Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.

Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.Funding for the project was provided by the Wellcome Trust for UK10K (WT091310) and DDD Study. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund [grant number HICF-1009-003] - see www.ddduk.org/access.html for full acknowledgement. This work was supported in part by the Intramural Research Program of the National Human Genome Research Institute and the Common Fund, NIH Office of the Director. This work was supported in part by the German Ministry of Research and Education (grant nos. 01GS08160 and 01GS08167; German Mental Retardation Network) as part of the National Genome Research Network to A.R. and D.W. and by the Deutsche Forschungsgemeinschaft (AB393/2-2) to A.R. Brain expression data was provided by the UK Human Brain Expression Consortium (UKBEC), which comprises John A. Hardy, Mina Ryten, Michael Weale, Daniah Trabzuni, Adaikalavan Ramasamy, Colin Smith and Robert Walker, affiliated with UCL Institute of Neurology (J.H., M.R., D.T.), King’s College London (M.R., M.W., A.R.) and the University of Edinburgh (C.S., R.W.)

Antimicrobial susceptibility of bacterial isolates from 33 thoroughbred horses with arytenoid chondropathy (2005‐2019)

Objective: To describe the prevalence and antimicrobial susceptibility of bacterial isolates cultured from surgical specimens of infected arytenoid cartilage and granulomas. Study design: Retrospective cohort study. Animals: Thirty-three thoroughbred horses. Methods: Hospital records were retrieved for all horses admitted to a referral hospital for arytenoid chondropathy surgery that had samples submitted for culture and sensitivity between 2005 and 2019. Descriptive analyses were performed. Results: In total, 56 bacterial isolates were obtained. Gram-positive bacteria (58%), Gram-negative bacteria (54%), and anaerobes (33%) were cultured from samples. Fifty-eight percent of horses had multiple bacteria isolated. Streptococcus spp were the most common (32%), followed by Enterobacteriaceae (13%). Bacterial isolates were sensitive to ceftiofur (83%), followed by ampicillin (64%), tetracycline (48%), enrofloxacin (45%), trimethoprim-sulfamethoxazole (41%), and gentamicin (18%). Multidrug resistance (MDR) was present in 44% of bacterial isolates. Conclusion: A wide variety of bacteria was cultured, providing evidence that secondary opportunistic infection by common respiratory bacteria is likely a factor in arytenoid chondropathy. Multidrug resistance was higher than what has been previously reported in equine respiratory samples. Trimethoprim-sulfamethoxazole had low effectiveness. Clinical significance: Because culture and sensitivity testing is not available in the diagnosis of mild to moderate arytenoid chondropathy, the information from this study may allow for more targeted broad-spectrum antimicrobial treatment to limit disease progression when the disease is first identified. The antimicrobial susceptibilities and MDR found in this study emphasize the importance of following current antimicrobial guidelines and highlight the requirement for surgical intervention rather than continued medical treatment in cases that do not resolve with initial antimicrobial therapy

Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.

Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.Funding for the project was provided by the Wellcome Trust for UK10K (WT091310) and DDD Study. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund [grant number HICF-1009-003] - see www.ddduk.org/access.html for full acknowledgement. This work was supported in part by the Intramural Research Program of the National Human Genome Research Institute and the Common Fund, NIH Office of the Director. This work was supported in part by the German Ministry of Research and Education (grant nos. 01GS08160 and 01GS08167; German Mental Retardation Network) as part of the National Genome Research Network to A.R. and D.W. and by the Deutsche Forschungsgemeinschaft (AB393/2-2) to A.R. Brain expression data was provided by the UK Human Brain Expression Consortium (UKBEC), which comprises John A. Hardy, Mina Ryten, Michael Weale, Daniah Trabzuni, Adaikalavan Ramasamy, Colin Smith and Robert Walker, affiliated with UCL Institute of Neurology (J.H., M.R., D.T.), King’s College London (M.R., M.W., A.R.) and the University of Edinburgh (C.S., R.W.)