August 28, 2019
Years published: 2009, 2013, 2015, 2019
NORD gratefully acknowledges Karen Orjuela, MD, Vascular Neurologist, Assistant Professor of Neurology, University of Colorado, Michael Wang, MD, PhD, Assistant Professor of Neurology, University of Michigan Health System, and cureCADASIL Association, for assistance in the preparation of this report
CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. The term CADASIL was first coined in 1993. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. CADASIL is an acronym that stands for:
(C)erebral – relating to the brain
(D)ominant – a form of inheritance in which one copy of an abnormal gene is necessary for the development of a disorder
(A)rteriopathy – disease of the arteries (blood vessels that carry blood away from the heart)
(S)ubcortical – relating to specific areas of the brain supplied by deep small blood vessels
(I)nfarcts – tissue loss in the brain caused by lack of blood flow to the brain, which occurs when circulation through the small arteries is severely reduced or interrupted
(L)eukoencephalopathy – lesions in the brain white matter caused by the disease and observed on MRI
Hallmark symptoms of CADASIL may include: 1) recurrent strokes, 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 weakness and/or loss of feeling of one part of the body, speech difficulties, visual loss 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 history of stroke-like 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 slowly progressive 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, abnormal feelings or warning signs called “aura” often precede these headaches. 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 in very rare situations. Finally, many individuals with CADASIL develop psychiatric abnormalities ranging from personality and behavioral changes to severe anxiety and depression.
CADASIL is caused by changes (mutations) in the NOTCH3 gene. 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, and narrowing of the lumen and thickening the vessel wall of the small blood vessels. Microscopic protein accumulations of debris called granular osmiophilic material (GOM) accumulate in blood vessels of CADASIL patients. As a consequence of these changes, there is reduction of blood flow to the brain causing small strokes (or lacunes), small bleeds (microbleeds), dilated spaces surrounded the vessels (dilated perivascular spaces) and tissue loss in the surface of the brain (cortex) as well underneath the cortex (subcortical region).
CADASIL is inherited in an autosomal dominant fashion. 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 rare 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. The risk is the same for males and females.
CADASIL affects males and females in equal numbers. The disorder is found worldwide and affects all races. The disease affects approximately 2 to 5 of 100,000 people. Research suggests 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 DNA testing of blood samples for characteristic mutations in the NOTCH3 gene or by identifying granular osmiophilic material (GOM) inclusions on a skin biopsy.
At the present, there is no treatment that can cure the disease or prevent its onset. Patients should be treated for factors that can further damage blood vessels, such as hypertension, and should be encouraged to abstain from smoking. The efficacy of tPA for treatment of acute strokes in CADASIL patients is uncertain; although no contraindication to tPA has been established for this specific population, careful evaluation of prior microbleeds is suggested. Migraines can be treated with traditional analgesics such as acetaminophen or NSAIDs. Other medicines commonly used to treat acute migraine attack such as vasoconstrictors: especially triptans or ergot derivates, are not recommended for patients with CADASIL. Medications such as anti-hypertensive, anti-convulsants, and anti-depressants may be used for prevention of migraines in CADASIL patients. Drug therapy for depression or other psychiatric abnormalities are sometimes needed. Psychological support is often essential, and genetic counseling is recommended 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.
L-Arginine was proposed as potential treatment after some benefit was seen on the cerebral circulation in subjects with CADASIL; limitations of the study preclude translating these results to the clinical practice with great accuracy.
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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Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
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