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Genes and genetics

CADASIL is a genetic disease, meaning that is caused by a gene. Genes are chemical codes that our bodies use to build proteins, which are the basic building blocks of life. The gene that causes CADASIL was discovered in 1996.

Genes are formed from groups of smaller molecules called nucleic acids. Humans have about 25,000 genes. The genes themselves are grouped together into larger molecules called DNA, which, in turn, are grouped into even larger molecules called chromosomes. Humans have 46 chromosomes grouped into 23 pairs, so each gene is paired – one member of each pair comes from the father, the other comes from the mother. Each cell in our body has all 23 pairs of chromosomes. Genes are responsible for many properties such as the color of our eyes and our height.

However, in many cases genes also play a role in the development of diseases. Genes can cause diseases when they become “mutated.” That is, there is a mistake in the order of nucleic acids that make up the gene, like a misprint in a book. Since genes are the codes for making proteins, mutated genes can produce abnormal proteins, which, in turn, can cause disease.

What does “autosomal dominant” mean?

An autosomal dominant disease is a particular kind of genetic disease. Some of our 23 chromosome pairs are important for sex characteristics and some are important for other functions. These non-sex chromosomes are called autosomes. So, the word “autosomal” just means the gene that causes CADASIL is not located on a sex chromosome.

As we said above, genes come in pairs located on chromosomes. Genes can be either “dominant” or “recessive”. A gene is dominant when the trait it controls is always expressed; a gene is recessive when the trait it controls is expressed only when paired with a recessive partner. For example, the gene for brown eyes is dominant and the gene for blue eyes is recessive. This means that you will have brown eyes whether you inherit two brown-eyed genes (one from each parent) or one brown-eyed and one blue-eyed gene. To have blue eyes, you must inherit the gene for blue eyes from both parents.

The gene involved in CADASIL is dominant. Patients with CADASIL have one mutated copy of the gene and one normal copy. This means that if one parent has CADASIL then each child has a 50% chance of inheriting the disease. Occasionally, a new mutation in the gene can occur and cause the disease even though both parents are healthy.

People who have the defective gene are called “mutation carriers.” Almost all mutation carriers will develop the symptoms of CADASIL at some point in their lives. Exactly when this will occur in any one person cannot be known for sure, and within one family there may be considerable differences in the disease among those affected. The reasons for this are not yet fully understood.

CADASIL and the NOTCH3 gene

CADASIL is caused by a mutation in the NOTCH3 gene located on chromosome 19. The NOTCH3 gene is responsible for making a protein called Notch3 which is important for the health of muscles in the walls of the small blood vessels in the brain. In CADASIL, the genetic mutation causes problems with the Notch3 protein and also causes deterioration of the muscles in the walls of the vessels.

Current research is aimed at trying to understand exactly how this process causes the disease and is looking for ways to stop or prevent it. However, today we already know a great deal about the indirect consequences of the genetic defect. High-powered microscopes show abnormal accumulations (clumps) of the Notch3 protein in the walls of the small blood vessels of CADASIL patients. In addition, there are a number of other vessel wall changes that result in the brain being inadequately supplied with oxygen and nutrients. Although these vascular wall changes can be detected throughout the entire body, CADASIL seems to damage only the brain.