New thesis on identification of disease genes in rare neurological conditions
Martin Engvall at the research group Inborn errors of Endocrinology and Metabolism, Department of Molecular Medicine and Surgery, will defend his thesis "Identification of disease genes in rare neurological conditions" on January 22nd, 2021. Main Supervisor is Anna Wedell.
What's the main focus of your thesis?
My dissertation is about how to establish diagnosis in individuals or families who have an unknown neurological disease. Many of these diseases have genetic causes and the work has been possible since the methods for genetic analysis have developed very strongly recently.
Which are the most important results?
The dissertation addresses three different families, a family with a severe muscle disease, a family with gait and balance disorders and a family with two siblings with developmental delays and very specific results in a biochemical investigations, mainly a strong elevation of the amino acid methionine.
The last part of the dissertation is about how we have worked to build a system for rapid genetic diagnosis in seriously ill infants.
In the first part of the dissertation, we managed to determine the cause in two of the families.
The muscle disease was found to be due to a mutation in the gene that encodes myoglobin, a protein found in the muscles and gives them its red color. However, myoglobin has several important functions, including transporting oxygen. We were able to show that those affected in this family did not have any clear problems with transporting oxygen, however, the mutation caused damage to the muscles as a result of increased oxidation.
For the family with gait and balance disorders, we discovered that they also had great difficulty controlling basic body functions such as blood pressure and gastrointestinal function. In this family, we have not yet found the exact cause, but we have found an area on chromosome 16 where we know that the mutation is located, and work is underway to locate the gene that causes the disease.
We managed to find the cause of the two siblings' developmental delay and biochemical abnormalities. We detected a mutation that affected an enzyme that causes the metabolism to be disturbed that results in a block in the degradation of methionine.
Finally, the construction of a system with rapid genetic diagnosis also succeeded. We examined three different infants and were able to diagnose two of them within 24 hours. For the third child, we could not make a diagnosis, but we believe that the child's disease had no genetic cause.
How can this new knowledge contribute to the improvement of people's health?
People with unusual diseases often have problems when they come into contact with healthcare. The healthcare staff, including the doctors, usually know nothing about the disease in question and it is not uncommon for the patient to know more about their condition than the doctors he or she encounters. Having an unusual disease often means that you receive poorer care because the personnel might be unsure whether the patient will be able to undergo surgery or if they will have side effects from various drugs. The consequence is often that care is delayed or absent. Fortunately, however, there are experts around the world who have knowledge of these unusual diseases and who can be consulted.
However, it is worst for individuals who have severe symptoms but where the diagnosis is lacking. These people often suffer from the uncertainty of not knowing what is wrong and for these people there are no experts to consult. It is these people who motivated me to start researching to try to at least give them an explanation.
When one has succeeded in finding the genetic cause of a disease, various forms of prenatal diagnosis also become possible. In the family with muscle disease, children have already been born who are known to be healthy with the help of our new knowledge about the mutation.
In the longer term, targeted treatment may be possible with either drugs that block a gene with a harmful effect or with gene therapy that replaces a damaged gene.
What are your future ambitions?
First of all, I plan to, in collaboration with other researchers, try to find the mutation in the family with gait and balance disorder. At the same time, however, I intend to continue to follow the family with muscle disease and try to contact partners, including the pharmaceutical industry, to investigate whether it is possible to develop any form of genetic modifying treatment. Otherwise, I now intend to partially shift my focus to my research and focus on genetic diseases that cause damage to the optic nerve.