Hallmark symptoms of CADASIL may include: 1) stroke, 2) cognitive impairment, 3) migraine with aura, and 4) psychiatric disturbances. These symptoms are caused by damage to small blood vessels, especially those within the brain. The specific symptoms and severity of the disorder can vary greatly among affected individuals, even among members of the same family.
Despite this variability, most individuals (approximately three out of four patients) experience recurrent stroke or transient ischemic attacks (TIAs), beginning at 40-50 years of age. Strokes cause arm and leg weakness, loss of feeling of one part of the body, speech difficulties or lack of coordination. TIAs result in similar symptoms as strokes but resolve in less than 24 hours. Repeated strokes can cause progression of symptoms listed above and also cause cognitive disturbances, loss of bladder control (urinary incontinence) or loss of balance.
Although strokes are the most common symptom associated with CADASIL, some affected individuals never have strokes. It is not uncommon for CADASIL patients to have evidence of stroke on MRI without any symptoms (silent strokes).
Cognitive impairment eventually develops in many affected individuals on average between the ages of 50-60, although the progression of the disease will vary. Symptoms may include difficulty with concentration, deficits in attention span or memory dysfunction, difficulty making decisions or solving problems, and general loss of interest (apathy). With age, continued cognitive decline may result in dementia, a progressive loss of memory and decline in intellectual abilities that interferes with performing routine tasks of daily life.
Migraine with aura may be a predominant symptom in some affected individuals, occurring in at least half of CADASIL patients. Migraines are severe headaches that often cause excruciating pain and can be disabling. In individuals with CADASIL, these headaches are often preceded by abnormal feelings called “aura.” These additional symptoms usually affect vision and may consist of the sudden appearance of a bright light in the center of the field of vision (scintillating scotoma) or, less frequently, disturbances in all or part of the field of vision. The auras preceding the migraine usually last 20 to 30 minutes but are sometimes longer. Some patients suffer from severe attacks with unusual symptoms such as confusion, fever or coma. Finally, many individuals with CADASIL develop psychiatric abnormalities ranging from personality and behavioral changes to severe depression.
CADASIL is caused by mutations of the NOTCH3 gene. This mutation is inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. Most individuals with CADASIL have a parent with the disorder but CADASIL can be due to a spontaneous genetic mutation that occurs for unknown reasons (de novo mutation). In these cases, there is no previous family history of the disorder. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the gender of the child.
The NOTCH3 gene contains instructions to create a protein that is predominantly expressed in smooth muscle cells in the walls of small arteries. Mutations in the NOTCH3 gene result in abnormal accumulation of this protein at the surface of smooth muscle cells. Ultimately, NOTCH3 mutations lead to progressive damage to the small blood vessels in the brain, premature destruction of smooth muscle cells, reduced blood flow to the brain and tissue loss within the white matter and the deeper parts of the brain, by means of a mechanism not entirely understood.
CADASIL affects males and females in equal numbers. The disorder is found worldwide. The incidence of the disorder is unknown. Researchers believe that the disorder often goes undiagnosed or misdiagnosed making it difficult to determine the true frequency of CADASIL in the general population.
CADASIL is suspected based on symptoms, family history, and brain MRI lesions compatible with the disease. Although MRI can identify characteristic changes in the brains of individuals with CADASIL, such changes are not unique to CADASIL and can occur with other disorders. As such, the CADASIL diagnosis can only be confirmed by testing blood samples for characteristic mutations in the NOTCH3 gene. In some cases, a skin biopsy can be used to diagnosis CADASIL.
At the present, there is no treatment that can cure the disease or prevent its onset. However, it is possible to treat symptoms as they occur to improve the patient’s quality of life. For example, migraines can be treated with traditional analgesics such as paracetamol, ibuprofen, aspirin and NSAIDs. Other medicines commonly used to treat migraine such as vasoconstrictors (especially triptans) are not recommended for patients with CADASIL. Aspirin may be used as preventive treatment after the first stroke has occurred. Drug therapy for depression or other psychiatric abnormalities are sometimes needed. Psychological support is often essential, and genetic counseling may be of benefit for affected individuals and their families.
The drug donepezil has been evaluated for individuals with CADASIL who have cognitive impairment. In this trial, researchers were not able to establish efficacy of this potential therapy.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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