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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) |
| Persistent link: | http://urn.fi/urn:nbn:fi-fe2023060552515 |
| Language: | English |
| Published: |
John Wiley & Sons,
2022
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| Publish Date: | 2023-06-05 |
| Description: |
AbstractBackground 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. see all
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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 |
| OADOI: | https://oadoi.org/10.1002/mds.29182 |
| Type of Publication: |
A1 Journal article – refereed |
| Field of Science: |
3121 General medicine, internal medicine and other clinical medicine |
| Subjects: | |
| 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. |
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https://creativecommons.org/licenses/by/4.0/ |