What is CADASIL?

This information is to assist with resources and learning about CADASIL

WHAT DOES THE NAME CADASIL MEAN?

Cerebral: relating to the brain or cerebrum.

Autosomal: inheritance means that the gene is located on one of the autosomal (chromosome pairs 1 through 22). This means that males and females are equally affected.

Dominant: only one gene is necessary to have the trait. When a parent has a dominant trait, there is a 50 percent chance that any child they have will also inherit the trait.

Arteriopathy: a disease affecting the small blood vessels.

Subcortical: the portion of the brain immediately below the cerebral cortex.

Infarcts: an area of tissue that undergoes necrosis as a result of obstruction of local blood supply, as by a thrombus or embolus.

Leukoencephalopathy: the destruction of the myelin sheaths that cover nerve fibers. These sheaths, composed of lipoprotein layers, promote the transmission of a neural impulse along an axon

WHAT IS CADASIL?
CADASIL is a hereditary disease affecting small and medium-sized arteries, predominantly in the brain. Progressive blood vessel damage reduces the blood flow and causes oxygen deficiency and subsequent tissue death (infarction). The symptoms of brain infarct commonly referred to stroke like symptoms, migraines with or without aura, speech problems, and cognitive impairment and depression. The disease is caused by a mutation (a defect) in NOTCH3, a gene located on chromosome 19. So far, over 130 different mutations causing the disorder have been identified. NOTCH3 plays an important role during fetal 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. 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 lacunars infarcts (diameter less than 20mm) develop in the white matter and in deep parts of the grey matter (the basal ganglia). Infarctions deep in the brain are often more serious than blood vessel infarctions in the cerebral cortex. This is because many blood vessels supply the outermost layer of grey brain matter with blood. Infarcts in this area are less likely to deprive the brain of oxygen and less damage results. 

WHAT CAUSES CADASIL?
A Mutation in the Notch3 gene. 

WHAT GENES ARE RELATED TO CADASIL? Mutations in the NOTCH3 gene cause CADASIL. The NOTCH3 gene makes a protein called the Notch3 receptor protein, which plays a role in the development, function and maintenance of vascular smooth muscle cells. Mutations in the NOTCH3 gene lead to an abnormal version of the Notch3 protein that builds up in vascular smooth muscle cells. Accumulation of the abnormal Notch3 protein is thought to cause the degeneration of these muscle cells, leading to the loss of function of blood vessels in the brain and heart.

WHAT MUTATIONS ARE EFFECTED WITH CADASIL? Almost all CADASIL mutations alter the number of cysteine residues in the epidermal growth factor (EGF)-like repeats in the extra cellular domain of the protein. More than 100 mutations that cause CADASIL have been reported. Almost all of these mutations change a single amino acid (a building block of proteins) in the Notch3 receptor. Evidence suggests that these mutations play a role in the degeneration of vascular smooth muscle cells. Loss of the muscle cells leads to reduction of blood flow to the brain and heart.

HOW DOES THE WHITE MATTER GET THERE? White matter is already in the brain. CADASIL cannot be only diagnosed as having matter disease. Patients who look normal and the MRI comes back so badly, it is hard to believe that the MRI results are correct for that person. Presence of white matter abnormalities on MRI does not mean that the deep white matter is destroyed. We know that many patients have extensive white matter abnormalities on MRI but no clinical symptoms.  The strokes are what we refer to as lacunars strokes (literally meaning a small lake or
hole in the brain). Because they are small, they tend to be fairly mild and individuals often recover well.

WHAT IS A TIA? is a reversible episode of oxygen depletion. The attacks are caused by blood clots that dissolve before oxygen deficiency has caused permanent brain damage. The symptoms are similar to stroke, but are relieved within a few hours.

WHAT IS A MINOR STROKE? It is 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. People who have suffered from a minor stroke may experience speech difficulties, particularly if they are fatigued. Temporary episodes of memory loss or other cognitive problems sometimes occur.

WHAT IS A STROKE? is a term for brain hemorrhage and brain infarction. If a brain artery is blocked, for instance by a blood clot, the flow of oxygen-saturated blood to a large number of nerve cells is obstructed. After only a few minutes, the cells are irreparably damaged, a condition known as brain infarct.

WHAT ARE THE SYMPTOMS
The symptoms differ from patient to patient. In CADASIL patients can experience migraines with or without aura. Aura can mean signs and symptoms that a headache is coming on. The aura is sometimes severe, involving symptoms such as arm and/or leg weakness, visual disturbances, slurred speech and aphasia. Anxiety, sleeping problems, loss of appetite, fatigue and other signs of depression occur.
A TIA is a reversible episode of oxygen depletion. The attacks are caused by blood clots that dissolve before oxygen deficiency has caused permanent 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. People who have suffered from a minor stroke may experience speech difficulties, particularly if they are fatigued. Temporary episodes of memory loss or other cognitive problems sometimes occur.
Stroke is a term for brain hemorrhage and brain infarction. If a brain artery is blocked, for instance by a blood clot, the flow of oxygen-saturated blood to a large number of nerve cells is obstructed. After only a few minutes, the cells are irreparably damaged, a condition known as brain infarct. CADASIL patients can has two or three strokes during a lifetime, but the variation is considerable. Some people are never affected by stroke, others have as many as 10. Motor function remains relatively in tact for several years.   The ability to take initiatives, make plans and solve problems is slowly weakened. Memory loss usually does not occur until a late stage of the disease. Dementia is a slowly progressive condition. In CADASIL, the dementia is of a frontal subcortical type, meaning that the deep parts of the frontal lobe are particularly affected. Episodic memory (memory of events) remains fairly well preserved in this type of dementia, but the ability to recall facts and concepts is impaired. Symptoms and the degree of disability vary a great deal, even among people in the same family. The reason why some individuals develop a more severe form of the disease is still unknown. 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. 

LONG TERM MANAGEMENT: CADASIL has no known treatment so far or no cure.  CADASIL tends to progress slowly.   However, many aspects of CADASIL can be treated effectively by treating the symptoms with medicines, etc. 

SHOULD A CADASIL PATIENT TAKE ASPIRIN? Yes, There is no scientific evidence that aspirin plays a preventive role in CADASIL, however, based on what is currently known in stroke patients, we usually recommend this treatment if there is non contra-indication and the occurrence of a first ischemic event. The tough decision is deciding what to do when patients have TIA’s and strokes despite treatment with aspirin. Because of the risk of hemorrhage and lack of evidence, blood thinners such as warfarin and clot busters like TPA are not recommended.  

HOW MUCH ASPIRIN SHOULD BE TAKEN? The dose of aspirin most currently evaluated in therapeutic trials is between 75 mg to 325mg.   Asymptomatic CADASIL patient should have a low dosage of aspirin and a patient with a history of TIA’s or stroke could be given a higher dose of aspirin per day. It is recommended to take coated aspirin. 

WHAT MEDICINES SHOULD I AVOID? Thrombolyisis & anticoagulant treatments, Arteriography, Vasoconstricting medicines (issued from rye ergot or from Tripoptan) and products aimed at unblocking blood vessels as they increase the risk of a hemorrhage. 

IT IS RECOMMENDED NOT TO TAKE: Warfarin (coumadin), TPA, Thrombolyisis and   anticoagulant treatments, Arteriography, Vasoconstricting medicines (issued from rye ergot or from Tripoptan) and products aimed at unblocking blood vessels or dissolve blood clots as they increase the risk of a hemorrhage  or have a risk of bleeding in the brain.  Triptans to treat migraines should also be avoided because the increase of the risk of stroke.  The contraceptive pill is also a risk factor.  If possible, women should stop using the pill or, if necessary, switch preparation having lower estrogen content (estrogen content less the 50 mg).  (http://www.memorydisorder.org)

HOW RARE IS CADASIL?  It is underestimated the number of people with CADASIL as differential diagnosis of CADASIL includes multiple sclerosis (MS) [Vahedi et al 1996], Binswanger's disease [Gutierrez-Molina et al 1994], and primary angiitis of the nervous system [Williamson et al 1999].    These three diseases have clinical characteristics and MRI abnormalities that may resemble those of CADASIL.    They are, however, sporadic diseases and specific signs such as hypertension in Binswanger's disease and oligoclonal bands in the spinal fluid of individuals with multiple sclerosis will (mostly) be lacking in individuals with CADASIL [Dichgans et al 1999].        CADASIL does not involve the spinal cord or optic nerves as is common in MS.

TESTING:  SPINAL TAP DOES NOT DIAGNOSE CADASIL.  CADASIL DOES NOT INVOLVE THE SPINAL CORD OR OPTICE NERVICE AS IN M.S.
MRI:  A magnetic resonance scan (MRI) is usually performed and shows characteristic appearances with abnormalities in the deeper parts of the brain or white matter. This is a safe scan that involves no radiation but some people find it rather cclaustrophobic. This scan may be repeated to determine whether the disease is progressing. A MRI Scan cannot diagnose CADASIL alone.  
Blood Tests: Detects mutations in the Notch3 gene.  Only a small amount of blood, which can be taken from a vein, is needed for this genetic test. There are over 100 mutations known.
Skin Biopsy: CADASIL results in characteristic changes in the blood vessels.   A very small skin biopsy is easily performed under local anesthetic. It is important this is processed in a special way allowing it to be looked at under high magnification using an electron microscope. Under this magnification, one can frequently see abnormal collections of material, which we call GOM (granular osmiophilic material) as shown by the arrows in the figures. If these GOM are present we can be almost certain that the individual does have CADASIL. However, the skin biopsy can be normal.

50% HEREDITARY   CADASIL is passed as a dominant mutation and offspring have a 50% chance of developing the disease. All mutation carriers develop some form of the illness (complete penetrance) though the timing and severity and symptoms may vary in family members with the same mutation. Women with CADASIL live longer than men on average. So there are other genetic and environmental factors, yet to be identified, that modulate gene expression. De novo mutations (A de novo mutation is a new mutation) can rarely occur in exceptional isolated cases without a prior family mutation.

IS THERE ANYTHING WE CAN DO TO SLOW DOWN THE PROGRESS OF CADASIL?  No treatment has so far prospectively been studied in this disease. CADASIL tends to progress slowly.

 
OTHER SYMPTOMS CADASIL PATIENTS HAVE REPORTED
Please note - CADASIL does not have a set pattern and causes  any different problems.  These are symptoms which have been reported by patients.   People can have one or more of these symptoms or none.

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Revised: April 11, 2008

CADASIL Together We Have Hope Non Profit Organization
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