Dystonia is one of the commonest movement disorders and is thought
to affect 70,000 people in the United Kingdom alone. It can cause a wide range of
disabling symptoms, including painful muscle spasms and abnormal
postures, and can affect walking and speech.
DNA sequencing has defined a new genetic disorder that affects
movement, enabling patients with dystonia to be targeted for treatment that brings
remarkable improvements, including restoring independent walking.
‘Genetic cause that identifies dystonia patients who can benefit from Deep Brain Stimulation has been uncovered by researchers.’
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
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
"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
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."