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, Adeline Ngoh, Natalie Trump, Esther Meyer, Xavier Vasques, Julia Rankin, Meredith W. Allain, Carolyn D. Applegate, Sanaz Attaripour Isfahani, Julien Baleine, Bettina BalintJennifer A. Bassetti, Emma L. Baple, Kailash P. Bhatia, Catherine Blanchet, Lydie Burglen, Gilles Cambonie, Emilie Chan Seng, Sandra Chantot Bastaraud, Fabienne Cyprien, Christine Coubes, Vincent d’Hardemare, Asif Doja, Nathalie Dorison, Diane Doummar, Marisela E. Dy-Hollins, Ellyn Farrelly, David R. Fitzpatrick, Conor Fearon, Elizabeth L. Fieg, Brent L. Fogel, Eva B. Forman, Rachel G. Fox, William A. Gahl, Serena Galosi, Victoria Gonzalez, Tracey D. Graves, Allison Gregory, Mark Hallett, Harutomo Hasegawa, Susan J. Hayflick, Ada Hamosh, Marie Hully, Sandra Jansen, Suh Young Jeong, Joel B. Krier, Sidney Krystal, Kishore R. Kumar, Chloé Laurencin, Hane Lee, Gaetan Lesca, Laurence Lion François, Timothy Lynch, Neil Mahant, Julian A. Martinez-Agosto, Christophe Milesi, Kelly A. Mills, Michel Mondain, Hugo Morales-Briceno, John R. Ostergaard, Swasti Pal, Juan C. Pallais, Frédérique Pavillard, Pierre Francois Perrigault, Andrea K. Petersen, Gustavo Polo, Gaetan Poulen, Tuula Rinne, Thomas Roujeau, Caleb Rogers, Agathe Roubertie, Michelle Sahagian, Elise Schaefer, Laila Selim, Richard Selway, Nutan Sharma, Rebecca Signer, Ariane G. Soldatos, David A. Stevenson, Fiona Stewart, Michel Tchan, Ishwar C. Verma, Bert B.A. de Vries, Jenny L. Wilson, Derek A. Wong, Raghda Zaitoun, Dolly Zhen, Anna Znaczko, Russell C. Dale, Claudio M. de Gusmão, Jennifer Friedman, Victor S.C. Fung, Mary D. King, Shekeeb S. Mohammad, Luis Rohena, Jeff L. Waugh, Camilo Toro, F. Lucy Raymond, Maya Topf, Philippe Coubes, Kathleen M. Gorman, Manju A. Kurian

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


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 languageEnglish (US)
Pages (from-to)3242-3261
Number of pages20
Issue number11
StatePublished - 2020


  • Deep brain stimulation (DBS)
  • Dystonia
  • Genetics
  • KMT2B
  • Neurodevelopment

ASJC Scopus subject areas

  • Clinical Neurology


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