Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, usually called CADASIL, is an inherited condition that causes stroke and other impairments. This condition affects blood flow in small blood vessels, particularly cerebral vessels within the brain. The muscle cells surrounding these blood vessels (vascular smooth muscle cells) are abnormal and gradually die. In the brain, the resulting blood vessel damage (arteriopathy) can cause migraines, often with visual sensations or auras, or recurrent seizures (epilepsy).
Damaged blood vessels reduce blood flow and can cause areas of tissue death (infarcts) throughout the body. An infarct in the brain can lead to a stroke. In individuals with CADASIL, a stroke can occur at any time from childhood to late adulthood, but typically happens during mid-adulthood. People with CADASIL often have more than one stroke in their lifetime. Recurrent strokes can damage the brain over time. Strokes that occur in the subcortical region of the brain, which is involved in reasoning and memory, can cause progressive loss of intellectual function (dementia) and changes in mood and personality.
Many people with CADASIL also develop leukoencephalopathy, which is a change in a type of brain tissue called white matter that can be seen with magnetic resonance imaging (MRI).
The age at which the signs and symptoms of CADASIL first begin varies greatly among affected individuals, as does the severity of these features.
CADASIL is not associated with the common risk factors for stroke and heart attack, such as high blood pressure and high cholesterol, although some affected individuals might also have these health problems.
A decline in thinking ability (cognitive deficit) is the second most common feature and occurs in over half of affected people. This may begin as early as 35 years of age. CADASIL typically causes a slow decline in thought processes, and approximately 75% of affected people eventually develop dementia (including significant difficulty with reasoning and memory). Thirty percent of people with CADASIL also experience psychiatric issues, varying from personality changes to severe depression.
Migraines with aura occur in about 35% of people with CADASIL, with the first attack occurring at an average age of 26 years. Epilepsy is present in 10% of affected people and usually presents at middle age.
- Abnormality of temperature regulation
- Abnormality of the retinal vasculature
- Amaurosis fugax
- Behavioral abnormality
- Developmental regression
- Neurological speech impairment
- Reduced consciousness/confusion
- Recurrent strokes
- Deterioration in mental state
- Stepwise progression of symptoms
- Mood disorders
This condition is inherited in an autosomal dominant pattern, which means one copy of the altered NOTCH3 gene in each cell is sufficient to cause the disorder. In most cases, an affected person inherits the mutation from one affected parent. A few rare cases may result from new mutations in the NOTCH3 gene. These cases occur in people with no history of the disorder in their family.
Mutations in the NOTCH3 gene cause CADASIL. The NOTCH3 gene provides instructions for producing the Notch3 receptor protein, which is important for the normal function and survival of vascular smooth muscle cells. When certain molecules attach (bind) to Notch3 receptors, the receptors send signals to the nucleus of the cell. These signals then turn on (activate) particular genes within vascular smooth muscle cells.
NOTCH3 gene mutations lead to the production of an abnormal Notch3 receptor protein that impairs the function and survival of vascular smooth muscle cells. Disruption of Notch3 functioning can lead to the self-destruction (apoptosis) of these cells. In the brain, the loss of vascular smooth muscle cells results in blood vessel damage that can cause the signs and symptoms of CADASIL.
The pathologic hallmark of CADASIL is electron-dense granules in the media of arterioles that can often be identified by electron microscopic (EM) evaluation of skin biopsies. NOTCH3 is the only gene known to be associated with CADASIL. More than 90% of individuals have mutations in the NOTCH3 gene. Molecular genetic testing is available on a clinical basis.
Symptoms usually progress slowly. By age 65, the majority of persons with CADASIL have severe cognitive problems and dementia. Some people lose the ability to walk and most become completely dependent due to multiple strokes.
There is currently no treatment for CADASIL that is proven to be effective. While antiplatelet treatment is often used, it is also not proven to be useful. Migraine should be treated both symptomatically and prophylactically (with preventative methods), depending on the frequency of symptoms. When hypertension, diabetes or hypercholesterolemia (high cholesterol) are also present, they should be treated. Supportive care, including practical help, emotional support, and counseling, is useful for affected people and their families. Smoking increases the risk of stroke, so affected people who smoke should quit.
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