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, 450% of subjects showed BFMDRS-M and BFMDRS-D improvements of 430%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for 45 years, n = 8), improvement of 430% 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 language | English (US) |
|---|---|
| Pages (from-to) | 3242-3261 |
| Number of pages | 20 |
| Journal | Brain |
| Volume | 143 |
| Issue number | 11 |
| DOIs | |
| State | Published - 2020 |
Keywords
- Deep brain stimulation (DBS)
- Dystonia
- Genetics
- KMT2B
- Neurodevelopment
ASJC Scopus subject areas
- Clinical Neurology
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In: Brain, Vol. 143, No. 11, 2020, p. 3242-3261.
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}
TY - JOUR
T1 - KMT2B-related disorders
T2 - Expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation
AU - Cif, Laura
AU - Demailly, Diane
AU - Lin, Jean Pierre
AU - Barwick, Katy E.
AU - Sa, Mario
AU - Abela, Lucia
AU - Malhotra, Sony
AU - Chong, Wui K.
AU - Steel, Dora
AU - Sanchis-Juan, Alba
AU - Ngoh, Adeline
AU - Trump, Natalie
AU - Meyer, Esther
AU - Vasques, Xavier
AU - Rankin, Julia
AU - Allain, Meredith W.
AU - Applegate, Carolyn D.
AU - Isfahani, Sanaz Attaripour
AU - Baleine, Julien
AU - Balint, Bettina
AU - Bassetti, Jennifer A.
AU - Baple, Emma L.
AU - Bhatia, Kailash P.
AU - Blanchet, Catherine
AU - Burglen, Lydie
AU - Cambonie, Gilles
AU - Seng, Emilie Chan
AU - Bastaraud, Sandra Chantot
AU - Cyprien, Fabienne
AU - Coubes, Christine
AU - d’Hardemare, Vincent
AU - Doja, Asif
AU - Dorison, Nathalie
AU - Doummar, Diane
AU - Dy-Hollins, Marisela E.
AU - Farrelly, Ellyn
AU - Fitzpatrick, David R.
AU - Fearon, Conor
AU - Fieg, Elizabeth L.
AU - Fogel, Brent L.
AU - Forman, Eva B.
AU - Fox, Rachel G.
AU - Gahl, William A.
AU - Galosi, Serena
AU - Gonzalez, Victoria
AU - Graves, Tracey D.
AU - Gregory, Allison
AU - Hallett, Mark
AU - Hasegawa, Harutomo
AU - Hayflick, Susan J.
AU - Hamosh, Ada
AU - Hully, Marie
AU - Jansen, Sandra
AU - Jeong, Suh Young
AU - Krier, Joel B.
AU - Krystal, Sidney
AU - Kumar, Kishore R.
AU - Laurencin, Chloé
AU - Lee, Hane
AU - Lesca, Gaetan
AU - François, Laurence Lion
AU - Lynch, Timothy
AU - Mahant, Neil
AU - Martinez-Agosto, Julian A.
AU - Milesi, Christophe
AU - Mills, Kelly A.
AU - Mondain, Michel
AU - Morales-Briceno, Hugo
AU - Ostergaard, John R.
AU - Pal, Swasti
AU - Pallais, Juan C.
AU - Pavillard, Frédérique
AU - Perrigault, Pierre Francois
AU - Petersen, Andrea K.
AU - Polo, Gustavo
AU - Poulen, Gaetan
AU - Rinne, Tuula
AU - Roujeau, Thomas
AU - Rogers, Caleb
AU - Roubertie, Agathe
AU - Sahagian, Michelle
AU - Schaefer, Elise
AU - Selim, Laila
AU - Selway, Richard
AU - Sharma, Nutan
AU - Signer, Rebecca
AU - Soldatos, Ariane G.
AU - Stevenson, David A.
AU - Stewart, Fiona
AU - Tchan, Michel
AU - Verma, Ishwar C.
AU - de Vries, Bert B.A.
AU - Wilson, Jenny L.
AU - Wong, Derek A.
AU - Zaitoun, Raghda
AU - Zhen, Dolly
AU - Znaczko, Anna
AU - Dale, Russell C.
AU - de Gusmão, Claudio M.
AU - Friedman, Jennifer
AU - Fung, Victor S.C.
AU - King, Mary D.
AU - Mohammad, Shekeeb S.
AU - Rohena, Luis
AU - Waugh, Jeff L.
AU - Toro, Camilo
AU - Raymond, F. Lucy
AU - Topf, Maya
AU - Coubes, Philippe
AU - Gorman, Kathleen M.
AU - Kurian, Manju A.
N1 - Funding Information: M.A.K. is funded by an NIHR Research Professorship and receives funding from the Sir Jules Thorn Award for Biomedical Research, Great Ormond Street Children’s Hospital Charity (GOSHCC) and Rosetrees Trust. M.A.K., K.E.B., L.A., D.S., A.N., N.T. and E.M. are supported by the NIHR GOSH BRC. K.M.G. received funding from Temple Street Foundation. L.A. is funded by the Swiss National Foundation. E.M. received funding from the Rosetrees Trust (CD-A53), and the Great Ormond Street Hospital Children’s Charity. A.S.J. is funded by NIHR Bioresource for Rare Diseases. S.A.I. and M.H. are supported by the NINDS Intramural program. K.P.B. is PI of the Movement disorders centre (MDC) at UCL, Institute of Neurology which has been funded by the BRC. He has grant support by EU Horizon 2020. M.E.D-H. has clinical training grant through Tourette Association of America, but the research is unrelated to KMT2B. T.L. received funding from Health Research Board, Ireland and Michael J Fox. Foundation. K.A.M. receives funding from the NIH (award number K23NS101096-01A1). N.S. receives funding from the NIH (award number NS 087997 0). D.D. was supported by KIM MUSE Biomarkers and Therapy study grant during this work. B.B.A.d.V. financially supported by grants from the Netherlands Organization for Health Research and Development (912-12-109). J.F. is funded by the Rady Children’s Institute for Genomic Medicine. F.L.R. is funded by Cambridge Biomedical Research Centre. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund [grant number HICF-1009-003], a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute [grant number WT098051]. This research Funding Information: We thank all our patients and their families for taking part in this study. This research was supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. We also acknowledge support from the UK Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s and St. Thomas’ National Health Service (NHS) Foundation Trust in partnership with King’s College London. The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health or Wellcome Trust. Sequencing for Patient 37 was provided by the University of Washington Center for Mendelian Genomics (UW-CMG) and was funded by the National Human Genome Research Institute and the National Heart, Lung and Blood Institute grant HG006493 to Drs Debbie Nickerson, Michael Bamshad, and Suzanne Leal. Funding Information: M.A.K. is funded by an NIHR Research Professorship and receives funding from the Sir Jules Thorn Award for Biomedical Research, Great Ormond Street Children’s Hospital Charity (GOSHCC) and Rosetrees Trust. M.A.K., K.E.B., L.A., D.S., A.N., N.T. and E.M. are supported by the NIHR GOSH BRC. K.M.G. received funding from Temple Street Foundation. L.A. is funded by the Swiss National Foundation. E.M. received funding from the Rosetrees Trust (CD-A53), and the Great Ormond Street Hospital Children’s Charity. A.S.J. is funded by NIHR Bioresource for Rare Diseases. S.A.I. and M.H. are supported by the NINDS Intramural program. K.P.B. is PI of the Movement disorders centre (MDC) at UCL, Institute of Neurology which has been funded by the BRC. He has grant support by EU Horizon 2020. M.E.D-H. has clinical training grant through Tourette Association of America, but the research is unrelated to KMT2B. T.L. received funding from Health Research Board, Ireland and Michael J Fox. Foundation. K.A.M. receives funding from the NIH (award number K23NS101096-01A1). N.S. receives funding from the NIH (award number NS 087997 0). D.D. was supported by KIM MUSE Biomarkers and Therapy study grant during this work. B.B.A.d.V. financially supported by grants from the Netherlands Organization for Health Research and Development (912-12-109). J.F. is funded by the Rady Children’s Institute for Genomic Medicine. F.L.R. is funded by Cambridge Biomedical Research Centre. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund [grant number HICF-1009-003], a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute [grant number WT098051]. This research was made possible through access to the data and findings generated by the 100 000 Genomes Project (Patient 34). The 100 000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health). The 100 000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100 000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. Research reported in this manuscript was supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director to the Undiagnosed Disease Network (UDN) and the NIH Undiagnosed Disease Program (Award numbers: U01HG007690 and U01HG007703). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: was made possible through access to the data and findings generated by the 100 000 Genomes Project (Patient 34). The 100 000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health). The 100 000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100 000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. Research reported in this manuscript was supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director to the Undiagnosed Disease Network (UDN) and the NIH Undiagnosed Disease Program (Award numbers: U01HG007690 and U01HG007703). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
PY - 2020
Y1 - 2020
N2 - 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, 450% of subjects showed BFMDRS-M and BFMDRS-D improvements of 430%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for 45 years, n = 8), improvement of 430% 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.
AB - 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, 450% of subjects showed BFMDRS-M and BFMDRS-D improvements of 430%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for 45 years, n = 8), improvement of 430% 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.
KW - Deep brain stimulation (DBS)
KW - Dystonia
KW - Genetics
KW - KMT2B
KW - Neurodevelopment
UR - http://www.scopus.com/inward/record.url?scp=85097570939&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85097570939&partnerID=8YFLogxK
U2 - 10.1093/brain/awaa304
DO - 10.1093/brain/awaa304
M3 - Article
C2 - 33150406
AN - SCOPUS:85097570939
SN - 0006-8950
VL - 143
SP - 3242
EP - 3261
JO - Brain
JF - Brain
IS - 11
ER -