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

Laura Cif; Diane Demailly; Jean-Pierre Lin; Katy E Barwick; Mario Sa; Lucia Abela; Sony Malhotra; Wui K Chong; Dora Steel; Alba Sanchis-Juan; Adeline Ngoh; Natalie Trump; Esther Meyer; Xavier Vasques; Julia Rankin; Meredith W Allain; Carolyn D Applegate; Sanaz Attaripour Isfahani; Julien Baleine; Bettina Balint; Jennifer A Bassetti; Emma L Baple; Kailash P Bhatia; Catherine Blanchet; Lydie Burglen; Gilles Cambonie; Emilie Chan Seng; Sandra Chantot Bastaraud; Fabienne Cyprien; Christine Coubes; Vincent d'Hardemare; Asif Doja; Nathalie Dorison; Diane Doummar; Marisela E Dy-Hollins; Ellyn Farrelly; David R Fitzpatrick; Conor Fearon; Elizabeth L Fieg; Brent L Fogel; Eva B Forman; Rachel G Fox; William A Gahl; Serena Galosi; Victoria Gonzalez; Tracey D Graves; Allison Gregory; Mark Hallett; Harutomo Hasegawa; Susan J Hayflick; Ada Hamosh; Marie Hully; Sandra Jansen; Suh Young Jeong; Joel B Krier; Sidney Krystal; Kishore R Kumar; Chloé Laurencin; Hane Lee; Gaetan Lesca; Laurence Lion François; Timothy Lynch; Neil Mahant; Julian A Martinez-Agosto; Christophe Milesi; Kelly A Mills; Michel Mondain; Hugo Morales-Briceno; John R Ostergaard; Swasti Pal; Juan C Pallais; Frédérique Pavillard; Pierre-Francois Perrigault; Andrea K Petersen; Gustavo Polo; Gaetan Poulen; Tuula Rinne; Thomas Roujeau; Caleb Rogers; Agathe Roubertie; Michelle Sahagian; Elise Schaefer; Laila Selim; Richard Selway; Nutan Sharma; Rebecca Signer; Ariane G Soldatos; David A Stevenson; Fiona Stewart; Michel Tchan; Ishwar C Verma; Bert B A de Vries; Jenny L Wilson; Derek A Wong; Raghda Zaitoun; Dolly Zhen; Anna Znaczko; Russell C Dale; Claudio M de Gusmão; Jennifer Friedman; Deciphering Developmental Disorders Study

Article de revue

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

Laura Cif, Diane Demailly, Jean-Pierre Lin, Katy E Barwick, Mario Sa, Lucia Abela, Sony Malhotra, Wui K Chong, Dora Steel, Alba Sanchis-Juan, …

ArXiv.org

10/02/2025

PMID: 39990802

Résumé

deep brain stimulation (DBS)

genetics

neurodevelopment

dystonia

KMT2B

Heterozygous mutations in 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 -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 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 ( = 53) in tandem with published cases ( = 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 ł months, 1 year and last follow-up (motor, = 0.001, = 0.004, and = 0.012; disability, = 0.009, = 0.002 and = 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, = 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 1ł.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. 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.

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Détails

Titre: KMT2B -related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation
Créateurs - sans rôle: Laura Cif - Université de Montpellier
Diane Demailly - Université de Montpellier
Jean-Pierre Lin - Children's Neuromodulation Group, Women and Children's Health Institute, Faculty of life Sciences and Medicine (FOLSM), King's Health Partners, London, UK
Katy E Barwick - Molecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK
Mario Sa - Guy's and St Thomas' NHS Foundation Trust
Lucia Abela - Molecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK
Sony Malhotra - University of London
Wui K Chong - Developmental Imaging and Biophysics, UCL Great Ormond Street Institute of Child Health, London, UK
Dora Steel - Great Ormond Street Hospital
Alba Sanchis-Juan - University of Cambridge
Adeline Ngoh - Great Ormond Street Hospital
Natalie Trump - Molecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK
Esther Meyer - Molecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK
Xavier Vasques - European IBM Systems Center, Montpellier, France
Julia Rankin - Royal Devon University Healthcare NHS Foundation Trust
Meredith W Allain - Stanford University
Carolyn D Applegate - Johns Hopkins University School of Medicine
Sanaz Attaripour Isfahani - Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
Julien Baleine - Unité de Soins Intensifs et Réanimation Pédiatrique et Néonatale, Hôpital Universitaire de Montpellier, Montpellier, France
Bettina Balint - Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany
Jennifer A Bassetti - Division of Medical Genetics, Department of Pediatrics, Weill Cornell Medical College, New York, NY, USA
Emma L Baple - University of Exeter
Kailash P Bhatia - Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
Catherine Blanchet - Département d'Oto-Rhino-Laryngologie et Chirurgie Cervico-Faciale, Hôpital Universitaire de Montpellier, Montpellier, France
Lydie Burglen - Hôpital Armand-Trousseau
Gilles Cambonie - Unité de Soins Intensifs et Réanimation Pédiatrique et Néonatale, Hôpital Universitaire de Montpellier, Montpellier, France
Emilie Chan Seng - Faculté demédecine, Université de Montpellier, France
Sandra Chantot Bastaraud - Unité Dyspa, Neurochirurgie Pédiatrique, Hôpital Fondation Rothschild, Paris, France
Fabienne Cyprien - Université de Montpellier
Christine Coubes - Département de Génétique médicale, Maladies rares et médecine personnalisée, CHU Montpellier, Montpellier, France
Vincent d'Hardemare - Unité Dyspa, Neurochirurgie Pédiatrique, Hôpital Fondation Rothschild, Paris, France
Asif Doja - Children's Hospital of Eastern Ontario
Nathalie Dorison - Unité Dyspa, Neurochirurgie Pédiatrique, Hôpital Fondation Rothschild, Paris, France
Diane Doummar - Hôpital Armand-Trousseau
Marisela E Dy-Hollins - Harvard Medical School
Ellyn Farrelly - Lucile Packard Children's Hospital
David R Fitzpatrick - University of Edinburgh
Conor Fearon - Mater Misericordiae University Hospital
Elizabeth L Fieg - Brigham and Women's Hospital
Brent L Fogel - University of California, Los Angeles
Eva B Forman - Department of Paediatric Neurology and Clinical Neurophysiology, Children's Health Ireland at Temple Street, Dublin, Ireland
Rachel G Fox - Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA
William A Gahl - National Human Genome Research Institute
Serena Galosi - Sapienza University of Rome
Victoria Gonzalez - Faculté demédecine, Université de Montpellier, France
Tracey D Graves - Hinchingbrooke Hospital
Allison Gregory - University of Portland
Mark Hallett - National Institute of Neurological Disorders and Stroke
Harutomo Hasegawa - Children's Neuromodulation Group, Women and Children's Health Institute, Faculty of life Sciences and Medicine (FOLSM), King's Health Partners, London, UK
Susan J Hayflick - University of Portland
Ada Hamosh - Johns Hopkins University School of Medicine
Marie Hully - Département de Neurologie, APHP-Necker-Enfants Malades, Paris, France
Sandra Jansen - Radboud University Medical Center
Suh Young Jeong - Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA
Joel B Krier - Brigham and Women's Hospital
Sidney Krystal - Département de Neuroradiologie, Hôpital Fondation Rothschild, Paris
Kishore R Kumar - Molecular Medicine Laboratory, Concord Hospital, Sydney, NSW, Australia
Chloé Laurencin - Département de Neurologie, Hôpital Neurologique Pierre Wertheimer, Lyon, France
Hane Lee - University of California, Los Angeles
Gaetan Lesca - Département de Génétique, Hôpital Universitaire de Lyon, Lyon, France
Laurence Lion François - Département de Pédiatrie, Hôpital Lyon-Sud, Pierre-Bénite, France
Timothy Lynch - University College Dublin
Neil Mahant - Westmead Hospital
Julian A Martinez-Agosto - University of California, Los Angeles
Christophe Milesi - Unité de Soins Intensifs et Réanimation Pédiatrique et Néonatale, Hôpital Universitaire de Montpellier, Montpellier, France
Kelly A Mills - Johns Hopkins University School of Medicine
Michel Mondain - Département d'Oto-Rhino-Laryngologie et Chirurgie Cervico-Faciale, Hôpital Universitaire de Montpellier, Montpellier, France
Hugo Morales-Briceno - The University of Sydney
John R Ostergaard - Aarhus University Hospital
Swasti Pal - Institute of Genetics and Genomics, Sir Ganga Ram Hospital, Rajender Nagar, New Delhi, India
Juan C Pallais - Brigham and Women's Hospital
Frédérique Pavillard - Département d'Anesthésie-Réanimation Gui de Chauliac, Centre Hospitalier Universitaire de Montpellier, Montpellier, France
Pierre-Francois Perrigault - Département d'Anesthésie-Réanimation Gui de Chauliac, Centre Hospitalier Universitaire de Montpellier, Montpellier, France
Andrea K Petersen - Randall Children's Hospital, Portland, OR, USA
Gustavo Polo - Département de Neurochirurgie Fonctionnelle, Hôpital Neurologique et Neurochirurgical, Pierre Wertheimer, Lyon, France
Gaetan Poulen - Université de Montpellier
Tuula Rinne - Radboud University Medical Center
Thomas Roujeau - Hôpital Gui de Chauliac
Caleb Rogers - University of Portland
Agathe Roubertie - Inserm
Michelle Sahagian - University of California San Diego
Elise Schaefer - Medical Genetics, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
Laila Selim - Cairo University
Richard Selway - King's College Hospital
Nutan Sharma - Brigham and Women's Hospital
Rebecca Signer - University of California, Los Angeles
Ariane G Soldatos - National Human Genome Research Institute
David A Stevenson - Stanford University
Fiona Stewart - Department of Genetic Medicine, Belfast Health and Social Care Trust, Belfast, UK
Michel Tchan - Westmead Hospital
Ishwar C Verma - Institute of Genetics and Genomics, Sir Ganga Ram Hospital, Rajender Nagar, New Delhi, India
Bert B A de Vries - Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
Jenny L Wilson - University of Portland
Derek A Wong - University of California, Los Angeles
Raghda Zaitoun - Department of Paediatrics, Neurology Division, Ain Shams University Hospital, Cairo, Egypt
Dolly Zhen - University of Portland
Anna Znaczko - Belfast Health and Social Care Trust
Russell C Dale - The University of Sydney
Claudio M de Gusmão - Department of Neurology, Boston Children's Hospital, Boston, MA, USA
Jennifer Friedman - Rady Children's Institute for Genomic Medicine, San Diego, CA, USA
Deciphering Developmental Disorders Study
Détails de publication: ArXiv.org
Note de subvention: U01 HG007703 / NHGRI NIH HHS U54 HG006493 / NHGRI NIH HHS UM1 HG006493 / NHGRI NIH HHS Wellcome Trust P01 NS087997 / NINDS NIH HHS U01 HG007690 / NHGRI NIH HHS K23 NS101096 / NINDS NIH HHS
Identifiants: 99156929909311
Unité académique: Pathogenesis and Control of Chronic and Emerging Infections - PCCEI; Recherche hors université; Mécanismes Moléculaires dans les Démences Neurodégénératives - MMDN
Langue: English
Type de ressource: Journal article