Evidence map›Paper›PMID 33150406›Full record

ArticleBrain : a journal of neurology2020

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 and 105 more

Registry-linked trialOpen access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Brain : a journal of neurology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02450851 (Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network), which is not on this map. Cited by 65 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
65citing papers in PubMed, 2 pooled it
11.0field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT02450851 recruitingnot on this map

Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network

TypeobservationalSponsorNational Human Genome Research Institute (NHGRI)Ran2015 to 2028Enrolled20,000ConditionsGenetic Disease
3 · Its place in the literature

Who cites it

65 citing papers in PubMed, 2 syntheses or guidelines pooled it, 104 citations in OpenAlex.

  1. Pooled it
  2. Pooled it
  3. Article
  4. Clinical, imaging and genetic profile of KMT2B-related dystonia: a review of published cases.Journal of neural transmission (Vienna, Austria : 1996) · 2026
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  11. Common and rare genetic variants explain distinct diagnostic variance in pediatric attention deficit hyperactivity disorder.Genetics in medicine : official journal of the American College of Medical Genetics · 2025
    Article
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  13. Observational
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5 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

  • Update of
    2025
5 · Who and what money

Authors and funding

115 authors at 20 institutions in 12 countries.

Laura CifDépartement 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.
Diane DemaillyDépartement 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.
Jean-Pierre LinComplex Motor Disorder Service, Children's Neurosciences Department, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.
Katy E BarwickMolecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK.
Mario SaComplex Motor Disorder Service, Children's Neurosciences Department, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.
Lucia AbelaMolecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK.
Sony MalhotraInstitute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, University of London, London, UK.
Wui K ChongDevelopmental Imaging and Biophysics, UCL Great Ormond Street Institute of Child Health, London, UK.
Dora SteelMolecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK.
Alba Sanchis-JuanNIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Adeline NgohMolecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK.
Natalie TrumpMolecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK.
Esther MeyerMolecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK.
Xavier VasquesEuropean IBM Systems Center, Montpellier, France.
Julia RankinClinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
Meredith W AllainDivision of Medical Genetics, Department of Pediatrics, Stanford University, Palo Alto, CA, USA.
Carolyn D ApplegateMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Sanaz Attaripour IsfahaniHuman Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Julien BaleineUnité de Soins Intensifs et Réanimation Pédiatrique et Néonatale, Hôpital Universitaire de Montpellier, Montpellier, France.
Bettina BalintDepartment of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
Jennifer A BassettiDivision of Medical Genetics, Department of Pediatrics, Weill Cornell Medical College, New York, NY, USA.
Emma L BapleClinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
Kailash P BhatiaDepartment of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
Catherine BlanchetDépartement d'Oto-Rhino-Laryngologie et Chirurgie Cervico-Faciale, Hôpital Universitaire de Montpellier, Montpellier, France.
Lydie BurglenDépartement de génétique médicale, APHP Hôpital Armand Trousseau, Paris, France.
Gilles CambonieUnité de Soins Intensifs et Réanimation Pédiatrique et Néonatale, Hôpital Universitaire de Montpellier, Montpellier, France.
Emilie Chan SengDépartement 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.
Sandra Chantot BastaraudUnité Dyspa, Neurochirurgie Pédiatrique, Hôpital Fondation Rothschild, Paris, France.
Fabienne CyprienDépartement 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.
Christine CoubesDépartement de Génétique médicale, Maladies rares et médecine personnalisée, CHU Montpellier, Montpellier, France.
Vincent d'HardemareUnité Dyspa, Neurochirurgie Pédiatrique, Hôpital Fondation Rothschild, Paris, France.
Deciphering Developmental Disorders Study
Asif DojaDivision of Neurology, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
Nathalie DorisonUnité Dyspa, Neurochirurgie Pédiatrique, Hôpital Fondation Rothschild, Paris, France.
Diane DoummarNeuropédiatrie, Centre de référence neurogénétique mouvement anormaux de l'enfant, Hôpital Armand Trousseau, AP-HP, Sorbonne Université, France.
Marisela E Dy-HollinsDepartment of Neurology, Massachusetts General Hospital, Boston, MA, USA.
Ellyn FarrellyDivision of Medical Genetics, Department of Pediatrics, Stanford University, Palo Alto, CA, USA.
David R FitzpatrickHuman Genetics Unit, Medical and Developmental Genetics, University of Edinburgh Western General Hospital, Edinburgh, Scotland, UK.
Conor FearonDepartment of Neurology, The Dublin Neurological Institute at the Mater Misericordiae University Hospital, Dublin, Ireland.
Elizabeth L FiegDivision of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Brent L FogelDepartment of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Eva B FormanDepartment of Paediatric Neurology and Clinical Neurophysiology, Children's Health Ireland at Temple Street, Dublin, Ireland.
Rachel G FoxDepartment of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA.
Genomics England Research Consortium
William A GahlUndiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Serena GalosiDepartment of Human Neuroscience, Sapienza University of Rome, Rome, Italy.
Victoria GonzalezDépartement 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.
Tracey D GravesDepartment of Neurology, Hinchingbrooke Hospital, North West Anglia NHS Foundation Trust, Huntingdon, UK.
Allison GregoryDepartment of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA.
Mark HallettHuman Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Harutomo HasegawaComplex Motor Disorder Service, Children's Neurosciences Department, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.
Susan J HayflickDepartment of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA.
Ada HamoshMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Marie HullyDépartement de Neurologie, APHP-Necker-Enfants Malades, Paris, France.
Sandra JansenDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Suh Young JeongDepartment of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA.
Joel B KrierDivision of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Sidney KrystalDépartement de Neuroradiologie, Hôpital Fondation Rothschild, Paris.
Kishore R KumarTranslational Genomics Group, Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
Chloé LaurencinDépartement de Neurologie, Hôpital Neurologique Pierre Wertheimer, Lyon, France.
Hane LeeDepartment of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Gaetan LescaDépartement de Génétique, Hôpital Universitaire de Lyon, Lyon, France.
Laurence Lion FrançoisDépartement de Pédiatrie, Hôpital Lyon-Sud, Pierre-Bénite, France.
Timothy LynchDepartment of Neurology, The Dublin Neurological Institute at the Mater Misericordiae University Hospital, Dublin, Ireland.
Neil MahantMovement Disorders Unit, Department of Neurology, Westmead Hospital, Westmead, NSW, Australia.
Julian A Martinez-AgostoDepartment of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Christophe MilesiUnité de Soins Intensifs et Réanimation Pédiatrique et Néonatale, Hôpital Universitaire de Montpellier, Montpellier, France.
Kelly A MillsDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Michel MondainDépartement d'Oto-Rhino-Laryngologie et Chirurgie Cervico-Faciale, Hôpital Universitaire de Montpellier, Montpellier, France.
Hugo Morales-BricenoMovement Disorders Unit, Department of Neurology, Westmead Hospital, Westmead, NSW, Australia.
NIHR BioResource
John R OstergaardCentre for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark.
Swasti PalInstitute of Genetics and Genomics, Sir Ganga Ram Hospital, Rajender Nagar, New Delhi, India.
Juan C PallaisDivision of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Frédérique PavillardDépartement d'Anesthésie-Réanimation Gui de Chauliac, Centre Hospitalier Universitaire de Montpellier, Montpellier, France.
Pierre-Francois PerrigaultDépartement d'Anesthésie-Réanimation Gui de Chauliac, Centre Hospitalier Universitaire de Montpellier, Montpellier, France.
Andrea K PetersenRandall Children's Hospital, Portland, OR, USA.
Gustavo PoloDépartement de Neurochirurgie Fonctionnelle, Hôpital Neurologique et Neurochirurgical, Pierre Wertheimer, Lyon, France.
Gaetan PoulenDépartement 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.
Tuula RinneDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Thomas RoujeauDépartement 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.
Caleb RogersDepartment of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA.
Agathe RoubertieDépartement de Neuropédiatrie, Hôpital Universitaire de Montpellier, Montpellier, France.
Michelle SahagianDivision of Neurology, Rady Children's Hospital San Diego, CA, USA.
Elise SchaeferMedical Genetics, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Laila SelimCairo University Children Hospital, Pediatric Neurology and Metabolic division, Cairo, Egypt.
Richard SelwayDepartment of Neurosurgery, King's College Hospital, London, UK.
Nutan SharmaDepartment of Neurology, Massachusetts General Hospital, Boston, MA, USA.
Rebecca SignerDepartment of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Ariane G SoldatosUndiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
David A StevensonDivision of Medical Genetics, Department of Pediatrics, Stanford University, Palo Alto, CA, USA.
Fiona StewartDepartment of Genetic Medicine, Belfast Health and Social Care Trust, Belfast, UK.
Michel TchanSydney Medical School, University of Sydney, Sydney, NSW, Australia.
Undiagnosed Diseases Network
Ishwar C VermaInstitute of Genetics and Genomics, Sir Ganga Ram Hospital, Rajender Nagar, New Delhi, India.
Bert B A de VriesDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Jenny L WilsonDivision of Pediatric Neurology, Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA.
Derek A WongDivision of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Raghda ZaitounDepartment of Paediatrics, Neurology Division, Ain Shams University Hospital, Cairo, Egypt.
Dolly ZhenDepartment of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA.
Anna ZnaczkoDepartment of Genetic Medicine, Belfast Health and Social Care Trust, Belfast, UK.
Russell C DaleDepartment of Paediatric Neurology, The Children's Hospital at Westmead, NSW, Australia.
Claudio M de GusmãoDepartment of Neurology, Harvard Medical School, Boston, MA, USA.
Jennifer FriedmanDivision of Neurology, Rady Children's Hospital San Diego, CA, USA.
Victor S C FungMovement Disorders Unit, Department of Neurology, Westmead Hospital, Westmead, NSW, Australia.
Mary D KingDepartment of Paediatric Neurology and Clinical Neurophysiology, Children's Health Ireland at Temple Street, Dublin, Ireland.
Shekeeb S MohammadDepartment of Paediatric Neurology, The Children's Hospital at Westmead, NSW, Australia.
Luis RohenaDivision of Medical Genetics, Department of Pediatrics, San Antonio Military Medical Center, San Antonio, TX, USA.
Jeff L WaughDivision of Pediatric Neurology, Department of Pediatrics, University of Texas Southwestern, Dallas, TX, USA.
Camilo ToroUndiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
F Lucy RaymondNIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Maya TopfInstitute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, University of London, London, UK.
Philippe CoubesDépartement 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.
Kathleen M GormanMolecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK.
Manju A KurianMolecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK.
Great Ormond Street Hospital · GBThe University of Sydney · AUUniversité de Montpellier · FRBrigham and Women's Hospital · USUniversity of California, Los Angeles · USNational Institutes of Health · USOregon Health & Science University · USJohns Hopkins University · USRadboud University Nijmegen · NLBelfast Health and Social Care Trust · GBUniversity College Dublin · IECentre Hospitalier Universitaire de Montpellier · FRBrooke Army Medical Center · USChildren's Hospital of Eastern Ontario · CAFondation de Rothschild · FRGuy's and St Thomas' NHS Foundation Trust · GBInserm · FRInstitute of Structural and Molecular Biology · GBLucile Packard Children's Hospital · USSorbonne Université · FR

Funding

UW Center for Mendelian GenomicsU54HG006493 · NHGRI · UNIVERSITY OF WASHINGTON · PI BAMSHAD, MICHAEL JOSEPH, NICKERSON, DEBORAH A · 2012 to 2015
$20.0M
UW Center for Mendelian GenomicsUM1HG006493 · NHGRI · UNIVERSITY OF WASHINGTON · PI BAMSHAD, MICHAEL JOSEPH, LEAL, SUZANNE M · 2016 to 2020
$15.3M
Center for Integrated Approaches to Undiagnosed DiseasesU01HG007690 · NHGRI · BRIGHAM AND WOMEN'S HOSPITAL · PI LOSCALZO, JOSEPH · 2014 to 2022
$10.4M
UCLA clinical site for the investigation of undiagnosed disordersU01HG007703 · NHGRI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI MARTINEZ-AGOSTO, JULIAN, NELSON, STANLEY F. · 2014 to 2022
$10.1M
TorsinA as a key link in receptor-mediated signalingP01NS087997 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI STANDAERT, DAVID G. · 2015 to 2019
$6.4M
Molecular Imaging of the Nicotinic Cholinergic Receptor in Parkinson's disease (PD): Implication of for understanding the neurobiology of cognitive impairmentK23NS101096 · NINDS · JOHNS HOPKINS UNIVERSITY · PI MILLS, KELLY ALEXANDER · 2017 to 2021
$1000k
Cancer Research UKDepartment of Health RP-2016-07-019Medical Research Council MC_UU_00007/3NHGRI NIH HHS U01 HG007690NHGRI NIH HHS U01 HG007703NHGRI NIH HHS U54 HG006493NHGRI NIH HHS UM1 HG006493NINDS NIH HHS K23 NS101096NINDS NIH HHS P01 NS087997Wellcome TrustWellcome Trust WT098051
6 · The paper itself

Abstract

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.

Indexed as

AdolescentAdultChildChild, PreschoolChromosome DeletionCohort StudiesComputer SimulationDeep Brain StimulationDisease ProgressionDystonic DisordersEndocrine System DiseasesFemaleFetal Growth RetardationGait Disorders, NeurologicHistone-Lysine N-MethyltransferaseHumansHistone-Lysine N-MethyltransferaseKMT2B protein, humandeep brain stimulation (DBS)dystoniageneticsKMT2Bneurodevelopment

Identifiers

PMID33150406
PMCPMC7719027
OpenAlexW3095145521

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.