KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.

Autor:	Cif L; Département de Neurochirurgie, Unité des Pathologies Cérébrales Résistantes, Unité de Recherche sur les Comportements et Mouvements Anormaux, Hôpital Gui de Chauliac, Centre Hospitalier Régional Montpellier, Montpellier, France.; Faculté de médecine, Université de Montpellier, France., Demailly D; Département de Neurochirurgie, Unité des Pathologies Cérébrales Résistantes, Unité de Recherche sur les Comportements et Mouvements Anormaux, Hôpital Gui de Chauliac, Centre Hospitalier Régional Montpellier, Montpellier, France.; Faculté de médecine, Université de Montpellier, France., Lin JP; Complex Motor Disorder Service, Children's Neurosciences Department, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.; Children's Neuromodulation Group, Women and Children's Health Institute, Faculty of life Sciences and Medicine (FOLSM), King's Health Partners, London, UK., Barwick KE; Molecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK., Sa M; Complex Motor Disorder Service, Children's Neurosciences Department, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK., Abela L; Molecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK., Malhotra S; Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, University of London, London, UK., Chong WK; Developmental Imaging and Biophysics, UCL Great Ormond Street Institute of Child Health, London, UK., Steel D; Molecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK.; Department of Neurology, Great Ormond Street Hospital, London, UK., Sanchis-Juan A; NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.; Department of Haematology, NHS Blood and Transplant Centre, University of Cambridge, Cambridge, UK., Ngoh A; Molecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK.; Department of Neurology, Great Ormond Street Hospital, London, UK., Trump N; Molecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK., Meyer E; Molecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK., Vasques X; European IBM Systems Center, Montpellier, France., Rankin J; Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK., Allain MW; Division of Medical Genetics, Department of Pediatrics, Stanford University, Palo Alto, CA, USA., Applegate CD; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Attaripour Isfahani S; Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA., Baleine J; Unité de Soins Intensifs et Réanimation Pédiatrique et Néonatale, Hôpital Universitaire de Montpellier, Montpellier, France., Balint B; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.; Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany., Bassetti JA; Division of Medical Genetics, Department of Pediatrics, Weill Cornell Medical College, New York, NY, USA., Baple EL; Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.; Institute of Biomedical and Clinical Science RILD Wellcome Wolfson Centre, University of Exeter Medical School, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK., Bhatia KP; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK., Blanchet C; Département d'Oto-Rhino-Laryngologie et Chirurgie Cervico-Faciale, Hôpital Universitaire de Montpellier, Montpellier, France., Burglen L; Département de génétique médicale, APHP Hôpital Armand Trousseau, Paris, France., Cambonie G; Unité de Soins Intensifs et Réanimation Pédiatrique et Néonatale, Hôpital Universitaire de Montpellier, Montpellier, France., Seng EC; Département de Neurochirurgie, Unité des Pathologies Cérébrales Résistantes, Unité de Recherche sur les Comportements et Mouvements Anormaux, Hôpital Gui de Chauliac, Centre Hospitalier Régional Montpellier, Montpellier, France.; Faculté de médecine, Université de Montpellier, France., Bastaraud SC; Unité Dyspa, Neurochirurgie Pédiatrique, Hôpital Fondation Rothschild, Paris, France., Cyprien F; Département de Neurochirurgie, Unité des Pathologies Cérébrales Résistantes, Unité de Recherche sur les Comportements et Mouvements Anormaux, Hôpital Gui de Chauliac, Centre Hospitalier Régional Montpellier, Montpellier, France.; Faculté de médecine, Université de Montpellier, France., Coubes C; Département de Génétique médicale, Maladies rares et médecine personnalisée, CHU Montpellier, Montpellier, France., d'Hardemare V; Unité Dyspa, Neurochirurgie Pédiatrique, Hôpital Fondation Rothschild, Paris, France., Doja A; Division of Neurology, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada., Dorison N; Unité Dyspa, Neurochirurgie Pédiatrique, Hôpital Fondation Rothschild, Paris, France., Doummar D; Neuropédiatrie, Centre de référence neurogénétique mouvement anormaux de l'enfant, Hôpital Armand Trousseau, AP-HP, Sorbonne Université, France., Dy-Hollins ME; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.; Department of Neurology, Harvard Medical School, Boston, MA, USA., Farrelly E; Division of Medical Genetics, Department of Pediatrics, Stanford University, Palo Alto, CA, USA.; Department of Pediatrics, Lucile Packard Children's Hospital at Stanford, CA, USA., Fitzpatrick DR; Human Genetics Unit, Medical and Developmental Genetics, University of Edinburgh Western General Hospital, Edinburgh, Scotland, UK., Fearon C; Department of Neurology, The Dublin Neurological Institute at the Mater Misericordiae University Hospital, Dublin, Ireland., Fieg EL; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Fogel BL; Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Forman EB; Department of Paediatric Neurology and Clinical Neurophysiology, Children's Health Ireland at Temple Street, Dublin, Ireland., Fox RG; Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA., Gahl WA; Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA., Galosi S; Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy., Gonzalez V; Département de Neurochirurgie, Unité des Pathologies Cérébrales Résistantes, Unité de Recherche sur les Comportements et Mouvements Anormaux, Hôpital Gui de Chauliac, Centre Hospitalier Régional Montpellier, Montpellier, France.; Faculté de médecine, Université de Montpellier, France., Graves TD; Department of Neurology, Hinchingbrooke Hospital, North West Anglia NHS Foundation Trust, Huntingdon, UK., Gregory A; Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA., Hallett M; Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA., Hasegawa H; Complex Motor Disorder Service, Children's Neurosciences Department, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.; Children's Neuromodulation Group, Women and Children's Health Institute, Faculty of life Sciences and Medicine (FOLSM), King's Health Partners, London, UK., Hayflick SJ; Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA.; Department of Paediatrics, Oregon Health and Science University, Portland, OR, USA., Hamosh A; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Hully M; Département de Neurologie, APHP-Necker-Enfants Malades, Paris, France., Jansen S; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands., Jeong SY; Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA., Krier JB; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Krystal S; Département de Neuroradiologie, Hôpital Fondation Rothschild, Paris., Kumar KR; Translational Genomics Group, Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.; Department of Neurogenetics, Kolling Institute, University of Sydney and Royal North Shore Hospital, St Leonards, NSW, Australia.; Molecular Medicine Laboratory, Concord Hospital, Sydney, NSW, Australia., Laurencin C; Département de Neurologie, Hôpital Neurologique Pierre Wertheimer, Lyon, France., Lee H; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Lesca G; Département de Génétique, Hôpital Universitaire de Lyon, Lyon, France., François LL; Département de Pédiatrie, Hôpital Lyon-Sud, Pierre-Bénite, France., Lynch T; Department of Neurology, The Dublin Neurological Institute at the Mater Misericordiae University Hospital, Dublin, Ireland.; UCD School of Medicine and Medical Science, University College Dublin, Dublin, Ireland., Mahant N; Movement Disorders Unit, Department of Neurology, Westmead Hospital, Westmead, NSW, Australia., Martinez-Agosto JA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.; Division of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Milesi C; Unité de Soins Intensifs et Réanimation Pédiatrique et Néonatale, Hôpital Universitaire de Montpellier, Montpellier, France., Mills KA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Mondain M; Département d'Oto-Rhino-Laryngologie et Chirurgie Cervico-Faciale, Hôpital Universitaire de Montpellier, Montpellier, France., Morales-Briceno H; Movement Disorders Unit, Department of Neurology, Westmead Hospital, Westmead, NSW, Australia.; Sydney Medical School, University of Sydney, Sydney, NSW, Australia., Ostergaard JR; Centre for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark., Pal S; Institute of Genetics and Genomics, Sir Ganga Ram Hospital, Rajender Nagar, New Delhi, India., Pallais JC; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Pavillard F; Département d'Anesthésie-Réanimation Gui de Chauliac, Centre Hospitalier Universitaire de Montpellier, Montpellier, France., Perrigault PF; Département d'Anesthésie-Réanimation Gui de Chauliac, Centre Hospitalier Universitaire de Montpellier, Montpellier, France., Petersen AK; Randall Children's Hospital, Portland, OR, USA., Polo G; Département de Neurochirurgie Fonctionnelle, Hôpital Neurologique et Neurochirurgical, Pierre Wertheimer, Lyon, France., Poulen G; Département de Neurochirurgie, Unité des Pathologies Cérébrales Résistantes, Unité de Recherche sur les Comportements et Mouvements Anormaux, Hôpital Gui de Chauliac, Centre Hospitalier Régional Montpellier, Montpellier, France.; Faculté de médecine, Université de Montpellier, France., Rinne T; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands., Roujeau T; Département de Neurochirurgie, Unité des Pathologies Cérébrales Résistantes, Unité de Recherche sur les Comportements et Mouvements Anormaux, Hôpital Gui de Chauliac, Centre Hospitalier Régional Montpellier, Montpellier, France., Rogers C; Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA., Roubertie A; Département de Neuropédiatrie, Hôpital Universitaire de Montpellier, Montpellier, France.; INSERM U1051, Institut des Neurosciences de Montpellier, Montpellier, France., Sahagian M; Division of Neurology, Rady Children's Hospital San Diego, CA, USA.; Department of Neuroscience, University of California San Diego, CA, USA., Schaefer E; Medical Genetics, Hôpitaux Universitaires de Strasbourg, Strasbourg, France., Selim L; Cairo University Children Hospital, Pediatric Neurology and Metabolic division, Cairo, Egypt., Selway R; Department of Neurosurgery, King's College Hospital, London, UK., Sharma N; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.; Department of Neurology, Harvard Medical School, Boston, MA, USA.; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA., Signer R; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Soldatos AG; Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA., Stevenson DA; Division of Medical Genetics, Department of Pediatrics, Stanford University, Palo Alto, CA, USA., Stewart F; Department of Genetic Medicine, Belfast Health and Social Care Trust, Belfast, UK., Tchan M; Sydney Medical School, University of Sydney, Sydney, NSW, Australia.; Department of Genetics, Westmead Hospital, Westmead, NSW, Australia., Verma IC; Institute of Genetics and Genomics, Sir Ganga Ram Hospital, Rajender Nagar, New Delhi, India., de Vries BBA; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands., Wilson JL; Division of Pediatric Neurology, Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA., Wong DA; Division of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Zaitoun R; Department of Paediatrics, Neurology Division, Ain Shams University Hospital, Cairo, Egypt., Zhen D; Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA., Znaczko A; Department of Genetic Medicine, Belfast Health and Social Care Trust, Belfast, UK., Dale RC; Department of Paediatric Neurology, The Children's Hospital at Westmead, NSW, Australia.; Faculty of Medicine and Health, Sydney Medical School, University of Sydney, Sydney NSW, Australia., de Gusmão CM; Department of Neurology, Harvard Medical School, Boston, MA, USA.; Department of Neurology, Boston Children's Hospital, Boston, MA, USA., Friedman J; Division of Neurology, Rady Children's Hospital San Diego, CA, USA.; Department of Neuroscience, University of California San Diego, CA, USA.; Departments of Paediatrics, University of California, San Diego, CA, USA.; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA., Fung VSC; Movement Disorders Unit, Department of Neurology, Westmead Hospital, Westmead, NSW, Australia.; Sydney Medical School, University of Sydney, Sydney, NSW, Australia., King MD; Department of Paediatric Neurology and Clinical Neurophysiology, Children's Health Ireland at Temple Street, Dublin, Ireland.; UCD School of Medicine and Medical Science, University College Dublin, Dublin, Ireland., Mohammad SS; Department of Paediatric Neurology, The Children's Hospital at Westmead, NSW, Australia.; Faculty of Medicine and Health, Sydney Medical School, University of Sydney, Sydney NSW, Australia., Rohena L; Division of Medical Genetics, Department of Pediatrics, San Antonio Military Medical Center, San Antonio, TX, USA.; Department of Pediatrics, Long School of Medicine, UT Health, San Antonio, TX, USA., Waugh JL; Division of Pediatric Neurology, Department of Pediatrics, University of Texas Southwestern, Dallas, TX, USA., Toro C; Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA., Raymond FL; NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.; Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK., Topf M; Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, University of London, London, UK., Coubes P; Département de Neurochirurgie, Unité des Pathologies Cérébrales Résistantes, Unité de Recherche sur les Comportements et Mouvements Anormaux, Hôpital Gui de Chauliac, Centre Hospitalier Régional Montpellier, Montpellier, France.; Faculté de médecine, Université de Montpellier, France., Gorman KM; Molecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK.; Department of Neurology, Great Ormond Street Hospital, London, UK., Kurian MA; Molecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK.; Department of Neurology, Great Ormond Street Hospital, London, UK.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2020 Dec 05; Vol. 143 (11), pp. 3242-3261.
DOI:	10.1093/brain/awaa304
Abstrakt:	Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5-37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden's Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution. (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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