated with various clinical phenotypes, mainly with neurodevelopment disorders (table e-1, links.lww.com/NXG/ A371). We describe here an interesting case suffering a persistent dystonia-parkinsonism syndrome (DPS) with motor tics, which expands the clinical phenotype of NR4A2-associated DPS. This is a 30-year-old man with no family history of neurologic disease who was born after a normal pregnancy and childbirth. He started walking with support at 13 months, but his gait was clumsy, resulting in numerous falls during childhood. At 2 years old, the patient presented attention deficit. He began to speak at 3 years of age but with impaired fluency, vocabulary, and articulation. The patient required special education to learn basic writing and arithmetic skills. At the age of 7 years, his intelligence quotient was 77. At 16 years old, he presented tricho- tillomania, and he began to experience motor tics characterized by an urge to move his right shoulder upward, an urge that was relieved after performing the movement. He was satisfac- torily treated with atomoxetine. He also noticed an abnormal backward-cervical deviation. This clinical situation remained stable for 10 years, although motor tics tended to improve with age. At 28 years old, the patient complained of slowness, walking difficulties, and a worsening abnormal craniocervical posture. He presented marked jaw-opening dystonia and parkinsonian features, with rigidity and a progressive reduction in the amplitude and frequency of repetitive movements in the left hemibody. The gait difficulties manifested with dragging steps, mainly in the left hemibody (Video 1). The patient also presented nonmotor symptoms such as gas- trointestinal and sleep-related symptoms, with the mobility and communication domains af- fecting his quality of life the most (figures e-1 and e-2, links.lww.com/NXG/A371). The results of supplementary and neuroimaging tests were normal (figure 1, table e-2, links. lww.com/NXG/A371), whereas 123FP-CIT-single photon emission CT revealed reduced bi- lateral (predominantly right sided) uptake in both striatum (figure e-1). A genetic analysis using a custom gene panel of 498 genes involved in movement disorders (MovDisord-498)3 revealed no causative mutations (appendix e-1, links.lww.com/NXG/ A371). The proband and healthy parents (trio) then underwent whole exome sequencing *These authors contributed equally to this work. From the Unidad de Trastornos del Movimiento (S.J., F.C., D.M.-G., A.A., P.M.), Servicio de Neurologı́a y Neurofisiologı́a Clı́nica, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocı́o/CSIC/Universidad de Sevilla, Spain; Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED) (S.J., F.C., D.M.-G., A.A., P.M.), Spain; Unit of Genetics and Genomics of Neuromuscular and Neurodegenerative Disorders (I.H., D.M.-R., A.S.-M., V.L., C.E.), Centro de Investigación Prı́ncipe Felipe (CIPF), Valencia, Spain; Joint Units INCLIVA and IIS La Fe Rare Diseases (I.H., D.M.-R., A.S.-M., V.L., C.E.), Centro de Investigación Prı́ncipe Felipe (CIPF), Valencia, Spain; Department of Pediatric Neurology (B.P.-D.), Hospital Universitari Vall d’Hebron, Barcelona, Spain; and Universitat Autònoma de Barcelona (B.P.-D.), Spain. Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article. The Article Processing Charge was funded by FISEVI CIF: ESG-41918830 Edificio de Laboratorios 6 ª planta Hospital Virgen del Rocı́o Avda. Manuel Siurot, s/n, 41013 Sevilla. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1 Figure 1 Functional and Structural Brain Images (A) 123FP-CIT-SPECT revealed bilateral uptake reduction with impairment of the caudate and putamen and a predominance in the right hemisphere and both putamen. (B and C) Normal 18FDG-PET coronal and axial images. (D) Normal cranial MRI T2 axial image. 18FDG = 18-fluorodeoxyglucose. (WES) using the Whole Exome Family Plus test (Blueprint comorbidity with motor tics, which are therefore a novel fea- Genetics, Helsinki, Finland). WES data were filtered as pre- ture associated with the NR4A2 phenotype, a feature that will viously described4 and 3 candidate disease-causing changes become clearer as more cases are reported. were found (table e-3). We further investigated the detected changes by Sanger sequencing in all the available relatives In NR4A2, there seems to be no association between the (figure e-3). The KCNQ2 c.1807-5A>T resulted to be a false- mutation type and the resulting phenotype, except for pa- positive result. The proband, his parents, and his brother tients with complex neurodevelopmental disorders that are carried the CEP170 c.2375C>A (p.S792*) change in hetero- caused by large deletions. In fact, diverse NR4A2-related zygosis, and therefore, this variant was discarded as disease- phenotypes can even be caused by the same mutation.7 In this causing mutation. Regarding the NR4A2 c.956G>A case study, we presented the first patient with DPS caused by a (p.R319Q) substitution, only the patient harbored it, and missense NR4A2 mutation, the p.R319Q. NR4A2-associated consequently, this mutation was de novo. Moreover, 2 DPS can therefore be caused by more than just loss-of- frameshift mutations in NR4A2 were recently described in 2 function mutations. patients with DPS.1 R319 is an evolutionarily conserved amino acid (data not shown) located on the essential domain In conclusion, motor tics and persistent dystonia in NR4A2- Zf-C4/DBD (figure e-4). The variant was considered likely associated DPS should be included within its phenotypic pathogenic according to the American College of Medical description along with early-onset parkinsonism and in- Genetics and Genomics classification, based mainly on the tellectual disability with language impairment. The de- PS2 and PM2 criteria, although the NR4A2 c.956G>A mu- scription of new cases may help to improve the correlation tation also meets the PP3 and PM1 criteria.5 between NR4A2 and its clinical picture, which, so far, is mainly relevant for neurodevelopmental disorders. Consistent with previous descriptions of NR4A2 subjects,1 our patient also presented craniocervical dystonia with par- Study Funding kinsonian features that started in early adulthood, with pre- This work was supported by the Health Institute Carlos vious intellectual disability and language impairment. In our III—General Subdirectorate for Research Evaluation and proband, however, the dystonia was persistent and worsened Promotion (PI16/01575, PI18/01898, PI18/00147, PI19/ in stressful situations, contrasting with the previously reported 01576), the Spanish Ministry of Economy and Competitive- paroxysmal dystonic episodes.1 Clinicians should therefore be ness (SAF2007-60700), the Ministry of Economy, In- aware of paroxysmal and persistent dystonia features related novation, Science and Business of the Government of to NR4A2. Andalucı́a (CVI-02526, CTS-7685), the Ministry of Health and Social Welfare of the Government of Andalucı́a (PI-0459- Our proband also shared with previously reported cases, clear 2018, PE-0210-2018, PE-0186-2019) and by the Valencian signs, and symptoms of dopaminergic degeneration,1 suggest- Government (PROMETEO/2018/135), within the frame- ing a relationship between the role of NR4A2 and dysfunction work of the National Research and Development Plan co- of the dopaminergic nigrostriatal network. Of interest, our funded with European Regional Development Funds. Part of patient also experienced motor tics and attention deficit during the equipment employed in this study was funded by the childhood. Previous reports have shown the involvement of Valencian Government and co-financed with European Re- gross deletions in NR4A2 in autism spectrum disorders, with gional Development Funds (OP ERDF of Valencian Com- some patients manifesting “restlessness” during childhood.6 To munity 2014-2020). I. Hinarejos has a PFIS-PhD fellowship date, however, there have been no reported data on the (FI19/00072), S. Jesús has a contract “Acción B Clı́nicos- 2 Neurology: Genetics | Volume 7, Number 1 | February 2021 Neurology.org/NG Investigadores” (Action B Clinicians-Researchers) contract (B- 0007-2019) funded by the Ministry of Health and Family of Appendix (continued) the Government of Andalucı́a, and D. Macı́as-Garcı́a has a Rı́o Name Location Contribution Hortega contract (CM18/00142) funded by the Health In- stitute Carlos III. Ana Sánchez- Research Centre Prı́ncipe Performed/interpreted Monteagudo, Felipe (CIPF), Valencia, the genetic study. MSc Spain Reviewed and critiqued Disclosure the manuscript. S. Jesús has received honoraria from AbbVie, Bial, Merz, UCB, Astrid Biomedical Institute of Clinically described and Italfarmaco and Zambon. F. Carrillo has received honoraria Adarmes, MD Seville/University Hospital supervised of patients. Virgen del Rocı́o, Spain Reviewed and critiqued from AbbVie, Bial, and Zambon. A. Adarmes has received the manuscript. honoraria from AbbVie and Italfarmaco. D. Macı́as-Garcı́a has Vincenzo Research Centre Prı́ncipe Conceived and designed received honoraria from AbbVie. P. Mir has received hono- Lupo, PhD Felipe (CIPF), Valencia, the study. Performed/ raria from AbbVie, Abbott, Allergan, Bial, Merz, UCB, and Spain interpreted the genetic study. Reviewed and Zambon. All other authors report no conflicts of interest. Go critiqued the manuscript. to Neurology.org/NG for full disclosures. Belén Pérez- Hospital Universitari Vall Conceived and designed Dueñas, MD, d’Hebron, Barcelona, the study. Reviewed and Publication History PhD Spain critiqued the manuscript. Received by Neurology: Genetics July 18, 2020. Accepted in final form Pablo Mir, Biomedical Institute of Clinically described and November 6, 2020. MD, PhD Seville/University Hospital supervised the patients. Virgen del Rocı́o, Spain Wrote the study/first draft. Reviewed and critiqued the manuscript. Appendix Authors Carmen Research Centre Prı́ncipe Conceived and designed Espinós, PhD Felipe (CIPF), Valencia, the study. Performed/ Name Location Contribution Spain interpreted the genetic study. Wrote the Silvia Jesús, Biomedical Institute of Clinically described and study/first draft. MD, PhD Seville/University Hospital supervised the patients. Reviewed and critiqued Virgen del Rocı́o, Spain Wrote the study/first draft. the manuscript. Reviewed and critiqued the manuscript. Isabel Research Centre Prı́ncipe Performed/interpreted Hinarejos, Felipe (CIPF), Valencia, the genetic study. Wrote References MSc Spain the study/first draft. 1. Wirth T, Mariani LL, Bergant G, et al. Loss-of-function mutations in NR4A2 cause Reviewed and critiqued dopa-responsive dystonia Parkinsonism. Mov Disord 2020;35:880–885. the manuscript. 2. Sakurada K, Ohshima-Sakurada M, Palmer TD, Gage FH. Nurr1, an orphan nuclear receptor, is a transcriptional activator of endogenous tyrosine hydroxylase in neural Fátima Biomedical Institute of Clinically described and progenitor cells derived from the adult brain. Development 1999;126:4017–4026. Carrillo, MD, Seville/University Hospital supervised the patients. 3. Correa-Vela M, Lupo V, Montpeyo M, et al. Impaired proteasome activity and PhD Virgen del Rocı́o, Spain Reviewed and critiqued neurodegeneration with brain iron accumulation in FBXO7 defect. Ann Clin Transl the manuscript. Neurol 2020;7:1436–1442. 4. Sanchez-Monteagudo A, Alvarez-Sauco M, Sastre I, et al. Genetics of Wilson disease Dolores Research Centre Prı́ncipe Conceived and designed and Wilson-like phenotype in a clinical series from eastern Spain. Clin Genet 2020;97: Martı́nez- Felipe (CIPF), Valencia, the study. Performed/ 758–763. Rubio, MSc Spain interpreted the genetic 5. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of study. Reviewed and sequence variants: a joint consensus recommendation of the American College of critiqued the manuscript. medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405–424. Daniel Biomedical Institute of Clinically described and 6. Levy J, Grotto S, Mignot C, et al. NR4A2 haploinsufficiency is associated with in- Macı́as- Seville/University Hospital supervised the patients. tellectual disability and autism spectrum disorder. Clin Genet 2018;94:264–268. Garcı́a, MD Virgen del Rocı́o, Spain Reviewed and critiqued 7. Ramos LLP, Monteiro FP, Sampaio LPB, et al. Heterozygous loss of function of the manuscript. NR4A2 is associated with intellectual deficiency, rolandic epilepsy, and language impairment. Clin Case Rep 2019;7:1582–1584. Neurology.org/NG Neurology: Genetics | Volume 7, Number 1 | February 2021 3