Public Release: 

Remarkable recovery in patients diagnosed with newly defined movement disorder

Genetic cause that identifies dystonia patients who can benefit from Deep Brain Stimulation uncovered by UCL, Great Ormond Street Hospital and University of Cambridge researchers using the NIHR Rare Disease Bioresource

Don Powell Associates Ltd

DNA sequencing has defined a new genetic disorder that affects movement, enabling patients with dystonia -- a disabling condition that affects voluntary movement -- to be targeted for treatment that brings remarkable improvements, including restoring independent walking.

A team of researchers from UCL Great Ormond Street Institute of Child Health, University of Cambridge and the NIHR Rare Disease Bioresource have identified mutations in a gene, called KMT2B, in 28 patients with dystonia. In most cases, the patients -- many of whom were young children who were thought to have a diagnosis of cerebral palsy -- were unable to walk without difficulty.

Remarkably, for some patients, treatment with Deep Brain Stimulation, in which electrical impulses are delivered to a specific brain region involved in movement, either restored or significantly improved independent walking and improved hand and arm movement. In one patient, improvements have been sustained over six years.

Given these observations, the team now suggest that testing for mutations in the gene should form part of standard testing for patients with dystonia, as this is emerging to be one of the commonest genetic causes of childhood-onset dystonia.

The research is published in Nature Genetics on Monday 19 December 2016.

Dystonia is one of the commonest movement disorders and is thought to affect 70,000 people in the UK alone. It can cause a wide range of disabling symptoms, including painful muscle spasms and abnormal postures, and can affect walking and speech.

Through research testing of patients, the team discovered a region of chromosome 19 that was deleted from the genome of some patients with childhood-onset dystonia. Together with the NIHR Rare Disease Bioresource and international collaborators, the team then identified abnormal genetic changes in genomes from a further 18 patients in one gene, called KMT2B, where affected patients carried a mutated in their DNA.

"Through DNA sequencing, we have identified a new genetic movement disorder that can be treated with Deep Brain Stimulation. This can dramatically improve the lives of children with the condition and enable them to have a wider range of movement with long-lasting effects," says Dr Manju Kurian, paediatric neurologist at Great Ormond Street Hospital and Wellcome Trust-funded researcher at UCL Great Ormond Street Institute of Child Health. "Our results, though in a relatively small group of patients, show the power of genomic research not only to identify new diseases, but also to reveal possible approaches that will allow other patients to benefit."

The KMT2B protein is thought to alter the activity of other genes. The team believes that the mutations impair the ability of the KMT2B protein to carry out its normal, crucial role in controlling the expression of genes involved in voluntary movement.

A number of patients were previously thought to have cerebral palsy prior to confirmation of their genetic diagnosis. Such uncertainty could be addressed by looking for KMT2B mutations as part of a diagnostic approach.

Although affected patients have been found to have a mutation in their DNA, this severe condition is rarely inherited from either parent but usually occurs for the first time in the affected child.

"Most patients show a progressive disease course with worsening dystonia over time," continues Dr Kurian. "Many patients did not show any response to the usual medications that we use for dystonia so we knew we would have to consider other strategies. We know, from our experience with other patients with dystonia, that Deep Brain Stimulation might improve our patient's symptoms, so were keen to see what response patients would have to this type of treatment."

"Remarkably nearly all patients who had Deep Brain Stimulation showed considerable improvements. One patient was able to walk independently within two weeks; in five patients, the improvement has lasted for more than three years. It is an astounding result."

Given the dramatic effects seen in their patients with this newly defined genetic condition, the team propose that referral for assessment of Deep Brain Stimulation should be considered for all patients with a mutation in KMT2B. In the future, the team hopes that, by diagnosing additional patients, the full spectrum of this new condition will be more apparent and patients and their families might see real benefit.

"It is only through the amazing generosity and efforts of patients and their families that we can begin to search for better answers and treatments: we admire their contribution," says Professor Raymond, Assistant Director of the NIHR Bioresource for Rare Diseases and Professor of Medical Genetics and Neurodevelopment at the University of Cambridge. "Through participating in our research, they have helped us to identify patients with KMT2B-related dystonia, meaning we can aim for a more "precision medicine approach" to target treatment with Deep Brain Stimulation to those likely to benefit: most importantly, we would anticipate improvement in many of those treated.

"The lesson from our study is simple and clear: because confirming this diagnosis has implications for therapy, we should test all patients with suspected genetic dystonia for mutations in KMT2B."

###

Notes to Editors

Publication

Meyer E, Carss KJ, Rankin J et al. (2016) Mutations in the Histone Methyltransferase Gene, KMT2B Cause Early Onset Dystonia. Nature Genetics. doi: 10.1038/ng.3740

Participating Centres

A full list of participating centres can be found at the Nature Genetics website.

About the UCL Great Ormond Street Institute of Child Health (ICH)

The UCL Great Ormond Street Institute of Child Health is part of the Faculty of Population Health Sciences within the School of Life and Medical Sciences at UCL. Together with its clinical partner Great Ormond Street Hospital for Children (GOSH), it forms the largest concentration of children's health research in Europe.

For more information visit http://www.ucl.ac.uk/ich

About NIHR BioResource

The research studies were undertaken as part of the NIHR BioResource. The NIHR BioResource (http://bioresource.nihr.ac.uk) functions as a partnership between the NIHR Biomedical Research Centres at Imperial College London, King's/Guy's and St Thomas' Hospitals London, Newcastle Hospitals, South London and Maudsley Hospitals, Oxford University Hospitals, University College London Hospitals and the Cardiovascular Biomedical Research Unit in Leicester. The NIHR BioResource, which currently includes over 100,000 research patients and volunteers and over 10,000 Individuals with rare genetic diseases most of whom have undergone analysis of their genome.

About the University of Cambridge

The mission of the University of Cambridge is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence. To date, 96 affiliates of the University have won the Nobel Prize.

Founded in 1209, the University comprises 31 autonomous Colleges, which admit undergraduates and provide small-group tuition, and 150 departments, faculties and institutions.

Cambridge is a global university. Its 19,000 student body includes 3,700 international students from 120 countries. Cambridge researchers collaborate with colleagues worldwide, and the University has established larger-scale partnerships in Asia, Africa and America.

The University sits at the heart of one of the world's largest technology clusters. The 'Cambridge Phenomenon' has created 1,500 hi-tech companies, 14 of them valued at over US$1 billion and two at over US$10 billion. Cambridge promotes the interface between academia and business, and has a global reputation for innovation. http://www.cam.ac.uk

About Cambridge University Hospitals and the Cambridge Biomedical Research Centre

Based within the most outstanding NHS and University partnerships in the country, the NIHR Biomedical Research Centres are leaders in scientific translation. They receive substantial levels of funding from the National Institute for Health Research (NIHR) to translate fundamental biomedical research into clinical research that benefits patients and they are early adopters of new insights in technologies, techniques and treatments for improving health. The Cambridge Biomedical Research Centre (http://www.cambridge-brc.org.uk/) coordinates the NIHR BioResource.

Contact information

Rachel Twinn, Senior Press Officer
Great Ormond Street Hospital and UCL Great Ormond Street Institute of Child Health
Phone 020 3841 3039
Email Rachel.Twinn@GOSH.ORG

Dr Don Powell
Don Powell Associates
Mobile +44 (0)778 6858 220
Phone +44 (0)1223 515436
Email don@donpowellassociates.co.uk

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.