New method maps severity and stages of hereditary cerebral vascular disease CADASIL

CADASIL

The Leiden University Medical Center (LUMC) is the Dutch center of expertise for the disease CADASIL. CADASIL stands for “cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.” CADASIL is an inherited disease and is caused by a mistake in the NOTCH3 gene. Such an error, also called a mutation, causes a wrong protein to be made in the blood vessels. This wrong protein accumulates in the wall of the small arteries in the brain. The accumulation of the wrong protein damages the blood vessels, resulting in reduced blood flow to the brain and lack of oxygen in the brain. Because of the reduced blood supply, a person may suffer a TIA or stroke. As a result of the damage to the brain, a significant proportion of patients also become demented over time. Other symptoms such as severe headache attacks (migraine with aura) and depression, also occur.

CADASIL patients are born with a mutation in the NOTCH3 gene. They most often inherited this mutation from their father or mother, who also has the disease. The build-up of the wrong protein increases over time, so patients often experience their first symptoms in adulthood, on average around the age of 50. But the onset age and severity of symptoms in CADASIL can vary greatly from one person to another. A good way for physicians and researchers to describe the varying degrees of severity of the disease, has not existed until now.

A broad clinical picture

The LUMC CADASIL research group at the department of clinical genetics discovered in 2016 that mutations in the NOTCH3 gene are common in the general population. 1 in 300 people have a NOTCH3 mutation, while CADASIL is a rare disorder. Thus, they discovered that not everyone with a NOTCH3 mutation develops the serious disease CADASIL and that there are many different mutations in the NOTCH3 gene. “Thanks to our research, we discovered that not all NOTCH3 gene mutations are equally severe and that some patients have a lower disease burden than others," said Dr. Julie Rutten. “We call the broad disease spectrum from mild to severe symptoms 'NOTCH3-small vessel disease.' The most severe form of 'NOTCH3-small vessel disease' we call CADASIL.”

“The vast differences in disease severity in someone with a NOTCH3 mutation prompted us to develop an approach that would allow physicians and researchers to describe disease severity easily and clearly for each person with a NOTCH3 mutation. The approach to describe the disease stage is determined by the severity of abnormalities observed in the brain using an MRI scan and the severity of symptoms in daily life," says Dr. Saskia Lesnik Oberstein.

Global collaboration

Dr. Gido Gravesteijn: “To develop the approach for describing the disease stages, we used data from 195 Dutch patients with CADASIL who participated in our study. Based on these data, we divided the disease into 5 stages that follow the natural course of the disease. The stages range from stage 0 (before symptoms develop) to stage 4 (final stage). Every patient with a NOTCH3 gene mutation can be assigned to one of the disease stages based on the brain MRI scan and a few simple questions. In our study, we show that these stages correspond to other measures of disease severity such as age at the time of the first stroke.”

The new approach for describing disease stages was then tested in nearly 2,000 people with CADASIL from 15 countries. Gravesteijn, “This is the first time such a large study has been done in this field of research with data from CADASIL patients from around the world. Our research shows that this approach is a simple but effective way to describe which stage of disease a patient is at. The system can now be used in scientific research and as a tool in patient care.”

Want to know more?

Want to read more about this research? The scientific paper was published in JAMA Neurology. In the Dutch patient leaflet you can find more information about hereditary disorders of the (small) blood vessels in the brain. Would you like to support the research on CADASIL? Then click here.

The Bontius Foundation contributed to this study. This foundation helps raise additional funding for scientific research at LUMC. They do this in part thanks to donations. Would you like to know more about the Bontius Foundation or see how you can contribute to the scientific research of the LUMC yourself? Then have a look at the website of the Bontius Foundation (all information at this website is provided in Dutch).

The different stages and disease severity of CADASIL.