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

TitleKMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.
Publication TypeJournal Article
Year of Publication2020
AuthorsCif, L, Demailly, D, Lin, J-P, 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, IsfAHni, SAttaripour, Baleine, J, Balint, B, Bassetti, JA, Baple, EL, Bhatia, KP, Blanchet, C, Burglen, L, Cambonie, G, Seng, EChan, Bastaraud, SChantot, Cyprien, F, Coubes, C, d'Hardemare, V, Doja, A, Dorison, N, Doummar, D, Dy-Hollins, ME, Farrelly, E, FitzPatrick, DR, Fearon, C, Fieg, EL, Fogel, BL, Forman, EB, Fox, RG, Gahl, WA, Galosi, S, Gonzalez, V, Graves, TD, Gregory, A, Hallett, M, Hasegawa, H, Hayflick, SJ, Hamosh, A, Hully, M, Jansen, S, Jeong, SYoung, Krier, JB, Krystal, S, Kumar, KR, Laurencin, C, Lee, H, Lesca, G, François, LLion, Lynch, T, MAHnt, N, Martinez-Agosto, JA, Milesi, C, Mills, KA, Mondain, M, Morales-Briceno, H, Ostergaard, JR, Pal, S, Pallais, JC, Pavillard, F, Perrigault, P-F, Petersen, AK, Polo, G, Poulen, G, Rinne, T, Roujeau, T, Rogers, C, Roubertie, A, SAHgian, M, Schaefer, E, Selim, L, Selway, R, Sharma, N, Signer, R, Soldatos, AG, Stevenson, DA, Stewart, F, Tchan, M, Verma, IC, de Vries, BBA, Wilson, JL, Wong, DA, Zaitoun, R, Zhen, D, Znaczko, A, Dale, RC, de Gusmão, CM, Friedman, J, Fung, VSC, King, MD, Mohammad, SS, Rohena, L, Waugh, JL, Toro, C, F Raymond, L, Topf, M, Coubes, P, Gorman, KM, Kurian, MA
Corporate AuthorsDeciphering Developmental Disorders Study, Genomics England Research Consortium, NIHR BioResource, Undiagnosed Diseases Network
Date Published2020 12 05
KeywordsAdolescent, Adult, Child, Child, Preschool, Chromosome Deletion, Cohort Studies, Computer Simulation, Deep Brain Stimulation, Disease Progression, Dystonic Disorders, Endocrine System Diseases, Female, Fetal Growth Retardation, Gait Disorders, Neurologic, Histone-Lysine N-Methyltransferase, Humans, Laryngeal Diseases, Male, Mutation, Mutation, Missense, Phenotype, Quality of Life, Treatment Outcome, Young Adult

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.

Alternate JournalBrain
PubMed ID33150406
PubMed Central IDPMC7719027
Grant ListMC_UU_00007/3 / MR / Medical Research Council / United Kingdom
RP-2016-07-019 / DH / Department of Health / United Kingdom
K23 NS101096 / NS / NINDS NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
/ WT / Wellcome Trust / United Kingdom
U01 HG007703 / HG / NHGRI NIH HHS / United States
P01 NS087997 / NS / NINDS NIH HHS / United States
U01 HG007690 / HG / NHGRI NIH HHS / United States
U54 HG006493 / HG / NHGRI NIH HHS / United States
/ CR / Cancer Research UK / United Kingdom
WT098051 / WT / Wellcome Trust / United Kingdom