University of Oulu

Pérez-Dueñas, B., Gorman, K., Marcé-Grau, A., Ortigoza-Escobar, J.D., Macaya, A., Danti, F.R., Barwick, K., Papandreou, A., Ng, J., Meyer, E., Mohammad, S.S., Smith, M., Muntoni, F., Munot, P., Uusimaa, J., Vieira, P., Sheridan, E., Guerrini, R., Cobben, J., Yilmaz, S., De Grandis, E., Dale, R.C., Pons, R., Peall, K.J., Leuzzi, V. and Kurian, M.A. (2022), The Genetic Landscape of Complex Childhood-Onset Hyperkinetic Movement Disorders. Mov Disord, 37: 2197-2209.

The genetic landscape of complex childhood-onset hyperkinetic movement disorders

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Author: Pérez-Dueñas, Belén1,2,3; Gorman, Kathleen4,5; Marcé-Grau, Anna1;
Organizations: 1Department of Pediatric Neurology, Vall d'Hebron Hospital Universitary and Vall d'Hebrón Research Institute (VHIR)., Barcelona, Spain
2Department of Pediatrics, Obstetrics, Gynecology, Preventative Medicine and Public Health, Universitat Autònoma de Barcelona, Barcelona, Spain
3Center for Biomedical Network Research on Rare Diseases (CIBERER) CB06/07/0063, Barcelona, Spain
4Developmental Neurosciences Programme, Great Ormond Street–Institute of Child Health, University College London, London, United Kingdom
5Dubowitz neuromuscular Center, Great Ormond Street Hospital for Children, London, United Kingdom
6Department of Pediatric Neurology, Sant Joan de Déu Hospital, Barcelona, Spain
7Unit of Child Neurology and Psychiatry, Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy
8Gene Transfer Technology Group, Institute for Women's Health, University College London, London, United Kingdom
9Kids Neuroscience Centre and Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, Westmead, New South Wales, Australia
10Department of Pediatric Neurology, John Radcliffe Hospital, Oxford, United Kingdom
11PEDEGO Research Unit, Department of Children and Adolescents, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
12School of Medicine, St James's University Hospital, University of Leeds, Leeds, United Kingdom
13Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A. Meyer Children's Hospital, University of Florence, Florence, Italy
14North West Thames Regional Genetic Service, Northwick Park Hospital, London, United Kingdom
15Department of Pediatrics, Division of Child Neurology, Ege University Medical Faculty, İzmir, Turkey
16Child Neuropsychiatry Unit, Istituto Giannina Gaslini, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Children's Sciences, University of Genoa, Genoa, Italy
17Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia
18First Department of Pediatrics, Agia Sofia Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece
19Neuroscience and Mental Health Research Institute, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.5 MB)
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Language: English
Published: John Wiley & Sons, 2022
Publish Date: 2023-06-05


Background and Objective: The objective of this study was to better delineate the genetic landscape and key clinical characteristics of complex, early-onset, monogenic hyperkinetic movement disorders.

Methods: Patients were recruited from 14 international centers. Participating clinicians completed standardized proformas capturing demographic, clinical, and genetic data. Two pediatric movement disorder experts reviewed available video footage, classifying hyperkinetic movements according to published criteria.

Results: One hundred forty patients with pathogenic variants in 17 different genes (ADCY5, ATP1A3, DDC, DHPR, FOXG1, GCH1, GNAO1, KMT2B, MICU1, NKX2.1, PDE10A, PTPS, SGCE, SLC2A1, SLC6A3, SPR, and TH) were identified. In the majority, hyperkinetic movements were generalized (77%), with most patients (69%) manifesting combined motor semiologies. Parkinsonism-dystonia was characteristic of primary neurotransmitter disorders (DDC, DHPR, PTPS, SLC6A3, SPR, TH); chorea predominated in ADCY5-, ATP1A3-, FOXG1-, NKX2.1-, SLC2A1-, GNAO1-, and PDE10A-related disorders; and stereotypies were a prominent feature in FOXG1- and GNAO1-related disease. Those with generalized hyperkinetic movements had an earlier disease onset than those with focal/segmental distribution (2.5 ± 0.3 vs. 4.7 ± 0.7 years; P = 0.007). Patients with developmental delay also presented with hyperkinetic movements earlier than those with normal neurodevelopment (1.5 ± 2.9 vs. 4.7 ± 3.8 years; P < 0.001). Effective disease-specific therapies included dopaminergic agents for neurotransmitters disorders, ketogenic diet for glucose transporter deficiency, and deep brain stimulation for SGCE-, KMT2B-, and GNAO1-related hyperkinesia.

Conclusions: This study highlights the complex phenotypes observed in children with genetic hyperkinetic movement disorders that can lead to diagnostic difficulty. We provide a comprehensive analysis of motor semiology to guide physicians in the genetic investigation of these patients, to facilitate early diagnosis, precision medicine treatments, and genetic counseling.

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Series: Movement disorders
ISSN: 0885-3185
ISSN-E: 1531-8257
ISSN-L: 0885-3185
Volume: 37
Issue: 11
Pages: 2197 - 2209
DOI: 10.1002/mds.29182
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
Funding: This work was supported by an NIHR Professorship (to M.A.K.). M.A.K. has received funding from the Sir Jules Thorn Award for Biomedical Research and Wellcome Trust. B.P.-D. was supported by Instituto de Salud Carlos III, PI 18/01319 and PI21/00248, and has received funding from Beca José Castillejos (CAS14/00328). K.J.P. was supported by an MRC Clinician–Scientist Fellowship (511015) and was supported by the Dystonia Medical Research Foundation and Fight for Sight. S.S.M. has received funding from the Winston Churchill Memorial trust and Cerebral Palsy Alliance.
Copyright information: © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in anymedium, provided the original work is properly cited.