KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation
Authors: 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 , Pal Swasti , Pallais Juan C , Pavillard Frédérique , Perrigault Pierre-Francois , Petersen Andrea K , Polo Gustavo , Poulen Gaetan , Rinne Tuula , Roujeau Thomas , Rogers Caleb , Roubertie Agathe , Sahagian Michelle , Schaefer Elise , Selim Laila , Selway Richard , Sharma Nutan , Signer Rebecca , Soldatos Ariane G , Stevenson David A , Stewart Fiona , Tchan Michel ,   Undiagnosed Diseases Network, Verma Ishwar C , de Vries Bert B A , Wilson Jenny L , Wong Derek A , Zaitoun Raghda , Zhen Dolly , Znaczko Anna , Dale Russell C , de Gusmão Claudio M , Friedman Jennifer , Fung Victor S C , King Mary D , Mohammad Shekeeb S , Rohena Luis , Waugh Jeff L , Toro Camilo , Raymond F Lucy , Topf Maya , Coubes Philippe , Gorman Kathleen M , Kurian Manju A 
Published: August 2020

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, &gt;50% of subjects showed BFMDRS-M and BFMDRS-D improvements of &gt;30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for &gt;5 years, n = 8), improvement of &gt;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.