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

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DOI

  • Laura Cif, Hopital Gui de Chauliac, Universite de Montpellier
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  • Diane Demailly, Hopital Gui de Chauliac, Universite de Montpellier
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  • Jean Pierre Lin, Guy's and St Thomas' NHS Foundation Trust, Faculty of life Sciences and Medicine (FOLSM)
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  • Katy E. Barwick, University College London
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  • Mario Sa, Guy's and St Thomas' NHS Foundation Trust
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  • Lucia Abela, University College London
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  • Sony Malhotra, Birkbeck University of London
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  • Wui K. Chong, University College London
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  • Dora Steel, University College London, UCL Great Ormond Street Institute of Child Health
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  • Alba Sanchis-Juan, Cambridge University Hospitals NHS Foundation Trust, University of Cambridge
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  • Adeline Ngoh, University College London, UCL Great Ormond Street Institute of Child Health
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  • Natalie Trump, University College London
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  • Esther Meyer, University College London
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  • Xavier Vasques, European IBM Systems Center
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  • Julia Rankin, Royal Devon & Exeter NHS Foundation Trust
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  • Meredith W. Allain, Stanford University
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  • Carolyn D. Applegate, Johns Hopkins University
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  • Sanaz Attaripour Isfahani, University of Rochester
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  • Julien Baleine, CHU Montpellier
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  • Bettina Balint, Department of Clinical and Movement Neurosciences, Heidelberg University 
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  • Jennifer A. Bassetti, Cornell University
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  • Emma L. Baple, Royal Devon & Exeter NHS Foundation Trust, University of Exeter
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  • Kailash P. Bhatia, Department of Clinical and Movement Neurosciences
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  • Catherine Blanchet, CHU Montpellier
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  • Lydie Burglen, Hopital Armand-Trousseau
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  • Gilles Cambonie, CHU Montpellier
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  • Emilie Chan Seng, Hopital Gui de Chauliac, Universite de Montpellier
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  • Sandra Chantot Bastaraud, Neurochirurgie Pédiatrique
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  • Fabienne Cyprien, Hopital Gui de Chauliac, Universite de Montpellier
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  • Christine Coubes, CHU Montpellier
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  • Vincent d'Hardemare, Neurochirurgie Pédiatrique
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  • Deciphering Developmental Disorders Study
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  • Asif Doja, University of Ottawa
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  • Nathalie Dorison, Neurochirurgie Pédiatrique
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  • Diane Doummar, Sorbonne Université
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  • Marisela E. Dy-Hollins, Harvard University
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  • Ellyn Farrelly, Stanford University, Lucile Packard Children's Hospital at Stanford
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  • David R. Fitzpatrick, University of Edinburgh
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  • Conor Fearon, University College Dublin
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  • Elizabeth L. Fieg, Harvard University
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  • Brent L. Fogel, University of California at Los Angeles
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  • Eva B. Forman, Department of Paediatric Neurology and Clinical Neurophysiology
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  • Rachel G. Fox, Oregon Health and Science University
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  • Genomics England Research Consortium
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  • William A. Gahl, University of Rochester
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  • Serena Galosi, University of Rome La Sapienza
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  • Victoria Gonzalez, Hopital Gui de Chauliac, Universite de Montpellier
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  • Tracey D. Graves, North West Anglia NHS Foundation Trust
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  • Allison Gregory, Oregon Health and Science University
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  • Mark Hallett, University of Rochester
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  • Harutomo Hasegawa, Guy's and St Thomas' NHS Foundation Trust, Faculty of life Sciences and Medicine (FOLSM)
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  • Susan J Hayflick
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  • Ada Hamosh
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  • Marie Hully
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  • Sandra Jansen
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  • Suh Young Jeong
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  • Joel B Krier
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  • Sidney Krystal
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  • Kishore R Kumar
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  • Chloé Laurencin
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  • Hane Lee
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  • Gaetan Lesca, CNRS, Centre National de la Recherche Scientifique (CNRS), Institut National de la Sante et de la Recherche Medicale (Inserm), INSERM, U1028, UMRS5292,Lyon Neurosci Res Ctr
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  • Laurence Lion François
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  • Timothy Lynch
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  • Neil Mahant
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  • Julian A Martinez-Agosto
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  • Christophe Milesi
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  • Kelly A Mills
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  • Michel Mondain
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  • Hugo Morales-Briceno
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  • NIHR BioResource
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  • John R. Ostergaard
  • Undiagnosed Diseases Network

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.

Original languageEnglish
JournalBrain : a journal of neurology
Volume143
Issue11
Pages (from-to)3242-3261
Number of pages20
ISSN0006-8950
DOIs
Publication statusPublished - Nov 2020

    Research areas

  • KMT2B, deep brain stimulation (DBS), dystonia, genetics, neurodevelopment

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