John Rosendahl Østergaard

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

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KMT2B-related disorders : expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation. / Cif, Laura; Demailly, Diane; Lin, Jean Pierre; Barwick, Katy E.; Sa, Mario; Abela, Lucia; Malhotra, Sony; Chong, Wui K.; Steel, Dora; Sanchis-Juan, Alba; Ngoh, Adeline; Trump, Natalie; Meyer, Esther; Vasques, Xavier; Rankin, Julia; Allain, Meredith W.; Applegate, Carolyn D.; Attaripour Isfahani, Sanaz; Baleine, Julien; Balint, Bettina; Bassetti, Jennifer A.; Baple, Emma L.; Bhatia, Kailash P.; Blanchet, Catherine; Burglen, Lydie; Cambonie, Gilles; Seng, Emilie Chan; Bastaraud, Sandra Chantot; Cyprien, Fabienne; Coubes, Christine; d'Hardemare, Vincent; Deciphering Developmental Disorders Study; Doja, Asif; Dorison, Nathalie; Doummar, Diane; Dy-Hollins, Marisela E.; Farrelly, Ellyn; Fitzpatrick, David R.; Fearon, Conor; Fieg, Elizabeth L.; Fogel, Brent L.; Forman, Eva B.; Fox, Rachel G.; Genomics England Research Consortium; Gahl, William A.; Galosi, Serena; Gonzalez, Victoria; Graves, Tracey D.; Gregory, Allison; Hallett, Mark; Hasegawa, Harutomo; Hayflick, Susan J ; Hamosh, Ada ; Hully, Marie; Jansen, Sandra ; Jeong, Suh Young ; Krier, Joel B ; Krystal, Sidney ; Kumar, Kishore R ; Laurencin, Chloé ; Lee, Hane; Lesca, Gaetan; François, Laurence Lion ; Lynch, Timothy ; Mahant, Neil ; Martinez-Agosto, Julian A ; Milesi, Christophe ; Mills, Kelly A; Mondain, Michel ; Morales-Briceno, Hugo ; NIHR BioResource ; Ostergaard, John R.; Undiagnosed Diseases Network.

In: Brain : a journal of neurology, Vol. 143, No. 11, 11.2020, p. 3242-3261.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

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 & Undiagnosed Diseases Network 2020, 'KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation', Brain : a journal of neurology, vol. 143, no. 11, pp. 3242-3261. https://doi.org/10.1093/brain/awaa304

APA

Cif, L., Demailly, D., Lin, J. P., Barwick, K. E., Sa, M., Abela, L., Malhotra, S., Chong, W. K., Steel, D., Sanchis-Juan, A., Ngoh, A., Trump, N., Meyer, E., Vasques, X., Rankin, J., Allain, M. W., Applegate, C. D., Attaripour Isfahani, S., Baleine, J., ... Undiagnosed Diseases Network (2020). KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation. Brain : a journal of neurology, 143(11), 3242-3261. https://doi.org/10.1093/brain/awaa304

CBE

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, Undiagnosed Diseases Network. 2020. KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation. Brain : a journal of neurology. 143(11):3242-3261. https://doi.org/10.1093/brain/awaa304

MLA

Vancouver

Cif L, Demailly D, Lin JP, Barwick KE, Sa M, Abela L et al. KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation. Brain : a journal of neurology. 2020 Nov;143(11):3242-3261. https://doi.org/10.1093/brain/awaa304

Author

Cif, Laura ; Demailly, Diane ; Lin, Jean Pierre ; Barwick, Katy E. ; Sa, Mario ; Abela, Lucia ; Malhotra, Sony ; Chong, Wui K. ; Steel, Dora ; Sanchis-Juan, Alba ; Ngoh, Adeline ; Trump, Natalie ; Meyer, Esther ; Vasques, Xavier ; Rankin, Julia ; Allain, Meredith W. ; Applegate, Carolyn D. ; Attaripour Isfahani, Sanaz ; Baleine, Julien ; Balint, Bettina ; Bassetti, Jennifer A. ; Baple, Emma L. ; Bhatia, Kailash P. ; Blanchet, Catherine ; Burglen, Lydie ; Cambonie, Gilles ; Seng, Emilie Chan ; Bastaraud, Sandra Chantot ; Cyprien, Fabienne ; Coubes, Christine ; d'Hardemare, Vincent ; Deciphering Developmental Disorders Study ; Doja, Asif ; Dorison, Nathalie ; Doummar, Diane ; Dy-Hollins, Marisela E. ; Farrelly, Ellyn ; Fitzpatrick, David R. ; Fearon, Conor ; Fieg, Elizabeth L. ; Fogel, Brent L. ; Forman, Eva B. ; Fox, Rachel G. ; Genomics England Research Consortium ; Gahl, William A. ; Galosi, Serena ; Gonzalez, Victoria ; Graves, Tracey D. ; Gregory, Allison ; Hallett, Mark ; Hasegawa, Harutomo ; Hayflick, Susan J ; Hamosh, Ada ; Hully, Marie ; Jansen, Sandra ; Jeong, Suh Young ; Krier, Joel B ; Krystal, Sidney ; Kumar, Kishore R ; Laurencin, Chloé ; Lee, Hane ; Lesca, Gaetan ; François, Laurence Lion ; Lynch, Timothy ; Mahant, Neil ; Martinez-Agosto, Julian A ; Milesi, Christophe ; Mills, Kelly A ; Mondain, Michel ; Morales-Briceno, Hugo ; NIHR BioResource ; Ostergaard, John R. ; Undiagnosed Diseases Network. / KMT2B-related disorders : expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation. In: Brain : a journal of neurology. 2020 ; Vol. 143, No. 11. pp. 3242-3261.

Bibtex

@article{9ecb64d1d9c54e2e93344f052717eb35,
title = "KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation",
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.",
keywords = "KMT2B, deep brain stimulation (DBS), dystonia, genetics, neurodevelopment",
author = "Laura Cif and Diane Demailly and Lin, {Jean Pierre} and Barwick, {Katy E.} and Mario Sa and Lucia Abela and Sony Malhotra and Chong, {Wui K.} and Dora Steel and Alba Sanchis-Juan and Adeline Ngoh and Natalie Trump and Esther Meyer and Xavier Vasques and Julia Rankin and Allain, {Meredith W.} and Applegate, {Carolyn D.} and {Attaripour Isfahani}, Sanaz and Julien Baleine and Bettina Balint and Bassetti, {Jennifer A.} and Baple, {Emma L.} and Bhatia, {Kailash P.} and Catherine Blanchet and Lydie Burglen and Gilles Cambonie and Seng, {Emilie Chan} and Bastaraud, {Sandra Chantot} and Fabienne Cyprien and Christine Coubes and Vincent d'Hardemare and {Deciphering Developmental Disorders Study} and Asif Doja and Nathalie Dorison and Diane Doummar and Dy-Hollins, {Marisela E.} and Ellyn Farrelly and Fitzpatrick, {David R.} and Conor Fearon and Fieg, {Elizabeth L.} and Fogel, {Brent L.} and Forman, {Eva B.} and Fox, {Rachel G.} and {Genomics England Research Consortium} and Gahl, {William A.} and Serena Galosi and Victoria Gonzalez and Graves, {Tracey D.} and Allison Gregory and Mark Hallett and Harutomo Hasegawa and Hayflick, {Susan J} and Ada Hamosh and Marie Hully and Sandra Jansen and Jeong, {Suh Young} and Krier, {Joel B} and Sidney Krystal and Kumar, {Kishore R} and Chlo{\'e} Laurencin and Hane Lee and Gaetan Lesca and Fran{\c c}ois, {Laurence Lion} and Timothy Lynch and Neil Mahant and Martinez-Agosto, {Julian A} and Christophe Milesi and Mills, {Kelly A} and Michel Mondain and Hugo Morales-Briceno and {NIHR BioResource} and Ostergaard, {John R.} and {Undiagnosed Diseases Network}",
note = "Publisher Copyright: {\textcopyright} The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com. Copyright: This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine",
year = "2020",
month = nov,
doi = "10.1093/brain/awaa304",
language = "English",
volume = "143",
pages = "3242--3261",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "11",

}

RIS

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 - Attaripour Isfahani, Sanaz

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 - Deciphering Developmental Disorders Study

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 - Genomics England Research Consortium

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 - NIHR BioResource

AU - Ostergaard, John R.

AU - Undiagnosed Diseases Network

N1 - Publisher Copyright: © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com. Copyright: This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine

PY - 2020/11

Y1 - 2020/11

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, >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.

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, >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.

KW - KMT2B

KW - deep brain stimulation (DBS)

KW - dystonia

KW - genetics

KW - neurodevelopment

UR - http://www.scopus.com/inward/record.url?scp=85097570939&partnerID=8YFLogxK

U2 - 10.1093/brain/awaa304

DO - 10.1093/brain/awaa304

M3 - Journal article

C2 - 33150406

AN - SCOPUS:85097570939

VL - 143

SP - 3242

EP - 3261

JO - Brain

JF - Brain

SN - 0006-8950

IS - 11

ER -