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

Cif, L. and Demailly, D. and Lin, J.-P. and Barwick, K.E. and Sa, M. and Abela, L. and Malhotra, S. and Chong, W.K. and Steel, D. and Sanchis-Juan, A. and Ngoh, A. and Trump, N. and Meyer, E. and Vasques, X. and Rankin, J. and Allain, M.W. and Applegate, C.D. and Attaripour Isfahani, S. and Baleine, J. and Balint, B. and Bassetti, J.A. and Baple, E.L. and Bhatia, K.P. and Blanchet, C. and Burglen, L. and Cambonie, G. and Seng, E.C. and Bastaraud, S.C. and Cyprien, F. and Coubes, C. and d’Hardemare, V. and Doja, A. and Dorison, N. and Doummar, D. and Dy-Hollins, M.E. and Farrelly, E. and Fitzpatrick, D.R. and Fearon, C. and Fieg, E.L. and Fogel, B.L. and Forman, E.B. and Fox, R.G. and Gahl, W.A. and Galosi, S. and Gonzalez, V. and Graves, T.D. and Gregory, A. and Hallett, M. and Hasegawa, H. and Hayflick, S.J. and Hamosh, A. and Hully, M. and Jansen, S. and Jeong, S.Y. and Krier, J.B. and Krystal, S. and Kumar, K.R. and Laurencin, C. and Lee, H. and Lesca, G. and François, L.L. and Lynch, T. and Mahant, N. and Martinez-Agosto, J.A. and Milesi, C. and Mills, K.A. and Mondain, M. and Morales-Briceno, H. and Ostergaard, J.R and Pal, S. and Pallais, J.C. and Pavillard, F. and Perrigault, P.-F. and Petersen, A.K. and Polo, G. and Poulen, G. and Rinne, T. and Roujeau, T. and Rogers, C. and Roubertie, A. and Sahagian, M. and Schaefer, E. and Selim, L. and Selway, R. and Sharma, N. and Signer, R. and Soldatos, A.G. and Stevenson, D.A. and Stewart, F. and Tchan, M. and Verma, I.C. and de Vries, B.B.A and Wilson, J.L. and Wong, D.A. and Zaitoun, R. and Zhen, D. and Znaczko, A. and Dale, R.C. and de Gusmão, C.M. and Friedman, J. and Fung, V.S.C. and King, M.D. and Mohammad, S.S and Rohena, L. and Waugh, J.L. and Toro, C. and Raymond, F.L. and Topf, Maya and Coubes, P. and Gorman, K.M. and Kurian, M.A. (2020) KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation. Brain 143 (11), pp. 3242-3261. ISSN 0006-8950.

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.

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