CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most common form of hereditary stroke disorder, and is thought to be caused by mutations of the Notch 3 gene on chromosome 19. The most common clinical manifestations are migraine headaches and transient ischemic attacks or strokes, which usually occur between 40 and 50 years of age, although MRI is able to detect signs of the disease years prior to clinical manifestation of disease.



Cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by recurrent subcortical ischemic strokes and dementia caused by mutations in the Notch3 gene. In Drosophila melanogaster, Notch signaling has a pleiotropic effect, affecting most tissues of the organism during development. Biochemical, histochemical, molecular, and genetic analyses were performed on muscle biopsy specimens and fibroblasts obtained from patients of a Spanish family with CADASIL. Additional biochemical and molecular analyses of the N(55e11) mutant of D. melanogaster were performed.

An abnormality in the muscle cells surrounding these blood vessels (vascular smooth muscle cells) gradually destroys these cells. The resulting blood vessel damage can cause migraines and other impairments of normal brain function. Later in life, the damaged blood vessels can cause reduced blood flow to various tissues in the body (ischemia). Although the severity of symptoms varies among those affected, people with CADASIL typically have more than one stroke in their lifetime. Recurrent strokes can progressively damage the brain, causing loss of intellectual function (dementia). 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.

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional.

The disease primarily affects small blood vessels in the white matter of the brain. A mutation in the Notch3 gene alters the muscular walls in these small arteries. CADASIL is characterized by migraine headaches and multiple strokes progressing to dementia. Other symptoms include white matter lesions throughout the brain, cognitive deterioration, seizures, vision problems, and psychiatric problems such as severe depression and changes in behavior and personality. Individuals may also be at higher risk of heart attack. Symptoms and disease onset vary widely, with signs typically appearing in the mid-30s. Some individuals may not show signs of the disease until later in life.

There are several different methods of diagnosing CADASIL. One of the most common methods is to take a skin biopsy, and examine it with a technique called electron microscopy, to look for the characteristic accumulations of granular material (called granular osmiophilic material, or GOM) commonly seen in CADASIL. This can positively diagnose CADASIL, though a negative result on this test does not necessarily mean that the disease is not present. Additionally, a skin biopsy can be tested for the accumulation of Notch3, using a molecule that specifically detects this protein.