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[Preprint]. 2025 Feb 10:arXiv:2502.06320v1.

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

Laura Cif^{1

2}, Diane Demailly^{1

2}, Jean-Pierre Lin^{3

4}, Katy E Barwick⁵, Mario Sa³, Lucia Abela⁵, Sony Malhotra⁶, Wui K Chong⁷, Dora Steel^{5

8}, Alba Sanchis-Juan^{9

10}, Adeline Ngoh^{5

8}, Natalie Trump⁵, Esther Meyer⁵, Xavier Vasques¹¹, Julia Rankin¹², Meredith W Allain¹³, Carolyn D Applegate¹⁴, Sanaz Attaripour Isfahani¹⁵, Julien Baleine¹⁶, Bettina Balint^{17

18}, Jennifer A Bassetti¹⁹, Emma L Baple^{12

20}, Kailash P Bhatia¹⁷, Catherine Blanchet²¹, Lydie Burglen²², Gilles Cambonie¹⁶, Emilie Chan Seng^{1

2}, Sandra Chantot Bastaraud²³, Fabienne Cyprien^{1

2}, Christine Coubes²⁴, Vincent d'Hardemare²³; Deciphering Developmental Disorders Study; Asif Doja²⁵, Nathalie Dorison²³, Diane Doummar²⁶, Marisela E Dy-Hollins^{27

28}, Ellyn Farrelly^{13

29}, David R Fitzpatrick³⁰, Conor Fearon³¹, Elizabeth L Fieg³², Brent L Fogel^{33

34}, Eva B Forman³⁵, Rachel G Fox³⁶; Genomics England Research Consortium; William A Gahl³⁷, Serena Galosi³⁸, Victoria Gonzalez^{1

2}, Tracey D Graves³⁹, Allison Gregory³⁶, Mark Hallett¹⁵, Harutomo Hasegawa^{3

4}, Susan J Hayflick^{36

40}, Ada Hamosh¹⁴, Marie Hully⁴¹, Sandra Jansen⁴², Suh Young Jeong³⁶, Joel B Krier³², Sidney Krystal⁴³, Kishore R Kumar^{44

45

46}, Chloé Laurencin⁴⁷, Hane Lee^{34

48}, Gaetan Lesca⁴⁹, Laurence Lion François⁵⁰, Timothy Lynch^{31

51}, Neil Mahant⁵², Julian A Martinez-Agosto^{34

53}, Christophe Milesi¹⁶, Kelly A Mills⁵⁴, Michel Mondain²¹, Hugo Morales-Briceno^{52

55}; NIHR BioResource; John R Ostergaard⁵⁶, Swasti Pal⁵⁷, Juan C Pallais³², Frédérique Pavillard⁵⁸, Pierre-Francois Perrigault⁵⁸, Andrea K Petersen⁵⁹, Gustavo Polo⁶⁰, Gaetan Poulen^{1

2}, Tuula Rinne⁴², Thomas Roujeau¹, Caleb Rogers³⁶, Agathe Roubertie^{61

62}, Michelle Sahagian^{63

64}, Elise Schaefer⁶⁵, Laila Selim⁶⁶, Richard Selway⁶⁷, Nutan Sharma^{27

28

68}, Rebecca Signer³⁴, Ariane G Soldatos³⁷, David A Stevenson¹³, Fiona Stewart⁶⁹, Michel Tchan^{55

70}; Undiagnosed Diseases Network; Ishwar C Verma⁵⁷, Bert B A de Vries⁴², Jenny L Wilson⁷¹, Derek A Wong⁵³, Raghda Zaitoun⁷², Dolly Zhen³⁶, Anna Znaczko⁶⁹, Russell C Dale^{73

74}, Claudio M de Gusmão^{28

75}, Jennifer Friedman^{63

64

76

77}, Victor S C Fung^{52

55}, Mary D King^{35

51}, Shekeeb S Mohammad^{73

74}, Luis Rohena^{78

79}, Jeff L Waugh⁸⁰, Camilo Toro³⁷, F Lucy Raymond^{9

81}, Maya Topf⁶, Philippe Coubes^{1

2}, Kathleen M Gorman^{5

8}, Manju A Kurian^{5

8}

Affiliations

¹ 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.
² Faculté demédecine, Université de Montpellier, France.
³ Complex Motor Disorder Service, Children's Neurosciences Department, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.
⁴ Children's Neuromodulation Group, Women and Children's Health Institute, Faculty of life Sciences and Medicine (FOLSM), King's Health Partners, London, UK.
⁵ Molecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK.
⁶ Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, University of London, London, UK.
⁷ Developmental Imaging and Biophysics, UCL Great Ormond Street Institute of Child Health, London, UK.
⁸ Department of Neurology, Great Ormond Street Hospital, London, UK.
⁹ NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹⁰ Department of Haematology, NHS Blood and Transplant Centre, University of Cambridge, Cambridge, UK.
¹¹ European IBM Systems Center, Montpellier, France.
¹² Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
¹³ Division of Medical Genetics, Department of Pediatrics, Stanford University, Palo Alto, CA, USA.
¹⁴ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁵ Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
¹⁶ Unité de Soins Intensifs et Réanimation Pédiatrique et Néonatale, Hôpital Universitaire de Montpellier, Montpellier, France.
¹⁷ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
¹⁸ Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany.
¹⁹ Division of Medical Genetics, Department of Pediatrics, Weill Cornell Medical College, New York, NY, USA.
²⁰ Institute of Biomedical and Clinical Science RILD Wellcome Wolfson Centre, University of Exeter Medical School, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
²¹ Département d'Oto-Rhino-Laryngologie et Chirurgie Cervico-Faciale, Hôpital Universitaire de Montpellier, Montpellier, France.
²² Département de génétique médicale, APHP Hôpital Armand Trousseau, Paris, France.
²³ Unité Dyspa, Neurochirurgie Pédiatrique, Hôpital Fondation Rothschild, Paris, France.
²⁴ Département de Génétique médicale, Maladies rares et médecine personnalisée, CHU Montpellier, Montpellier, France.
²⁵ Division of Neurology, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
²⁶ Neuropédiatrie, Centre de référence neurogénétique mouvement anormaux de l'enfant, Hôpital Armand Trousseau, AP-HP, Sorbonne Université, France.
²⁷ Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
²⁸ Department of Neurology, Harvard Medical School, Boston, MA, USA.
²⁹ Department of Pediatrics, Lucile Packard Children's Hospital at Stanford, CA, USA.
³⁰ Human Genetics Unit, Medical and Developmental Genetics, University of Edinburgh Western General Hospital, Edinburgh, Scotland, UK.
³¹ Department of Neurology, The Dublin Neurological Institute at the Mater Misericordiae University Hospital, Dublin, Ireland.
³² Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
³³ Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
³⁴ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
³⁵ Department of Paediatric Neurology and Clinical Neurophysiology, Children's Health Ireland at Temple Street, Dublin, Ireland.
³⁶ Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA.
³⁷ Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
³⁸ Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy.
³⁹ Department of Neurology, Hinchingbrooke Hospital, North West Anglia NHS Foundation Trust, Huntingdon, UK.
⁴⁰ Department of Paediatrics, Oregon Health and Science University, Portland, OR, USA.
⁴¹ Département de Neurologie, APHP-Necker-Enfants Malades, Paris, France.
⁴² Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
⁴³ Département de Neuroradiologie, Hôpital Fondation Rothschild, Paris.
⁴⁴ Translational Genomics Group, Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
⁴⁵ Department of Neurogenetics, Kolling Institute, University of Sydney and Royal North Shore Hospital, St Leonards, NSW, Australia.
⁴⁶ Molecular Medicine Laboratory, Concord Hospital, Sydney, NSW, Australia.
⁴⁷ Département de Neurologie, Hôpital Neurologique Pierre Wertheimer, Lyon, France.
⁴⁸ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
⁴⁹ Département de Génétique, Hôpital Universitaire de Lyon, Lyon, France.
⁵⁰ Département de Pédiatrie, Hôpital Lyon-Sud, Pierre-Bénite, France.
⁵¹ UCD School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
⁵² Movement Disorders Unit, Department of Neurology, Westmead Hospital, Westmead, NSW, Australia.
⁵³ Division of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
⁵⁴ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵⁵ Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
⁵⁶ Centre for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark.
⁵⁷ Institute of Genetics and Genomics, Sir Ganga Ram Hospital, Rajender Nagar, New Delhi, India.
⁵⁸ Département d'Anesthésie-Réanimation Gui de Chauliac, Centre Hospitalier Universitaire de Montpellier, Montpellier, France.
⁵⁹ Randall Children's Hospital, Portland, OR, USA.
⁶⁰ Département de Neurochirurgie Fonctionnelle, Hôpital Neurologique et Neurochirurgical, Pierre Wertheimer, Lyon, France.
⁶¹ Département de Neuropédiatrie, Hôpital Universitaire de Montpellier, Montpellier, France.
⁶² INSERM U1051, Institut des Neurosciences de Montpellier, Montpellier, France.
⁶³ Division of Neurology, Rady Children's Hospital San Diego, CA, USA.
⁶⁴ Department of Neuroscience, University of California San Diego, CA, USA.
⁶⁵ Medical Genetics, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
⁶⁶ Cairo University Children Hospital, Pediatric Neurology and Metabolic division, Cairo, Egypt.
⁶⁷ Department of Neurosurgery, King's College Hospital, London, UK.
⁶⁸ Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
⁶⁹ Department of Genetic Medicine, Belfast Health and Social Care Trust, Belfast, UK.
⁷⁰ Department of Genetics, Westmead Hospital, Westmead, NSW, Australia.
⁷¹ Division of Pediatric Neurology, Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA.
⁷² Department of Paediatrics, Neurology Division, Ain Shams University Hospital, Cairo, Egypt.
⁷³ Department of Paediatric Neurology, The Children's Hospital at Westmead, NSW, Australia.
⁷⁴ Faculty of Medicine and Health, Sydney Medical School, University of Sydney, Sydney NSW, Australia.
⁷⁵ Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
⁷⁶ Departments of Paediatrics, University of California, San Diego, CA, USA.
⁷⁷ Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
⁷⁸ Division of Medical Genetics, Department of Pediatrics, San Antonio Military Medical Center, San Antonio, TX, USA.
⁷⁹ Department of Pediatrics, Long School of Medicine, UT Health, San Antonio, TX, USA.
⁸⁰ Division of Pediatric Neurology, Department of Pediatrics, University of Texas Southwestern, Dallas, TX, USA.
⁸¹ Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.

PMID: 39990802
PMCID: PMC11844621

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

Laura Cif et al. ArXiv. 2025.

[Preprint]. 2025 Feb 10:arXiv:2502.06320v1.

Authors

Affiliations

¹ 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.
² Faculté demédecine, Université de Montpellier, France.
³ Complex Motor Disorder Service, Children's Neurosciences Department, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.
⁴ Children's Neuromodulation Group, Women and Children's Health Institute, Faculty of life Sciences and Medicine (FOLSM), King's Health Partners, London, UK.
⁵ Molecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK.
⁶ Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, University of London, London, UK.
⁷ Developmental Imaging and Biophysics, UCL Great Ormond Street Institute of Child Health, London, UK.
⁸ Department of Neurology, Great Ormond Street Hospital, London, UK.
⁹ NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹⁰ Department of Haematology, NHS Blood and Transplant Centre, University of Cambridge, Cambridge, UK.
¹¹ European IBM Systems Center, Montpellier, France.
¹² Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
¹³ Division of Medical Genetics, Department of Pediatrics, Stanford University, Palo Alto, CA, USA.
¹⁴ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁵ Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
¹⁶ Unité de Soins Intensifs et Réanimation Pédiatrique et Néonatale, Hôpital Universitaire de Montpellier, Montpellier, France.
¹⁷ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
¹⁸ Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany.
¹⁹ Division of Medical Genetics, Department of Pediatrics, Weill Cornell Medical College, New York, NY, USA.
²⁰ Institute of Biomedical and Clinical Science RILD Wellcome Wolfson Centre, University of Exeter Medical School, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
²¹ Département d'Oto-Rhino-Laryngologie et Chirurgie Cervico-Faciale, Hôpital Universitaire de Montpellier, Montpellier, France.
²² Département de génétique médicale, APHP Hôpital Armand Trousseau, Paris, France.
²³ Unité Dyspa, Neurochirurgie Pédiatrique, Hôpital Fondation Rothschild, Paris, France.
²⁴ Département de Génétique médicale, Maladies rares et médecine personnalisée, CHU Montpellier, Montpellier, France.
²⁵ Division of Neurology, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
²⁶ Neuropédiatrie, Centre de référence neurogénétique mouvement anormaux de l'enfant, Hôpital Armand Trousseau, AP-HP, Sorbonne Université, France.
²⁷ Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
²⁸ Department of Neurology, Harvard Medical School, Boston, MA, USA.
²⁹ Department of Pediatrics, Lucile Packard Children's Hospital at Stanford, CA, USA.
³⁰ Human Genetics Unit, Medical and Developmental Genetics, University of Edinburgh Western General Hospital, Edinburgh, Scotland, UK.
³¹ Department of Neurology, The Dublin Neurological Institute at the Mater Misericordiae University Hospital, Dublin, Ireland.
³² Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
³³ Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
³⁴ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
³⁵ Department of Paediatric Neurology and Clinical Neurophysiology, Children's Health Ireland at Temple Street, Dublin, Ireland.
³⁶ Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA.
³⁷ Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
³⁸ Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy.
³⁹ Department of Neurology, Hinchingbrooke Hospital, North West Anglia NHS Foundation Trust, Huntingdon, UK.
⁴⁰ Department of Paediatrics, Oregon Health and Science University, Portland, OR, USA.
⁴¹ Département de Neurologie, APHP-Necker-Enfants Malades, Paris, France.
⁴² Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
⁴³ Département de Neuroradiologie, Hôpital Fondation Rothschild, Paris.
⁴⁴ Translational Genomics Group, Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
⁴⁵ Department of Neurogenetics, Kolling Institute, University of Sydney and Royal North Shore Hospital, St Leonards, NSW, Australia.
⁴⁶ Molecular Medicine Laboratory, Concord Hospital, Sydney, NSW, Australia.
⁴⁷ Département de Neurologie, Hôpital Neurologique Pierre Wertheimer, Lyon, France.
⁴⁸ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
⁴⁹ Département de Génétique, Hôpital Universitaire de Lyon, Lyon, France.
⁵⁰ Département de Pédiatrie, Hôpital Lyon-Sud, Pierre-Bénite, France.
⁵¹ UCD School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
⁵² Movement Disorders Unit, Department of Neurology, Westmead Hospital, Westmead, NSW, Australia.
⁵³ Division of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
⁵⁴ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵⁵ Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
⁵⁶ Centre for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark.
⁵⁷ Institute of Genetics and Genomics, Sir Ganga Ram Hospital, Rajender Nagar, New Delhi, India.
⁵⁸ Département d'Anesthésie-Réanimation Gui de Chauliac, Centre Hospitalier Universitaire de Montpellier, Montpellier, France.
⁵⁹ Randall Children's Hospital, Portland, OR, USA.
⁶⁰ Département de Neurochirurgie Fonctionnelle, Hôpital Neurologique et Neurochirurgical, Pierre Wertheimer, Lyon, France.
⁶¹ Département de Neuropédiatrie, Hôpital Universitaire de Montpellier, Montpellier, France.
⁶² INSERM U1051, Institut des Neurosciences de Montpellier, Montpellier, France.
⁶³ Division of Neurology, Rady Children's Hospital San Diego, CA, USA.
⁶⁴ Department of Neuroscience, University of California San Diego, CA, USA.
⁶⁵ Medical Genetics, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
⁶⁶ Cairo University Children Hospital, Pediatric Neurology and Metabolic division, Cairo, Egypt.
⁶⁷ Department of Neurosurgery, King's College Hospital, London, UK.
⁶⁸ Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
⁶⁹ Department of Genetic Medicine, Belfast Health and Social Care Trust, Belfast, UK.
⁷⁰ Department of Genetics, Westmead Hospital, Westmead, NSW, Australia.
⁷¹ Division of Pediatric Neurology, Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA.
⁷² Department of Paediatrics, Neurology Division, Ain Shams University Hospital, Cairo, Egypt.
⁷³ Department of Paediatric Neurology, The Children's Hospital at Westmead, NSW, Australia.
⁷⁴ Faculty of Medicine and Health, Sydney Medical School, University of Sydney, Sydney NSW, Australia.
⁷⁵ Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
⁷⁶ Departments of Paediatrics, University of California, San Diego, CA, USA.
⁷⁷ Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
⁷⁸ Division of Medical Genetics, Department of Pediatrics, San Antonio Military Medical Center, San Antonio, TX, USA.
⁷⁹ Department of Pediatrics, Long School of Medicine, UT Health, San Antonio, TX, USA.
⁸⁰ Division of Pediatric Neurology, Department of Pediatrics, University of Texas Southwestern, Dallas, TX, USA.
⁸¹ Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.

PMID: 39990802
PMCID: PMC11844621

Update in

KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.
Cif L, Demailly D, Lin JP, Barwick KE, Sa M, Abela L, Malhotra S, Chong WK, Steel D, Sanchis-Juan A, Ngoh A, Trump N, Meyer E, Vasques X, Rankin J, Allain MW, Applegate CD, Attaripour Isfahani S, Baleine J, Balint B, Bassetti JA, Baple EL, Bhatia KP, Blanchet C, Burglen L, Cambonie G, Seng EC, Bastaraud SC, Cyprien F, Coubes C, d'Hardemare V; Deciphering Developmental Disorders Study; Doja A, Dorison N, Doummar D, Dy-Hollins ME, Farrelly E, Fitzpatrick DR, Fearon C, Fieg EL, Fogel BL, Forman EB, Fox RG; Genomics England Research Consortium; Gahl WA, Galosi S, Gonzalez V, Graves TD, Gregory A, Hallett M, Hasegawa H, Hayflick SJ, Hamosh A, Hully M, Jansen S, Jeong SY, Krier JB, Krystal S, Kumar KR, Laurencin C, Lee H, Lesca G, François LL, Lynch T, Mahant N, Martinez-Agosto JA, Milesi C, Mills KA, Mondain M, Morales-Briceno H; NIHR BioResource; Ostergaard JR, Pal S, Pallais JC, Pavillard F, Perrigault PF, Petersen AK, Polo G, Poulen G, Rinne T, Roujeau T, Rogers C, Roubertie A, Sahagian M, Schaefer E, Selim L, Selway R, Sharma N, Signer R, Soldatos AG, Stevenson DA, Stewart F, Tchan M; Undiagnosed Diseases Network; Verma IC, de Vries BBA, Wilson JL, Wong DA, Zaitoun R, Zhen D, Znacz… See abstract for full author list ➔ Cif L, et al. Brain. 2020 Dec 5;143(11):3242-3261. doi: 10.1093/brain/awaa304. Brain. 2020. PMID: 33150406 Free PMC article.

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 ł 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 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. 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.

Keywords: KMT2B; deep brain stimulation (DBS); dystonia; genetics; neurodevelopment.

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Figures

**Figure 1. *KMT2B* missense constraint analysis.**
**(A)** Missense allele counts for all *KMT2B* missense variants were obtained from gnomAD v2.1 (Karczewski *et al.*, 2020). All missense amino acid substitutions are represented in grey (*top* section). Exons by constraint ranges were obtained from Decipher v.9.29 (Firth *et al.*, 2009). Schematic representation of the coding exons of *KMT2B* shows the gene regions by predicted intolerance to missense changes, ranging from grey (relatively tolerant) through yellow, orange and red with increasing intolerance (track for exons are coloured by constraint values, obtained from Decipher). Highly constrained regions encompass exons encoding key protein domains, including the CxxC, PHD, PHD-like, FYR and SET-binding domain. All variants reported in the extended cohort are represented. While pathogenic protein truncating variants (red circles) are distributed throughout the protein coding sequence, disease-associated missense variants (blue triangles) appear to localize in regions of missense constraint, which represent key protein domains. Coordinates for the protein domains were obtained from Pfam 32.0 (El-Gebali *et al.*, 2019). **(B)** Schematic representation of *KMT2B* (NM_014727.2) indicating the positions of 22 frameshift insertions and deletions (red squares), 10 stop-gain mutations (red circles), four splice-site variants (red three quarter circles) and nine missense changes (blue inverted triangles) of the study cohort. Mutations associated with dystonic phenotypes are depicted in black and those associated with non-dystonia phenotypes in green. The functional domain architecture of *KMT2B* is located above the gene diagram.

**Figure 2. Predicted effect of KMT2B variants on structure-function properties.**
**(A–F)** Structural modelling for PHD-like domain of KMT2B (residues 1574–1688). **(A)** The wild-type residue Arg1597 (yellow) lies on the exposed flexible loop, which is involved in the salt bridge with Asp1591. **(B)** Substitution of the arginine with a tryptophan is predicted to remove this salt bridge interaction by placing a bulkier hydrophobic side chain in this position. **(C)** The wild-type residue Ala1616 (yellow) is close to the residue Arg1635, which is involved in salt bridge with Glu1617. **(D)** Ala1616Val may result in a steric clash with Arg1635 and disrupt the salt bridge between Arg1635 and Glu1617. **(E)** This PHD-like domain is known to have three zinc fingers (zinc ions shown in orange). Cys1644 is involved in formation of one of the zinc-fingers (*top*). Substitution with a phenylalanine will result in loss of coordination of zinc ion in a zinc finger and a detrimental effect on the protein function (*bottom*). **(F)** Cys1654 is present adjacent to Cys1653 which is involved in coordinating zinc ion in another zinc finger motif (*bottom left*). Substitution of a cysteine with an arginine might cause a steric clash and repulsion with Lys1679 present in its vicinity, hence impacting on protein structure (*bottom right*). **(G)** Structural modelling for SET domain of KMT2B (residues 2539–2715). The side chain of Arg2649 forms an H-bond with the backbone of Ala2641 (*top*). Substitution at amino acid 2649 of the arginine with a cysteine will disrupt this bond (*bottom*) and impact the stability of the domain.

**Figure 3. Evolution of BFMDRS for the DBS cohort (n= 18) and evolution of dystonia and motor function with DBS for patients followed >5 years with DBS (n= 8).**
**(A)** Mean score of BFMDRS-M (range: 0–120). **(B)** Mean score of BFMDRS-D (range: 0–30). **(C)** Spaghetti plots displaying individual dystonia evolution with DBS, as assessed by the BFMDRS-M. **(D)** Spaghetti plots displaying individual dystonia evolution with DBS, as assessed by the BFMDRS-D. **(E)** Evolution of motor function as assessed by the motor section of the BFMDRS followed for >5 years with DBS. **(F)** Evolution of motor function as assessed by the disability section of the BFMDRS followed for >5 years with DBS.

**Figure 4. Relationship between genotype, dystonia severity and DBS (n= 18).**
**(A)** Dystonia BFMDRS-M scores evolution with DBS according to the class of mutation. Eleven protein-truncating variants (blue), six microdeletions (orange) and a single missense variant (grey). **(B)** Relationship between genotype and dystonia severity at baseline (BFMDRS-M). **(C)** XgBoost Tree Predictor Importance model was used to predict the type of mutation class according to the evolution of the motor scores. The BFMDRS-M scores preoperative (F-score, 38), 1-year post operative (F-score, 21) and 6 months (F-score, 13) were able to predict the type of mutation with 94.4% accuracy.

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References

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

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