Dafsari, Hormos Salimi
Sprute, Rosanne
Wunderlich, Gilbert
Daimagüler, Hülya-Sevcan
Karaca, Ezgi http://orcid.org/0000-0002-4926-7991
Contreras, Adriana
Becker, Kerstin
Schulze-Rhonhof, Mira
Kiening, Karl
Karakulak, Tülay
Kloss, Manja
Horn, Annette
Pauls, Amande
Nürnberg, Peter
Altmüller, Janine
Thiele, Holger
Assmann, Birgit
Koy, Anne
Cirak, Sebahattin
Funding for this research was provided by:
Deutsche Forschungsgemeinschaft (CI 218/1-1)
Article History
Received: 6 March 2019
Revised: 9 May 2019
Accepted: 21 May 2019
First Online: 5 June 2019
Change Date: 6 August 2019
Change Type: Correction
Change Details: Rapid progress has recently been made in the elucidation of the genetic basis of childhood-onset inherited generalized dystonia (IGD) due to the implementation of genomic sequencing methodologies. We identified four patients with childhood-onset IGD harboring novel disease-causing mutations in lysine-specific histone methyltransferase 2B gene (<i>KMT2B</i>) by whole-exome sequencing. The main focus of this paper is to gain novel pathophysiological insights through understanding the molecular consequences of these mutations.The disease course is mostly progressive, evolving from lower limbs into generalized dystonia, which could be associated with dysarthria, dysphonia, intellectual disability, orofacial dyskinesia, and sometimes distinct dysmorphic facial features. In two patients, motor performances improved after bilateral implantation of deep brain stimulation in the globus pallidus internus (GPi-DBS). Pharmacotherapy with trihexyphenidyl reduced dystonia in two patients.We discovered three novel <i>KMT2B</i> mutations. Our analyses revealed that the mutation in patient 1 (c.7463 A > G, p.Y2488C) is localized in the highly conserved FYRC domain of KMT2B. This mutation holds the potential to alter the inter-domain FYR interactions, which could lead to <i>KMT2B</i> instability. The mutations in patients 2 and 3 (c.3602dupC, p.M1202Dfs*22; c.4229delA, p.Q1410Rfs*12) lead to predicted unstable transcripts, likely to be subject to degradation by non-sense mediated decay.Childhood-onset progressive dystonia with orofacial involvement is one of the main clinical manifestations of <i>KMT2B</i> mutations. In all, 26% (18/69) of the reported cases have T2 signal alterations of the globus pallidus internus, mostly at a younger age. Anticholinergic medication and GPi-DBS are promising treatment options and shall be considered early.An amendment to this paper has been published and can be accessed via a link at the top of the paper
Compliance with ethical standards
:
: The authors declare that they have no conflict of interest.
: Informed consent was obtained from the patients for genetic investigations, recording, and publishing the disease-related information. The study was approved by the institutional review board of the Ethics Committee of the University Hospital of Cologne.