Prof. Thomas Klockgether, head of the Department of Neurology, of the University Hospital Bonn describes how research progress is providing useful insight into the functioning of a rare hereditary disease: Ataxia by REBECCA PARSONS (Jun. '10)
With a prevalence of about 1 in 10.000, Ataxia is considered a rare hereditary disease that attacks the central nervous system. As a result, it is not at the top of the list in terms of research topics for pharmaceutical companies. A team of researchers at the University Hospital in Bonn has been working for three years on a project funded by the European Commission - EUROSCA - about this incurable disease. In the first effort of its kind, EUROSCA has networked a total of 22 expert groups at universities and research institutes in nine countries. Their collective goal is to research the hereditary disease in all its details. Over the course of three years, a study with over 300 patients has been pivotal in setting international standards for clinical diagnosis. The patients’ coordination and specific motion sequences have been examined together with the movements of the eyes; depending on the reactions of the patient, doctors are able to determine exactly which stage of development the Ataxia is in.
Can you give us an idea of the dimension of this rare disease?
In every 100.000 people, about 20 may have Ataxia. This means that in a city like Bonn, with a population of about 300.000 people, 60 patients will have Ataxia. The form of Ataxia we are interested in, dominant hereditary Ataxia, is even rarer. It makes up one seventh of the Ataxia patients in general, meaning about 3 out of 100.000.
How many forms of Ataxia are known today?
A total of 30 forms of Ataxia are known today. In one of these forms the nerve cells of the cerebellum are destroyed. This results in increasing coordination problems. Thanks to the EUROSCA projects, it has been possible to build up the world's largest database on this disease. The data collected from over 3.300 patients from all over Europe is available for clinical studies and analyses. The most common form of dominant hereditary Ataxia is SCA3.
How much do heredity factors affect the development of the disease?
Dominant heredity implies that the chance of developing the disease lies around 50%, provided one of the parents was affected. In most cases of dominant hereditary spinocerebellar Ataxiae the disease begins between 30 and 40 years of age. The first symptoms include slight almost imperceptible coordination problems, like for example an unsteady walk. Over the years coordination deteriorates. After about 15 years the patient usually requires walking aids, sometimes wheelchairs. In advanced stages, patients usually become bedridden.
How does Ataxia develop from a genetic point of view?
The disease is triggered by a defective gene in the patient. In the University Hospital in Bonn genetic analyses of patients and control persons have been able to show exactly which gene is mutated, and thus functioning differently from those of healthy patients. This process is complicated by the fact existence of many different forms of Ataxia. The forms display similar symptoms, yet each one is caused by a different gene. Thus, to this day only a handful of genetic tests are available. In future we hope to have many more tests that will be able to identify further forms of Ataxia. The one thing that all forms of Ataxia have in common is that the mutated gene produces a protein that penetrates the cerebellum and destroys the nerve cells. In this nerve cell the destructive protein is highlighted. It forms lumps and then kills the cell. The nerve cells in the brain die, and thus become visible through problems of coordination and movement in the patient. The fatal characteristic of this disease is the fact that the nerve cells are not able to regenerate like other cells, for example muscle cells. In other words, the nerve cells need to survive our whole lifetime.
Is there any treatment for this disease?
There is no cure at the moment. Regular magnetic resonance imaging scans are performed on the patients’ brain. In this way the neurologists are able to determine if the cerebellum has experienced changes or not. Some medications are already being tested on animals. Through the EUROSCA research project we have been able to discover substances that are able to prevent the destructive protein from entering into the cell nucleus and destroying the cell. Some of these substances are naturally contained in celery or parsley. We hope that we will one day be able to conduct clinical trials with these substances, thus greatly extending the life expectancy of SCA3 patients.
Is there a possibility to at least postpone the development of the disease?
We have noticed that people with healthy lifestyles, regular exercise routines and who deal with the situation pro-actively will develop symptoms later and with less intensity than those that do not.
In order to discover the way the disease functions and to develop possible treatments, researchers at the University Clinic Tübingen, led by Prof. Olaf Ries, an international leader in the Ataxia research community, have bred mice with the mutated gene. This enables the study of the disease and its trajectory in comparison to healthy animals. Among other aspects, the researchers are trying to discover why the gene affects and kills only certain nerve cells in the brain, despite it being present in other organs too. Their research with mice has already provided useful insight into the functioning of the disease. In this way it was discovered that the mutated gene is also active in other cells. Yet it is only in the cerebellum that it causes serious damage. This is where researchers need to develop medication that is able to penetrate the nerve cells of the cerebellum and prevent the damage.
(9 June 2010)
Rebecca Parsons