CADASIL

CADASIL is caused by a mutation in the NOTCH3 gene on chromosome 19. This genetic mutation is found worldwide, and it affects people of all sexes, races, and ethnicities. The disorder is hereditary, and those who have a family history of CADASIL are at risk, but it can also result from a spontaneous genetic mutation. The cause of spontaneous mutation is currently unknown. 

While it is possible for anyone to have the NOTCH3 gene mutation, this remains a rare occurrence. Studies have come up with varying estimates for the prevalence of CADASIL, but the ratio is thought to be between 2 and 4 people out of 100,000. However, the actual prevalence is likely higher, due to the disorder being misdiagnosed or undetected.  

The NOTCH3 gene mutation causes misfolding of a protein called granular osmiophilic material (GOM), which deposits into the walls of small and medium blood vessels. This gradually causes those blood vessels to leak or collapse. While the accumulation of misfolded GOM proteins can occur throughout the body, it has the most significant effect on blood vessels in the brain, ultimately leading to neurodegeneration. 

People who have CADASIL have varying symptoms, but they typically appear between the ages of 20 and 40. The most common symptoms include the following: 

• Migraine headaches with aura
• Transient Ischemic Attacks (TIA)
• Multiple strokes progressing toward dementia
• Confusion
• Acute encephalopathy, leading to coma
• Declining memory and cognitive skills
• Bipolar disorder
• Depression, apathy, and other mood disturbances

There are also other symptoms that are less common:

• Seizures
• Tremors and slow movements (resembling symptoms of Parkinson’s disease)
• Physical weakness or numbness
• Vision problems
• Rapid onset of vertigo, nausea, vomiting

A person with CADASIL might not display all of these symptoms, which can vary in severity. They can also appear at different stages throughout a person’s lifetime. Strokes typically occur between 45 and 59 years of age. CADASIL symptoms tend to progress slowly, but by the age of 65, most people who have this disease will have dementia or vascular cognitive impairment. Immediately before death, 80% of patients are completely dependent on others. The average life expectancy is 61 years, but women tend to live longer than men. 

Doctors will diagnose CADASIL based on an individual’s symptoms, family history, and certain changes in the brain that show up in an MRI (magnetic resonance imaging) scan: 

• Changes in the brain’s white matter
• Subcortical (occurring below the cortex) strokes
• Brain atrophy
• Cerebral microbleeds (small areas of bleeding in cerebrum)

These changes can occur with other disorders, however, so a CADASIL diagnosis needs to be confirmed with an additional test: 

• Genetic testing. NOTCH3 gene mutations can be detected by analyzing DNA obtained through a blood sample.
• Skin biopsy. CADASIL causes changes in the blood vessels in other parts of the body besides the brain, including the skin.

CADASIL can be overlooked or misdiagnosed because it shares symptoms with several other disorders that also occur independently: 

• Mood disturbances – These are also very common and can occur for many possible reasons.
• Migraine – This is a common condition among the general public, which can occur without a genetic component.
• Limb tremors – These movements can be mistaken for symptoms of Parkinson’s disease or ALS.
• Cognitive decline – This can be associated with aging or head trauma.
• White matter disease – This can also occur with aging.
• Small strokes – These can look like lesions in multiple sclerosis.
• Microbleeds – These can easily go unnoticed.

Currently, there is no cure for CADASIL, nor are there any effective treatments. That said, people who have CADASIL should follow their doctors’ advice to prevent strokes. It is important to maintain healthy blood pressure, cholesterol, and glucose levels. In some cases, doctors might recommend antiplatelet therapy, which involves medications that stop blood cells from forming clots. 

Patients who experience migraine episodes associated with CADASIL can address migraine concerns with prescription medication or by knowing and avoiding migraine triggers, and those who experience depression can and should pursue treatment for that condition. 

Supportive care from others is also important for those living with CADASIL. This includes emotional support, counselling, and help with everyday activities. 

Some research on CADASIL focuses on developing a potential treatment using NOTCH3 agonist antibodies. These are specific proteins that activate or enhance the function of receptors on the surfaces of cells, in this case the mutated NOTCH3 receptors. This approach has already shown some promising results, preventing the loss of cells called mural cells.

The National Institute of Neurological Disorders and Stroke (NINDS) has funded other studies to explore small vessel dysfunction in CADASIL to determine how changes to blood vessels relate to tissue oxygenation, which is the process by which oxygen is supplied to the body’s cells. The institute has also funded research to study the role of the blood–brain barrier (BBB) in small vessel disease (SVD) among people with CADASIL, using MRI technology.

At Mt. Sinai Hospital in New York City, 2016 Next Generation Research Grant recipient Dr. Fanny Elahi has been working to identify molecular biomarkers to detect CADASIL in blood.

Reading scientific studies

New to research? Read our guide, How to Read a Research Study, to learn some tips for reading scientific publications and interpreting results.