Simply put,
dystonia is a problem with the way the brain controls movement. There is a
particular part of the brain (one on either side controlling one half of the
body) that controls the turning on or off of muscles. In fact there is a map or
model of our body laid out in this part of the brain, so it might look very
simple to get the right muscle to move. All one has to do is turn on the right
bit of the “map” in the brain, and the appropriate muscle will contract.
Unfortunately it is more complicated than this, as all messages from the map
pass through the basal ganglia, a part of the brain that goes wrong in
dystonia. The role of the basal ganglia is to focus and control the messages that
come down to it from the map. If the basal ganglia fail to work, then
disorganised and unwanted messages can come through to the muscles and cause
them to contract in unusual ways which are not under the control of the
affected person.
I am
particularly interested in a condition that causes dystonia due to an
abnormality in a particular gene. This condition is called DYT1 dystonia (DYT1
stand for the dystonia 1 gene, as it was the first dystonia gene to be
discovered). This gene problem causes young-onset generalised dystonia,
although some people can be more mildly affected. One of the very interesting
things about this condition is that only about 30% of people who carry the gene
abnormality get dystonia, leaving about 70% of gene carriers entirely well. I
am very interested in finding out how these unaffected gene carriers stay well,
as if we knew this, perhaps we could help those who have developed dystonia.
DYT1 dystonia is fairly rare, but it is likely that any information we gain
from people with this condition will be relevant to people with more common
types of dystonia.
So, how are
some people who carry this abnormal gene managing not to get dystonia? Well, it
is possible that somehow the abnormal gene is “switched off” in them. Another
possibility is that the abnormal gene is active, but for some reason does not
affect them as much as it does people who go on to get dystonia. In other words
people have to reach a “threshold” of abnormality, and if they get over this
threshold they get dystonia. A final possibility is that there are only certain
parts of the brain affected by the DYT1 gene, and other parts need to go wrong
(perhaps due to another, as yet unknown gene problem) for dystonia to be
produced
Together with
colleagues at the Institute of Neurology I examined a group of people carrying
the DYT1 gene, some with dystonia and some without, and compared them to DYT1
negative subjects. We looked at the motor cortex (where the “map” is that I
mentioned above) using a technique called transcranial magnetic stimulation
(TMS). TMS is a way of assessing the brain using magnetic pulses. The tests we
did looked to see if the brain was “overexcited” – something that we would
expect in people with dystonia. We also examined a reflex in the arm to see if
these problems with the brain were translated through to dystonia in the arms.
To our
surprise, we found that people with the abnormal DYT1 gene, but without
dystonia had abnormal overexcitability of the brain of a similar severity to
that seen in gene carriers with dystonia. However, there was no evidence that
these abnormalities led to problems with the reflex we were studying in the
arm, which was only abnormal if people had dystonia.
So, what does
this mean? Well, it is clear that the DYT1 gene causes problems in the brain in
all people who carry it, regardless of whether they have dystonia or not. Interestingly,
all people with the gene have a similar severity of these brain abnormalities,
even those without dystonia. However it was clear that these abnormalities did
not “escape” from the brain in those without dystonia.
The most likely explanation is that there are other
systems in the brain that we did not test that have to go wrong in order for
dystonia to be produced. We are conducting further experiments at the moment to
try and find out what these problems are. If we could identify them, then we
would understand much more about how dystonia is produced by the brain, and
therefore where we should target future therapies. This would be likely to have
implications for all those with dystonia, and not just those with this
particular genetic abnormality.
Acknowledgements: I would like to thank my
collaborators in this research: Dr Ying-Zu Huang, Dr Kailash Bhatia and
Professor John Rothwell. I would also especially like to thank the patients and
their families who were so kind to participate in this research project.