CADASIL is caused by a mutation (a defect) in NOTCH3, a gene located on chromosome 19.  So far, over 150 different mutations causing the disorder have been identified. NOTCH3 plays an important role during foetal development as it regulates the formation of different kinds of tissues, for example smooth muscle in the arteriolar wall. The function of the gene later in life is still unknown. CADASIL symptoms result from changes in the arteriolar wall.  Cells in the smooth muscle layer of the arteriolar walls gradually degenerate, and are replaced by connective tissue. As a consequence, the arteries thicken and become more rigid,  resulting in decreased blood flow and ischemia.   The exchange of nutrients between blood and tissue is also disturbed. CADASIL typically affects small branches of long arteries penetrating deep into the white matter of the brain. The long arteries have few branches and the obstruction of a branch causes restricted blood flow and oxygen deficiency.  As a consequence, small lacunar infarcts (diameter less than 20mm) develop in the white matter and in deep parts of the grey matter (the basal ganglia).  This is because many blood vessels supply the outermost layer of grey brain matter. Infarcts in this area are less likely to deprive the brain of oxygen and less damage results.    

The current term Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) was named in 1993. The disease was previously known as hereditary multi-infarct dementia. In the 1990s, it was shown to be caused by mutations in the NOTCH3 gene.  The disease was possibly first described by the neurologist Van Bogaert in 1955.

Hereditary

This is a hereditary familial disease. Its transmission is autosomal dominant, which means that a person already affected by the disease has a 50 percent chance of passing the abnormal gene on to his or her children.  In a few known exceptional cases, the mutation of the Notch3 gene has occurred randomly ("de novo mutation"), without having been transmitted by one of the parents.

It is important for you to know that there is nothing that you or your family did that caused you to inherit the CADASIL gene. We have no control over the genes we inherit, just as we have no control over the genes we pass on to our own children.

Symptoms

TRANSIENT ISCHEMIC ATTACK (TIA) is a reversible episode of oxygen depletion. The attacks are caused by the occlusion of a small artery leading to oxygen deficiency that can cause  brain damage. The symptoms are similar to stroke, but are relieved within a few hours. The most common symptom of minor stroke is mild paresis or numbness in the arm or leg on one side of the body. The condition usually improves within a few days. 

Patients who have suffered from a MINOR STROKE may experience speech difficulties, temporary episodes of memory loss or other cognitive problems sometimes occur.

STROKE is a term for brain hemorrhage and brain infarction.  A stroke occurs when a blood vessel that carries oxygen and nutrients to the brain is either blocked by a clot or bursts (or ruptures). When that happens, part of the brain cannot get the blood (and oxygen) it needs, so it and brain cells die. After only a few minutes, the cells are irreparably damaged, a condition known as brain infarct. CADASIL is slowly progressive and around half of all individuals with the disease will suffer several TIAs or strokes. The average patient has two or three significant strokes during a lifetime, but the variation is considerable.

In the vast majority of cases, patients affected patients will present with ischemic episodes, cognitive defects, migraine like headaches or psychiatric disturbances. The onset and severity of these symptoms is highly variable, even within families. Cognitive function worsens slowly over time, there is variability in the onset and severity of cognitive impairment. Patients demonstrate dementia in presence of  severe loss of cognitive function. Seizures, although rare, has been observed in affected individuals. Other symptoms may include speech defects. The overall course of CADASIL is variable. Early onset of symptoms does not necessarily mean that the disorder will progress rapidly. People with CADASIL manage their daily lives for a long time despite having suffered several strokes. Concentration problems may arise, and the ability to think clearly declines. Please note: other symptoms may occur which are not listed.

It is important to tell the doctors you have CADASIL so that certain treatments or tests can be avoided. 

  • Avoid Thrombolytics and Anticoagulant Treatments, which aim at unblocking blood vessels as they increase the risk of a cerebral hemorrhage. 

  • Avoid Vasoconstricting Medicines (issued from rye ergot or from Triptan) may increase the risk of cerebral infarction.  

  • Avoid Cerebral conventional angiographies (contrast agent within the arteries in the brain for examination of the cerebral vasculature) should be avoided because of potential neurological complications (migraine with extended and severe aura).

  • Using Anesthesia must be monitored as it could cause abrupt changes in blood pressure.

Finally, you must tell the medical teams about current medications and the corresponding doses.  This is a precaution so as to avoid the combinations of incompatible medication and any risk of overdose.

Long Term Management

At present, there is no treatment either to cure or to prevent the evolution of the disease.  A healthy lifestyle and the treatment of individual symptoms as they appear can improve the quality of life of sufferers.  Smoking is an established risk factor in this disease. Supportive care is needed. 

Research Studies


Further research or studies are crucial to providing a treatment or cure for better quality of life.  Keep abreast of the latest research projects by searching the worldwide web. 
http://clinicaltrials.gov

Further research or studies are crucial to providing a treatment or cure for better quality of life.  Keep abreast of the latest research projects by searching the worldwide web.  Go  http://clinicaltrials.gov/.

Professionals

Partners Telestroke Center, Boston
15 Parkman Street, WACC 729J 
Boston, Massachusetts, 02114 USA
Telephone: 617-724-3999

University of Michigan Health System
Taubman Center Floor, Reception C,
1500 E Medical Center Dr SPC 5322,
Ann Arbor, Michigan, 48109 USA 
Telephone: 734-936-9020

University of Utah Health Care,
Vascular Neurology Clinic, Neurosciences Center
175 North Medical Drive
Salt Lake City, Utah  84132  USA
Telephone: 801-585-7575

Centre de référence des maladies  vasculaires
rares du cerveau et de l’œil  (CERVCO) Service de
Neurologie, Hôpital Lariboisière Paris, France
Telephone: 33 (0)1 49 95 25 91 

References

Butler General Hospital, Rhode Island
CERVO, Paris, France
Mass. General Hospital, Stroke Services
National Board of Health & Welfare, Sweden
National Institute of Health, USA

print the brochure "Understanding CADASIL"

 

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