Top

Current Neurology and Neuroscience Reports

Published in:

01-11-2019 | Dystonia | Genetics (V. Bonifati, Section Editor)

Update on KMT2B-Related Dystonia

Authors: Michael Zech, Daniel D. Lam, Juliane Winkelmann

Published in: Current Neurology and Neuroscience Reports | Issue 11/2019

Abstract

Purpose of Review

To summarize the molecular and clinical findings of KMT2B-related dystonia (DYT-KMT2B), a newly identified genetic dystonia syndrome.

Recent Findings

Since first described in 2016, 66 different KMT2B-affecting variants, encompassing a set of frameshift, nonsense, splice-site, missense, and deletion mutations, have been reported in 76 patients. Most mutations are de novo and expected to mediate epigenetic dysregulation by inducing KMT2B haploinsufficiency. DYT-KMT2B is characterized phenotypically by limb-onset childhood dystonia that tends to spread progressively, resulting in generalized dystonia with cranio-cervical involvement. Co-occuring signs such as intellectual disability are frequently observed. Sustained response to deep brain stimulation (DBS), including restoration of independent ambulation, is seen in 93% (27/29) of patients.

Summary

DYT-KMT2B is emerging as a prevalent monogenic dystonia. Childhood-onset dystonia presentations should prompt a search for KMT2B mutations, preferentially via next-generation-sequencing and genomic-array technologies, to enable specific counseling and treatment. Prospective multicenter studies are desirable to establish KMT2B mutational status as a DBS outcome predictor.

Deciphering Developmental Disorders S. Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2015;519(7542):223–8. https://doi.org/10.1038/nature14135.CrossRef

Epi KC, Epilepsy Phenome/Genome P, Allen AS, Berkovic SF, Cossette P, Delanty N, et al. De novo mutations in epileptic encephalopathies. Nature. 2013;501(7466):217–21. https://doi.org/10.1038/nature12439.CrossRef

Fromer M, Pocklington AJ, Kavanagh DH, Williams HJ, Dwyer S, Gormley P, et al. De novo mutations in schizophrenia implicate synaptic networks. Nature. 2014;506(7487):179–84. https://doi.org/10.1038/nature12929.CrossRefPubMedPubMedCentral

•• Zech M, Boesch S, Maier EM, Borggraefe I, Vill K, Laccone F, et al. Haploinsufficiency of KMT2B, encoding the lysine-specific histone methyltransferase 2B, results in early-onset generalized dystonia. Am J Hum Genet. 2016;99(6):1377–87. https://doi.org/10.1016/j.ajhg.2016.10.010. In four independent families, this study identifies for the first time protein-truncating variants in the epigenetic regulator gene KMT2B as a cause of childhood-onset generalized dystonia. Based on the observations that (1) KMT2B mRNA levels were significantly decreased in patient-derived cells and (2) literature-reported whole-gene deletions of KMT2B were also associated with dystonia, the authors suggest haploinsufficiency as the most likely molecular mechanism of disease. CrossRefPubMedPubMedCentral

•• Meyer E, Carss KJ, Rankin J, Nichols JM, Grozeva D, Joseph AP, et al. Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia. Nat Genet. 2017;49(2):223–37. https://doi.org/10.1038/ng.3740. Published in parallel with the paper by Zech et al., this work decribes a large cohort of dystonia patients harboring protein-truncating, missense, and deletion mutations in KMT2B. The authors provide detailed genotypic and phenotypic data on 28 individuals with DYT-KMT2B, show that KMT2B mutations result in impaired expression of the dystonia-linked genes TOR1A and THAP1, and highlight deep brain stimulation as a promising treatment option for DYT-KMT2B. In addition, they elaborate on the broad spectrum of non-dystonic KMT2B-related symptoms and demonstrate that hypointense basal ganglia lesions can be seen on brain MRI scans of patients with DYT-KMT2B. CrossRefPubMed

Shen E, Shulha H, Weng Z, Akbarian S. Regulation of histone H3K4 methylation in brain development and disease. Philos Trans R Soc Lond Ser B Biol Sci. 2014;369(1652). https://doi.org/10.1098/rstb.2013.0514.CrossRef

Ansari KI, Mandal SS. Mixed lineage leukemia: roles in gene expression, hormone signaling and mRNA processing. FEBS J. 2010;277(8):1790–804. https://doi.org/10.1111/j.1742-4658.2010.07606.x.CrossRefPubMed

Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419. https://doi.org/10.1126/science.1260419.CrossRefPubMed

Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature. 2007;445(7124):168–76. https://doi.org/10.1038/nature05453.CrossRefPubMed

10.

Glaser S, Schaft J, Lubitz S, Vintersten K, van der Hoeven F, Tufteland KR, et al. Multiple epigenetic maintenance factors implicated by the loss of Mll2 in mouse development. Development. 2006;133(8):1423–32. https://doi.org/10.1242/dev.02302.CrossRefPubMed

11.

Lubitz S, Glaser S, Schaft J, Stewart AF, Anastassiadis K. Increased apoptosis and skewed differentiation in mouse embryonic stem cells lacking the histone methyltransferase Mll2. Mol Biol Cell. 2007;18(6):2356–66. https://doi.org/10.1091/mbc.e06-11-1060.CrossRefPubMedPubMedCentral

12.

• Zech M, Jech R, Havrankova P, Fecikova A, Berutti R, Urgosik D, et al. KMT2B rare missense variants in generalized dystonia. Mov Disord. 2017;32(7):1087–91. https://doi.org/10.1002/mds.27026. This paper highlights the importance of accurate clinical interpretation of KMT2B missense variants, illustrated by clinico-genetic descriptions of three unrelated individuals with novel missense changes in KMT2B. CrossRefPubMed

13.

Zech M, Jech R, Wagner M, Mantel T, Boesch S, Nocker M, et al. Molecular diversity of combined and complex dystonia: insights from diagnostic exome sequencing. Neurogenetics. 2017;18(4):195–205. https://doi.org/10.1007/s10048-017-0521-9.CrossRefPubMed

14.

• Lange LM, Tunc S, Tennstedt S, Munchau A, Klein C, Assmann B, et al. A novel, in-frame KMT2B deletion in a patient with apparently isolated, generalized dystonia. Mov Disord. 2017;32(10):1495–7. https://doi.org/10.1002/mds.27137. In this manuscript, the first de novo in-frame deletion variant is reported, and the authors point out that KMT2B mutation should also be considered in the differential diagnosis of seemingly isolated dystonia. CrossRefPubMed

15.

Dafsari HS, Sprute R, Wunderlich G, Daimaguler HS, Karaca E, Contreras A, et al. Novel mutations in KMT2B offer pathophysiological insights into childhood-onset progressive dystonia. J Hum Genet. 2019;64:803–13. https://doi.org/10.1038/s10038-019-0625-1.CrossRefPubMed

16.

• Carecchio M, Invernizzi F, Gonzalez-Latapi P, Panteghini C, Zorzi G, Romito L, et al. Frequency and phenotypic spectrum of KMT2B dystonia in childhood: a single-center cohort study. Mov Disord. 2019. https://doi.org/10.1002/mds.27771 By identifying 14 novel dystonia patients with. KMT2B variants, this very recent study expands the mutational spectrum of DYT-KMT2B and provides supportive evidence for positive DBS response in DYT-KMT2B. CrossRefPubMed

17.

Bras A, Ribeiro JA, Sobral F, Moreira F, Morgadinho A, Januario C. Early-onset oromandibular-laryngeal dystonia and Charlot gait: new phenotype of DYT-KMT2B. Neurology. 2019;92(19):919. https://doi.org/10.1212/WNL.0000000000007469.CrossRefPubMed

18.

Garrido A, Simonet C, Martí MJ, Pérez-Dueñas B, Rumià J, Valldeoriola F. Good response to bilateral GPI-DBS after 2 years in generalized dystonia due to a mutation in the KMT2B gene (DYT28) [abstract]. Mov Disord. 2018;33(suppl 2) https://www.mdsabstracts.org/abstract/good-response-to-bilateral-gpi-dbs-after-2-years-in-generalized-dystonia-due-to-a-mutation-in-the-kmt2b-gene-dyt28/. Accessed 14 June 2019.

19.

Hackenberg A, Wagner M, Pahnke J, Zeitler P, Boltshauser E. Low voice, spasmodic dysphonia, and hand dystonia as clinical clues for KMT2B-associated early-onset dystonia. Neuropediatrics. 2018;49(5):356. https://doi.org/10.1055/s-0038-1661343.CrossRefPubMed

20.

Baizabal-Carvallo JF, Alonso-Juarez M. Generalized dystonia associated with mutation in the histone methyltransferase gene KMT2B (DYT28) and white matter abnormalities. Parkinsonism Relat Disord. 2018;49:116–7. https://doi.org/10.1016/j.parkreldis.2018.01.016.CrossRefPubMed

21.

Klein C, Baumann H, Olschewski L, Hanssen H, Munchau A, Ferbert A, et al. De-novo KMT2B mutation in a consanguineous family: 15-year follow-up of an Afghan dystonia patient. Parkinsonism Relat Disord. 2019;64:337–9. https://doi.org/10.1016/j.parkreldis.2019.03.018.CrossRefPubMed

22.

• Dai L, Ding C, Fang F. An inherited KMT2B duplication variant in a Chinese family with dystonia and/or development delay. Parkinsonism Relat Disord. 2018. https://doi.org/10.1016/j.parkreldis.2018.08.021. This case report shows that KMT2B mutations can cause generalized dystonia and developmental disease without dystonia within the same family. CrossRef

23.

Zhou XY, Wu JJ, Sun YM. An atypical case of early-onset dystonia with a novel missense variant in KMT2B. Parkinsonism Relat Disord. 2018;63:224–6. https://doi.org/10.1016/j.parkreldis.2018.09.020.CrossRefPubMed

24.

Ma J, Wan XH. Novel missense variants in KMT2B in segmental dystonia [abstract]. Mov Disord. 2018;33(suppl 2) https://www.mdsabstracts.org/abstract/novel-missense-variants-in-kmt2b-in-segmental-dystonia/. Accessed 14 June 2019.

25.

• Kawarai T, Miyamoto R, Nakagawa E, Koichihara R, Sakamoto T, Mure H, et al. Phenotype variability and allelic heterogeneity in KMT2B-associated disease. Parkinsonism Relat Disord. 2018;52:55–61. https://doi.org/10.1016/j.parkreldis.2018.03.022. This study confirms high efficacy of DBS treatment in DYT-KMT2B and provides experimental evidence for a role of nonsense-mediated decay in the degregation of truncating variant-bearing KMT2B transcripts. CrossRefPubMed

26.

Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536(7616):285–91. https://doi.org/10.1038/nature19057.CrossRefPubMedPubMedCentral

27.

Traynelis J, Silk M, Wang Q, Berkovic SF, Liu L, Ascher DB, et al. Optimizing genomic medicine in epilepsy through a gene-customized approach to missense variant interpretation. Genome Res. 2017;27(10):1715–29. https://doi.org/10.1101/gr.226589.117.CrossRefPubMedPubMedCentral

28.

Jones WD, Dafou D, McEntagart M, Woollard WJ, Elmslie FV, Holder-Espinasse M, et al. De novo mutations in MLL cause Wiedemann-Steiner syndrome. Am J Hum Genet. 2012;91(2):358–64. https://doi.org/10.1016/j.ajhg.2012.06.008.CrossRefPubMedPubMedCentral

29.

Kleefstra T, Kramer JM, Neveling K, Willemsen MH, Koemans TS, Vissers LE, et al. Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability. Am J Hum Genet. 2012;91(1):73–82. https://doi.org/10.1016/j.ajhg.2012.05.003.CrossRefPubMedPubMedCentral

30.

Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet. 2010;42(9):790–3. https://doi.org/10.1038/ng.646.CrossRefPubMedPubMedCentral

31.

O'Donnell-Luria AH, Pais LS, Faundes V, Wood JC, Sveden A, Luria V, et al. Heterozygous variants in KMT2E cause a spectrum of neurodevelopmental disorders and epilepsy. Am J Hum Genet. 2019;104(6):1210–22. https://doi.org/10.1016/j.ajhg.2019.03.021.CrossRefPubMedPubMedCentral

32.

Singh T, Kurki MI, Curtis D, Purcell SM, Crooks L, McRae J, et al. Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders. Nat Neurosci. 2016;19(4):571–7. https://doi.org/10.1038/nn.4267.CrossRefPubMedPubMedCentral

33.

Segel R, Ben-Pazi H, Zeligson S, Fatal-Valevski A, Aran A, Gross-Tsur V, et al. Copy number variations in cryptogenic cerebral palsy. Neurology. 2015;84(16):1660–8. https://doi.org/10.1212/WNL.0000000000001494.CrossRefPubMed

34.

Gana S, Veggiotti P, Sciacca G, Fedeli C, Bersano A, Micieli G, et al. 19q13.11 cryptic deletion: description of two new cases and indication for a role of WTIP haploinsufficiency in hypospadias. Eur J Human Gen: EJHG. 2012;20(8):852–6. https://doi.org/10.1038/ejhg.2012.19.CrossRef

35.

Melo JB, Estevinho A, Saraiva J, Ramos L, Carreira IM. Cutis Aplasia as a clinical hallmark for the syndrome associated with 19q13.11 deletion: the possible role for UBA2 gene. Mol Cytogenet. 2015;8:21. https://doi.org/10.1186/s13039-015-0123-x.CrossRefPubMedPubMedCentral

36.

Zhao K, van der Spoel A, Castiglioni C, Gale S, Fujiwara H, Ory DS, et al. 19q13.12 microdeletion syndrome fibroblasts display abnormal storage of cholesterol and sphingolipids in the endo-lysosomal system. Biochim Biophys Acta Mol Basis Dis. 2018;1864(6 Pt A):2108–18. https://doi.org/10.1016/j.bbadis.2018.03.020.CrossRefPubMedPubMedCentral

37.

Bragin E, Chatzimichali EA, Wright CF, Hurles ME, Firth HV, Bevan AP, et al. DECIPHER: database for the interpretation of phenotype-linked plausibly pathogenic sequence and copy-number variation. Nucleic Acids Res. 2014;42(Database issue):D993–D1000. https://doi.org/10.1093/nar/gkt937.CrossRefPubMed

38.

Goldsworthy M, Absalom NL, Schroter D, Matthews HC, Bogani D, Moir L, et al. Mutations in Mll2, an H3K4 methyltransferase, result in insulin resistance and impaired glucose tolerance in mice. PLoS One. 2013;8(6):e61870. https://doi.org/10.1371/journal.pone.0061870.CrossRefPubMedPubMedCentral

39.

Kerimoglu C, Agis-Balboa RC, Kranz A, Stilling R, Bahari-Javan S, Benito-Garagorri E, et al. Histone-methyltransferase MLL2 (KMT2B) is required for memory formation in mice. J Neurosci. 2013;33(8):3452–64. https://doi.org/10.1523/JNEUROSCI.3356-12.2013.CrossRefPubMedPubMedCentral

40.

• Barbagiovanni G, Germain PL, Zech M, Atashpaz S, Lo Riso P, D’Antonio-Chronowska A, et al. KMT2B is selectively required for neuronal transdifferentiation, and its loss exposes dystonia candidate genes. Cell Rep. 2018;25(4):988–1001. https://doi.org/10.1016/j.celrep.2018.09.067. This study elucidates the KMT2B-sensitive transcriptome required for transdifferentiation of murine embryonic fibroblasts into induced neuronal cells and tests the hypothesis that KMT2B target genes could represent novel disease candidates for dystonia. By interrogating 216 targets in whole-exome sequencing data from 225 dystonia patients, the authors prioritize variants in three candidates, namely NOL4, SLC35F1, and SLC40A1. CrossRefPubMedPubMedCentral

41.

Zech M, Boesch S, Jochim A, Weber S, Meindl T, Schormair B, et al. Clinical exome sequencing in early-onset generalized dystonia and large-scale resequencing follow-up. Mov Disord. 2017;32(4):549–59. https://doi.org/10.1002/mds.26808.CrossRefPubMed

42.

Morimoto Y, Ono S, Imamura A, Okazaki Y, Kinoshita A, Mishima H, et al. Deep sequencing reveals variations in somatic cell mosaic mutations between monozygotic twins with discordant psychiatric disease. Human Genome Variation. 2017;4:17032. https://doi.org/10.1038/hgv.2017.32.CrossRefPubMedPubMedCentral

43.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24. https://doi.org/10.1038/gim.2015.30.CrossRefPubMedPubMedCentral

44.

Carlston CM, O'Donnell-Luria AH, Underhill HR, Cummings BB, Weisburd B, Minikel EV, et al. Pathogenic ASXL1 somatic variants in reference databases complicate germline variant interpretation for Bohring-Opitz syndrome. Hum Mutat. 2017;38(5):517–23. https://doi.org/10.1002/humu.23203.CrossRefPubMedPubMedCentral

45.

Faundes V, Newman WG, Bernardini L, Canham N, Clayton-Smith J, Dallapiccola B, et al. Histone lysine methylases and demethylases in the landscape of human developmental disorders. Am J Hum Genet. 2018;102(1):175–87. https://doi.org/10.1016/j.ajhg.2017.11.013.CrossRefPubMed

46.

Gorman KM, Meyer E, Kurian MA. Review of the phenotype of early-onset generalised progressive dystonia due to mutations in KMT2B. Eur J Paediatr Neurol. 2018;22(2):245–56. https://doi.org/10.1016/j.ejpn.2017.11.009.CrossRefPubMed

Title: Update on KMT2B-Related Dystonia
Authors: Michael Zech
Daniel D. Lam
Juliane Winkelmann
Publication date: 01-11-2019
Publisher: Springer US
Keywords: Dystonia
Deep Brain Stimulation
Published in: Current Neurology and Neuroscience Reports / Issue 11/2019
Print ISSN: 1528-4042
Electronic ISSN: 1534-6293
DOI: https://doi.org/10.1007/s11910-019-1007-y

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Update on KMT2B-Related Dystonia

Abstract

Purpose of Review

Recent Findings

Summary

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose of Review

Recent Findings

Summary

Please log in to get access to this content

Other articles of this Issue 11/2019

Stroke in the Young: a Global Update

Machine Learning and Artificial Intelligence in Neurocritical Care: a Specialty-Wide Disruptive Transformation or a Strategy for Success

Updates in the Treatment of Post-Stroke Pain

Sleep Disorders in Wilson’s Disease

Clinical Characteristics of Multiple Sclerosis in African-Americans

Gray Matter Changes in Parkinson’s and Alzheimer’s Disease and Relation to Cognition