A Presentation on the state of CADASIL's Medical Research was performed by Professor Elisabeth TOURNIER-LASSERVE and doctor Hugues CHABRIAT, with the contribution of Professor Marie-Germaine BOUSSER and Mrs. Annie KURTZ, psychologist.
During this conference, the following subjects have been discussed:
- Research: it has now reached an international scope. Some scientific collaboration programs are being set up. The French team notably has contacts with English and German researchers. A meeting was held with the latter ones in December 2000. At the European level, the number of persons identified with having CADASIL is significant enough to develop various Research programs, in different fields.
- The CADASIL disease is due to a genetic abnormality, which has been mapped to the 19th chromosome (Notch 3 gene). This genetic mutation is at the origin of the generation of an abnormal protein that alters the vessels' walls. It leads to a lack in blood circulation within the brain white matter. This deficit in blood supply is probably responsible for the damages in the brain white matter. These lesions can be observed on MRI images in the form of white spots.
- MRI examination: A study among 75 patients has determined that the extend of these white spots doesn't account for the gravity of symptoms: bright and numerous lesions do not compulsorily mean that the disease is severe.
Neuro imagery can be used as a tool for measuring the cerebral lesions and will have a crucial role in the future therapeutical tests (in particular, the diffusion MRI technique).
The diffusion imaging technique (diffusion MRI) permits to measure water moves within the brain matter. These movements are hindered by the presence of axons (prolongation of nervous brain cells) and myelin within the white matter. In the case of CADASIL patients, the myelin sheath around the axons and the axons by themselves can be damaged by the lack of blood supply within the white matter. As a consequence of these modifications, water can circulate more freely within the brain. The studies performed by doctor CHABRIAT have shown that measuring the mobility of water within the white matter is a close marker of the disease's gravity. This measurement can permit to determine the loss of axons and myelin within the brain and to track precisely the microscopic modifications in the brain tissue during the course of the disease.
The perfusion MRI technique, using Gadolinium in order to measure the brain blood flood, has permitted to show, within the abnormal white matter, a lack in blood supply and an abnormal reactivity of cerebral vessels, progressing with the disease.
In the CADASIL's case, it's indeed the "pipes' network" which is firstly impaired and is at the origin of the disease: symptoms are mainly the consequence of the diminution in blood circulation, which causes lesions within the white matter, and the deep areas of the brain.
- Skin biopsy: the abnormal protein which is produced as a consequence of the genetic anomaly is also to be met in contact of the skin's small vessels' cells. A skin biopsy enables therefore to diagnose the presence of this protein and the characteristic changes in skin arteries. This exam is nowadays a first step to confirm the diagnostic of the disease.
- The genetic Research is being developed in two directions:
- Disease's diagnostic by molecular genetic testing.
- Research of an adequate treatment.
Genetic Analyze:
This analyze is performed in the cells of a blood sample, in the DNA of the 19th chromosome.
Some people may have the genetic mutation without having developed the disease's clinical manifestations (but they can transmit it to their children). The abnormal gene on chromosome 19 is named Notch3.
Location of the mutation on gene Notch3: according to families, the anomaly is not always situated in the same area of the gene: in 70% of cases, it is located on the 3rd and 4th exons of the gene, but in some other cases, it is located outside these exons. When doing a genetic test: if it concerns a person belonging to a family for which the mutation is identified, the exploration can be aimed at the identified spot. In the case of a new family: the most frequent place is explorated, and if not successful, the rest of the gene is analyzed. Recently, a person was discovered with having the Notch3 abnormality, whereas his parents didn't have it: the mutation in his genetic patrimony appeared therefore during his conception.
Characters of the genetic anomaly: normally, 6 amino acids (cysteins) are linked to each other by couples in the Notch 3 protein. In the case of CADASIL, there is an additional or missing acid. The number of cysteins is therefore uneven and bonds links between the acids are unbalanced. The Notch3 gene on the 19th chromosome exists in the DNA of all cells but it has only manifestations (by producing the Notch 3 protein) in the muscular cells (smooth muscles' cells) of vessels. The Notch3 protein is found in all body's vessels (lever, kidney…) although tissular changes are only observed in the brain.
- Therapeutic tests will focus on finding treatments for improving the brain blood circulation or for reinforcing the defenses of the brain tissue in order to diminish the occurrence of brain lesions.
- Genetic research for a treatment: the protein that is produced by the abnormal gene accumulates in the vessels. Means for avoiding this deposit have to be searched for: it's the aim of the genetic laboratory of Professor Elisabeth Tournier-Lasserve. A tool for tracking the efficiency of treatments could be Magnetic Resonance Imagery, using in particular the diffusion MRI technique (see above)
Transgenic mice have been conceived, they are growing and their evolution is regularly observed. In the United States, some mice have been brought to life, without having the Notch3 gene, in order to have a better idea of the role of this gene. This genome's area is the field of many Research programs and numerous scientific articles have been issued and are still published on the Notch 1, 2 and 4 genes.
- Diagnostic and Ethic matters:
When at-risk symptomatic family members ask for genetic testing, whereas they have no symptom of the illness, it is necessary to go deeper in their request, with outside helps, mainly because there is presently no treatment for this disease. Their request can only be approved after informing them precisely and after a reflection period. The genetic analyze can only be done in a specialized research center with the follow-up of a genetics professional, a psychologist and a neurologist. ♦
Written by Chantal Neau
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