The Genetic Landscape of Complex Childhood-Onset Hyperkinetic Movement Disorders
Por:
Pérez-Dueñas B, Gorman K, Marcé-Grau A, Ortigoza-Escobar JD, Macaya A, Danti FR, Barwick K, Papandreou A, Ng J, Meyer E, Mohammad SS, Smith M, Muntoni F, Munot P, Uusimaa J, Vieira P, Sheridan E, Guerrini R, Cobben J, Yilmaz S, De Grandis E, Dale RC, Pons R, Peall KJ, Leuzzi V and Kurian MA
Publicada:
1 nov 2022
Ahead of Print:
1 ago 2022
Resumen:
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. (C) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
Filiaciones:
Pérez-Dueñas B:
Department of Pediatric Neurology, Vall d'Hebron Hospital Universitary and Vall d'Hebrón Research Institute (VHIR)., Barcelona, Spain
Department of Pediatrics, Obstetrics, Gynecology, Preventative Medicine and Public Health, Universitat Autònoma de Barcelona, Barcelona, Spain
Center for Biomedical Network Research on Rare Diseases (CIBERER) CB06/07/0063, Barcelona, Spain
Gorman K:
Developmental Neurosciences Programme, Great Ormond Street-Institute of Child Health, University College London, London, United Kingdom
Dubowitz neuromuscular Center, Great Ormond Street Hospital for Children, London, United Kingdom
Marcé-Grau A:
Department of Pediatric Neurology, Vall d'Hebron Hospital Universitary and Vall d'Hebrón Research Institute (VHIR)., Barcelona, Spain
Ortigoza-Escobar JD:
Department of Pediatric Neurology, Sant Joan de Déu Hospital, Barcelona, Spain
Macaya A:
Department of Pediatric Neurology, Vall d'Hebron Hospital Universitary and Vall d'Hebrón Research Institute (VHIR)., Barcelona, Spain
Department of Pediatrics, Obstetrics, Gynecology, Preventative Medicine and Public Health, Universitat Autònoma de Barcelona, Barcelona, Spain
Center for Biomedical Network Research on Rare Diseases (CIBERER) CB06/07/0063, Barcelona, Spain
Danti FR:
Unit of Child Neurology and Psychiatry, Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy
Barwick K:
Developmental Neurosciences Programme, Great Ormond Street-Institute of Child Health, University College London, London, United Kingdom
Papandreou A:
Developmental Neurosciences Programme, Great Ormond Street-Institute of Child Health, University College London, London, United Kingdom
Dubowitz neuromuscular Center, Great Ormond Street Hospital for Children, London, United Kingdom
Ng J:
Gene Transfer Technology Group, Institute for Women's Health, University College London, London, United Kingdom
Meyer E:
Developmental Neurosciences Programme, Great Ormond Street-Institute of Child Health, University College London, London, United Kingdom
Mohammad SS:
Kids Neuroscience Centre and Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, Westmead, New South Wales, Australia
Smith M:
Department of Pediatric Neurology, John Radcliffe Hospital, Oxford, United Kingdom
Muntoni F:
Developmental Neurosciences Programme, Great Ormond Street-Institute of Child Health, University College London, London, United Kingdom
Dubowitz neuromuscular Center, Great Ormond Street Hospital for Children, London, United Kingdom
Munot P:
Dubowitz neuromuscular Center, Great Ormond Street Hospital for Children, London, United Kingdom
Uusimaa J:
PEDEGO Research Unit, Department of Children and Adolescents, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
Vieira P:
PEDEGO Research Unit, Department of Children and Adolescents, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
Sheridan E:
School of Medicine, St James's University Hospital, University of Leeds, Leeds, United Kingdom
Guerrini R:
Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A. Meyer Children's Hospital, University of Florence, Florence, Italy
Cobben J:
North West Thames Regional Genetic Service, Northwick Park Hospital, London, United Kingdom
Yilmaz S:
Department of Pediatrics, Division of Child Neurology, Ege University Medical Faculty, Izmir, Turkey
De Grandis E:
Child Neuropsychiatry Unit, Istituto Giannina Gaslini, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Children's Sciences, University of Genoa, Genoa, Italy
Dale RC:
Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia
Pons R:
First Department of Pediatrics, Agia Sofia Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece
Peall KJ:
Neuroscience and Mental Health Research Institute, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
Leuzzi V:
Unit of Child Neurology and Psychiatry, Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy
Kurian MA:
Developmental Neurosciences Programme, Great Ormond Street-Institute of Child Health, University College London, London, United Kingdom
Dubowitz neuromuscular Center, Great Ormond Street Hospital for Children, London, United Kingdom
Green Submitted, hybrid
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