Article Dans Une Revue Brain - A Journal of Neurology Année : 2020

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 Barwick (5) , Mario Sa (3, 4) , Lucia Abela (5) , Sony Malhotra (6) , Wui Kling Chong (5) , Dora Steel (5, 7) , Alba Sanchis-Juan (8, 9) , Adeline Ngoh (5, 7) , Natalie Trump (5) , Esther Meyer (5) , Xavier Vasques (10) , Julia Rankin (11) , Meredith Allain (12) , Carolyn Applegate (13) , Sanaz Attaripour Isfahani (14) , Julien Frédéric Baleine (15) , Bettina Balint (16, 17) , Jennifer Bassetti (18) , Emma L Baple (19, 11) , Kailash P Bhatia (16) , Catherine Blanchet (15) , Lydie Burglen (20) , Gilles Cambonie (15) , Emilie Chan-Seng (1, 2) , Sandra Chantot-Bastaraud (21) , Fabienne Cyprien (1, 2) , Christine Coubes (22) , Vincent D’hardemare (21) , Asif Doja (23) , Nathalie Dorison (21) , Diane Doummar (20) , Marisela Dy-Hollins (24, 25) , Ellyn Farrelly (12) , David R Fitzpatrick (26) , Conor Fearon (27) , Elizabeth Fieg (28) , Brent L. Fogel (29) , Eva Forman (30) , Rachel Fox (31) , William Gahl (14) , Serena Galosi (32) , Victoria Gonzalez (1, 2) , Tracey Graves (33) , Allison Gregory (31) , Mark Hallett (14) , Harutomo Hasegawa (3, 4) , Susan Hayflick (31) , Ada Hamosh (13) , Marie Hully (34) , Sandra Jansen (35) , Suh Young Jeong (31) , Joel Krier (28) , Sidney Krystal (21) , Kishore Kumar (36, 37, 38) , Chloé Laurencin (39) , Hane Lee (29) , Gaëtan Lesca (40) , Laurence Lion-François (40) , Timothy Lynch (41, 27) , Neil Mahant (42) , Julian A Martinez-Agosto (29) , Christophe Milési (15) , Kelly Mills (13) , Michel Mondain (15) , Hugo Morales-Briceno (43, 37) , John R. Ostergaard (44) , Swasti Pal (45) , Juan Pallais (28) , Frédérique Pavillard (46) , Pierre-François Perrigault (46) , Andrea K. Petersen (47) , Gustavo Polo (39) , Gaëtan Poulen (1, 2) , Tuula Rinne (35) , Thomas Roujeau (1) , Caleb Rogers (31) , Agathe Roubertie (15, 48) , Michelle Sahagian (49, 50) , Elise Schaefer (51) , Laila Selim (52) , Richard Selway (53) , Nutan Sharma (24, 25, 54) , Rebecca Signer (29) , Ariane Soldatos (14) , David A Stevenson (12) , Fiona Stewart (55) , Michel Tchan (37, 42) , Ishwar C Verma (45) , Bert B.A. de Vries (35) , Jenny Wilson (31) , Derek Wong (29) , Raghda Zaitoun (56) , Dolly Zhen (31) , Anna Znaczko (55) , Russell C. Dale (43, 37) , Claudio de Gusmao (57) , Jennifer Friedman (49, 57, 58) , Victor S.C. Fung (42, 37) , Mary D. King (30, 41) , Shekeeb S. Mohammad (37, 43) , Luis Rohena (59) , Jeff L Waugh (60) , Camilo Toro (14) , F. Lucy Raymond (8, 61) , Maya Topf (6) , Philippe Coubes (1, 2) , Kathleen Gorman (5, 7) , Manju A Kurian (5, 7)
1 Service de Neurochirurgie [CHRU Montpellier]
2 UM - Université de Montpellier
3 Evelina London Children's Hospital
4 Guy's and St Thomas' NHS Foundation Trust
5 Institute of Child Health [London]
6 Birkbeck College [University of London]
7 GOSH - Great Ormond Street Hospital for Children [London]
8 CUH - Cambridge University Hospitals - NHS
9 CAM - University of Cambridge [Cambridge, UK]
10 IBM PSSC Montpellier - Innovation Lab.
11 RDEH - Royal Devon and Exeter Hospital [Exeter, UK]
12 Stanford University
13 Johns Hopkins University School of Medicine [Baltimore]
14 NIH - National Institutes of Health [Bethesda, MD, USA]
15 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
16 UCL Queen Square Institute of Neurology
17 Heidelberg University Hospital [Heidelberg]
18 Weill Medical College of Cornell University [New York]
19 University of Exeter Medical School
20 CHU Trousseau [APHP]
21 Hôpital Fondation Adolphe de Rothschild = Adolphe de Rothschild Foundation Hospital
22 Département de génétique médicale, maladies rares et médecine personnalisée [CHU Montpellier]
23 Children's Hospital of Eastern Ontario [Ottawa, Canada]
24 Massachusetts General Hospital [Boston]
25 HMS - Harvard Medical School [Boston]
26 The University of Edinburgh
27 The Mater Hospital - Mater Misericordiae University Hospital
28 BWH - Brigham & Women’s Hospital [Boston]
29 David Geffen School of Medicine [Los Angeles]
30 Children's Health Ireland at Temple Street
31 OHSU - Oregon Health and Science University [Portland]
32 UNIROMA - Università degli Studi di Roma "La Sapienza" = Sapienza University [Rome]
33 North West Anglia NHS Foundation Trust [ Huntingdon, UK]
34 Hôpital Necker - Enfants Malades [AP-HP]
35 RadboudUMC - Radboud University Medical Center [Nijmegen]
36 Garvan Institute of medical research
37 The University of Sydney
38 RNSH - Royal North Shore Hospital
39 Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL]
40 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
41 UCD - University College Dublin [Dublin]
42 Westmead Hospital [Sydney]
43 Children's Hospital [Westmead, Australia]
44 Aarhus University Hospital
45 Sir Ganga Ram Hospital
46 Département d'Anesthésie-Réanimation [Gui de Chauliac - CHU Montpellier]
47 Randall Children's Hospital [Portland]
48 INM - Institut des Neurosciences de Montpellier
49 Rady Children's Hospital
50 UC San Diego - University of California [San Diego]
51 HUS - Hôpitaux Universitaires de Strasbourg
52 Cairo University
53 KCH - King's College Hospital
54 Brigham and Women's Hospital [Boston]
55 Belfast Health and Social Care Trust
56 ASU - جامعة عين شمس - Ain Shams University [Cairo]
57 Boston Children's Hospital
58 Rady Children’s Institute of Genomic Medicine [La Jolla, CA, USA]
59 University of Texas Health Science Center
60 University of Texas Southwestern Medical Center
61 CIMR - Cambridge Institute for Medical Research
Xavier Vasques
  • Fonction : Auteur
  • PersonId : 872531
Lydie Burglen
Diane Doummar
David R Fitzpatrick
Marie Hully
Joel Krier
  • Fonction : Auteur
  • PersonId : 1445178
Laila Selim
  • Fonction : Auteur
Fiona Stewart
Claudio de Gusmao
Maya Topf

Résumé

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.

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hal-02992682 , version 1 (27-02-2024)

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Laura Cif, Diane Demailly, Jean-Pierre Lin, Katy Barwick, Mario Sa, et al.. KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation. Brain - A Journal of Neurology , 2020, 143 (11), pp.3242-3261. ⟨10.1093/brain/awaa304⟩. ⟨hal-02992682⟩
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