Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

CADASIL

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About CADASIL

CADASIL is an inherited (or “genetic”) disease of the small blood vessels in the brain that can lead to stroke, other injuries, especially in the deep parts of the brain, and dementia. The term “CADASIL” stands for Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy. Although this technical name is quite cumbersome, it accurately describes the key features of the disease:

  • Cerebral means that the disease has to do with the brain.
  • Autosomal Dominant means the disease is genetic and inherited in a particular way.
  • Arteriopathy means that there is damage to blood vessels.
  • Subcortical means that the disease affects internal parts of the brain.
  • Infarcts and Leukoencephalopathy means strokes and other injury to the brain, particularly within a deep part of the brain called white matter.

Specializing in cognitive disorders, the Memory and Aging Program at Butler Hospital employs a comprehensive team of experts which includes neurologists, neuropsychologists, research and clinical nurses, interns and post-doctoral fellows, and research assistants. Together the team offers evaluation and diagnosis, along with compassionate care and the latest diagnostic and treatment tools to address the impact of CADASIL on patients and families.

Contact Information:

Memory and Aging Program
345 Blackstone Boulevard
1st Floor Weld Building
Providence, RI 02906
P: (401) 455-6402
F: (401) 455-6405
E: memory@butler.org

Symptoms, Diagnosis, and Treatment

Symptoms
Memory and Thinking

In a majority of patients, problems in memory and other thinking skills occur. These symptoms are usually mild at first but may become worse in the later stages of the disease. Some treatments are available which may help with memory symptoms.

Strokes

The most common symptom of CADASIL is a stroke. Strokes are characterized by a number of neurological symptoms including paralysis, loss of sensation, problems walking, slurred speech or other speech problems, etc. These symptoms might improve rapidly (so-called transient ischemic attacks (TIAs)) or lead to more persistent losses (completed stroke). Strokes caused by CADASIL usually occur for the first time between the ages of 30 and 50. However, as with all the other symptoms, there is a great range of variation and individual patients may remain free of symptoms for many years.

Headaches and Migraines

Approximately one-third of patients with CADASIL suffer from migraine-like headaches. The headache attacks often begin between the ages of 20 and 30, but again there is a lot of variability from person to person. Migraines in CADASIL are usually accompanied by an “aura”. Auras are transient neurological symptoms that occur before or during the headache, such as changes in vision, numbness in the hands or feet, and speech problems. A variety of treatments are available for headaches.

Mood Changes
CADASIL patients also frequently suffer from psychological symptoms such as anxiety or depression. It is not uncommon for a patient to respond psychologically to a stroke by becoming depressed, but in many cases this is reversible and treatable. In individual cases psychiatric symptoms such as hallucinations, delusions, anxieties, changes in perception or mood (manic or depressive) may be the first symptoms of this disease. In these patients a specialist should be consulted for therapy.
Seizures

In a small percentage of patients, epileptic seizures occur but can be treated well with medication. In individual cases, episodes of confusion or disturbances in consciousness have been observed and last for a few hours to days and may be associated with fever or epileptic seizures.

Diagnosis
Magnetic Resonance Imaging (MRI)

Magnetic resonance imaging (MRI) is a method for making detailed images of the brain. In CADASIL, the MRI shows changes in the deep regions of the brain, particularly in the white matter. The white matter lies below the outer layers of the brain (the cortex or gray matter) and forms the connections among brain areas so that they work in a unified way. The blood supply to the white matter is provided by small blood vessels which make it especially vulnerable to CADASIL. Other disorders, such as multiple sclerosis, cause white matter changes that look similar on MRI, so CADASIL cannot be diagnosed from MRI alone. However, CADASIL might be suspected if the white matter changes are concentrated in certain brain areas (frontal lobes and/or temporal lobes).

MRI uses magnetic fields and radio waves to make its images and involves no x-rays or other forms of radiation. It is a safe and reliable test method with few health risks. However, it is not safe for people with pacemakers or certain other implanted medical devices or for people who may have small metal fragments or dust in their eyes. It is often helpful to have MRI scans repeated every few years to look for progression of the disease.

Genetic Testing

CADASIL is caused by a mutation (mistake) in the structure of the NOTCh5 gene. It turns out, however, that the mutation can take different forms, and that not all people with CADASIL have the same precise mutation. Within a family, all those affected with the disease will have the same NOTCh5 mutation. Detection of a mutation is considered 100% proof of the existence of the disease. Since the NOTCh5 gene is very large, the search for mutations can be complex. For this reason, if a mutation is known in a family, the laboratory may limit testing in individuals at risk to specific mutations. For initial testing in a family, the laboratory will sequence large segments of the NOTCh5 gene in search of a mutation.

Only a small amount of blood, which can be taken from a vein, is needed for genetic testing. In the United States, there is only one commercial laboratory that offers genetic testing for CADASIL. Your insurance may or may not cover the test. You and/or your physician can find more detailed information about the lab by visiting the Athena Diagnostics site.

A decision to test for a genetic disorder is an important and sometimes difficult one. Learning that you have a genetic disorder can be psychologically distressing and can have an impact on health insurance. Some people with symptoms may want to know – others may not. The decision to have the test can be even more difficult for healthy members of a CADASIL family. You should discuss your concerns with your doctor before having the test. Genetic counselors have special expertise in working with people with genetic disorders and may provide helpful advice and guidance in making your decisions.

Skin Biopsy

CADASIL causes characteristic changes in the blood vessels in almost all regions of the body. These vascular changes may be crucial in making a diagnosis but can only be seen under a powerful electron microscope. Since the blood vessels of the brain cannot be analyzed directly, microscopic examination is performed on the more readily accessible blood vessels in the skin. Under local anesthesia, a small piece of skin is taken from the upper arm or thigh and the resulting wound is closed with one or two sutures. The tissue sample is then sent to a facility that has an electron microscope. Under magnification, the changes typical of CADASIL can be seen in the vascular walls. One of these characteristics is called granular osmiophilic material, or GOM, which is thought to be made of clumps of excess protein. If such changes can be detected, the CADASIL diagnosis can be regarded as confirmed. The key limitation to skin biopsy is that there is a small chance that the disease could be missed if the skin specimen does not happen to contain any diseased blood vessels.  A skin biopsy may be helpful in a specialized laboratory if genetic testing is negative as the diagnosis of CADASIL is still considered likely by a CADASIL specialist.

Treatment
Treatment of CADASIL

So far there is no cure for CADASIL, and there are no medications that reliably slow or prevent progression of the disease. Cures or treatments might become available in the future as more is learned about the mechanisms of CADASIL, but it is impossible to predict when this will happen.

Treating the Symptoms of CADASIL

Although there is no cure for CADASIL itself, many symptoms of the disease can be treated effectively. For example, migraine attacks and epileptic seizures can be treated with conventional migraine and anti-seizure drugs. Other forms of therapy, in addition to medication, should also be considered. Physical therapy, counseling, speech therapy, and occupational therapy often have a positive influence on symptoms of the disease. Depression and memory loss can also be treated with medications and therapy. These treatments should be prescribed by a trained neurologist or psychiatrist.

We still do not know whether CADASIL patients benefit from treatments such as aspirin, that are often used to help prevent stroke.. Your neurologist may recommend that you take a low-dose aspirin or a similar medication daily to try to prevent a stroke. Warfarin (coumadin) and TPA (to dissolve blood clots) should be avoided because they increase the risk of bleeding in the brain. Triptans to treat migraine should also be avoided because they increase the risk of stroke.

Taking Care of Your Health

Currently, there are limited medical interventions for controlling the natural progression of CADASIL. However, patients with the disease should make healthy lifestyle choices that reduce the risk of additional injury to the blood vessels. Such risk factors include high blood pressure, diabetes, high cholesterol, obesity, smoking, lack of physical exercise, and other controllable conditions. This means, for example, that smokers should stop smoking. Blood pressure, blood sugar levels and cholesterol levels should be monitored at regular intervals and treated if necessary. Exercise is also important.

The contraceptive pill is also a risk factor. Therefore, if possible, women should stop using the pill or, if necessary, switch to a preparation having a lower estrogen content (estrogen content less than 50 µg). In addition, subjects should ensure an adequate intake of fluids (2 to 3 liters of fluid per day, not counting coffee, tea or alcoholic beverages). This is especially true in hot weather.

Family Discussions

CADASIL is an autosomal dominant condition. This means that if a parent has it, each of the parent's children has a fifty percent chance of having it as well. For many families, this is an especially difficult aspect of CADASIL to deal with. Parents may worry about their children's health and wonder if they should be tested for CADASIL. Patients who experienced the illness of their own parent or grandparent with CADASIL may find it upsetting to think about how the condition will affect them as they grow older. These are normal concerns. You may want to discuss them with your physician, a genetics counselor, or a therapist.

Our view is that it is appropriate and important, at some point in time, for your children to learn of your disease and the fact that it is hereditary. This information may be particularly important with respect to your adult children’s family planning. There is no “best time” to talk with your children about CADASIL, and the decision will depend on many factors such as their age, maturity, and typical psychological reactions to stressful news. Parents often have a better sense of this than do physicians. As a rule of thumb, we feel that the discussion should preferably occur before the start of family planning.

Genes and Genetics

Genes and genetics

CADASIL is a genetic disease, meaning that is caused by a gene. Genes are chemical codes that our bodies use to build proteins, which are the basic building blocks of life. The gene that causes CADASIL was discovered in 1996.

Genes are formed from groups of smaller molecules called nucleic acids. Humans have about 25,000 genes. The genes themselves are grouped together into larger molecules called DNA, which, in turn, are grouped into even larger molecules called chromosomes. Humans have 46 chromosomes grouped into 23 pairs, so each gene is paired – one member of each pair comes from the father, the other comes from the mother. Each cell in our body has all 23 pairs of chromosomes. Genes are responsible for many properties such as the color of our eyes and our height.

However, in many cases genes also play a role in the development of diseases. Genes can cause diseases when they become “mutated.” That is, there is a mistake in the order of nucleic acids that make up the gene, like a misprint in a book. Since genes are the codes for making proteins, mutated genes can produce abnormal proteins, which, in turn, can cause disease.

What does “autosomal dominant” mean?

An autosomal dominant disease is a particular kind of genetic disease. Some of our 23 chromosome pairs are important for sex characteristics and some are important for other functions. These non-sex chromosomes are called autosomes. So, the word “autosomal” just means the gene that causes CADASIL is not located on a sex chromosome.

As we said above, genes come in pairs located on chromosomes. Genes can be either “dominant” or “recessive”. A gene is dominant when the trait it controls is always expressed; a gene is recessive when the trait it controls is expressed only when paired with a recessive partner. For example, the gene for brown eyes is dominant and the gene for blue eyes is recessive. This means that you will have brown eyes whether you inherit two brown-eyed genes (one from each parent) or one brown-eyed and one blue-eyed gene. To have blue eyes, you must inherit the gene for blue eyes from both parents.

The gene involved in CADASIL is dominant. Patients with CADASIL have one mutated copy of the gene and one normal copy. This means that if one parent has CADASIL then each child has a 50% chance of inheriting the disease. Occasionally, a new mutation in the gene can occur and cause the disease even though both parents are healthy.

People who have the defective gene are called “mutation carriers.” Almost all mutation carriers will develop the symptoms of CADASIL at some point in their lives. Exactly when this will occur in any one person cannot be known for sure, and within one family there may be considerable differences in the disease among those affected. The reasons for this are not yet fully understood.

CADASIL and the NOTCH3 gene

CADASIL is caused by a mutation in the NOTCH3 gene located on chromosome 19. The NOTCH3 gene is responsible for making a protein called Notch3 which is important for the health of muscles in the walls of the small blood vessels in the brain. In CADASIL, the genetic mutation causes problems with the Notch3 protein and also causes deterioration of the muscles in the walls of the vessels.

Current research is aimed at trying to understand exactly how this process causes the disease and is looking for ways to stop or prevent it. However, today we already know a great deal about the indirect consequences of the genetic defect. High-powered microscopes show abnormal accumulations (clumps) of the Notch3 protein in the walls of the small blood vessels of CADASIL patients. In addition, there are a number of other vessel wall changes that result in the brain being inadequately supplied with oxygen and nutrients. Although these vascular wall changes can be detected throughout the entire body, CADASIL seems to damage only the brain.

Genetic Testing

Deciding whether and when to have genetic testing for CADASIL is an important decision for family members at risk for the disease. You should discuss your questions and concerns about genetic testing with a genetics counselor. Click here To find a genetics counselor in your area,

It is generally not advisable for children who are minors to have genetic testing for CADASIL, particularly if they are not showing symptoms of the disease. There are a number of practical and psychological reasons why this is discouraged, the details of which can be discussed with your physician or a genetics counselor. If your child is an adult, you may wish to talk with him or her about your diagnosis and about the fact that CADASIL is inherited. Your child can then discuss this with his or her own treating physician and make a decision about whether or not to have a detailed neurological evaluation including MRI and genetic testing.

FAQs and Resources

  • Resources
  • FAQs - Brain Donation
  • FAQs - CADASIL

Since CADASIL is a rare disease and has only recently become well known, information for patients and family members is still quite sparse. To our knowledge there is no book of advice for lay people. Websites on the internet can be of inconsistent quality, but some of them are helpful for patients and families dealing with the disease. We recommend the following websites:

Groups Involved in CADASIL Research and Patient Advocacy

CureCADASIL Association

United Leukodystrophy Foundation
Click "Types of Leukodystrophy" for information about CADASIL.

CADASIL Foundation (Together We Have Hope Non-Profit Organization)
A patient advocacy group based in the U.S.

CADASIL Information Site
A patient advocacy group based in the U.K

Background Information on CADASIL

Genetics Home Reference for CADASIL
U.S. National Library of Medicine website on CADASIL with many useful links

CADASIL Brochure

The brochure contains some of the information on this subsite. (Note: the page order in this document is designed to print in booklet form, so the pages will appear out of order on the computer screen.)

CADASIL Family Registry

Why is brain donation important to CADASIL research?

Although CADASIL can be detected in other parts of the body, it only causes noticeable effects in the brain. For this reason, it is crucial for researchers to study the brains of patients who have had CADASIL in order to develop better treatments and someday a cure for the disease. However, the brain of a living person can only be studied with imaging techniques like MRI. Researchers therefore rely on donated brains to investigate how CADASIL affects the physical functioning of the brain.

Who can donate?

Any current or past patients or research participants at the Memory & Aging Program are welcome to donate.

What should I consider when deciding to donate?

It is important to discuss your wishes with your family members and to include them in your decision-making process. You should also ask your doctor any questions you have when deciding to enroll or after enrolling. It is always your decision whether or not to donate your brain.

Is brain donation compatible with my religious beliefs?

This is an important question to many potential donors and their families. Most religions allow and even encourage donation of the brain and other organs for research, but you may wish to discuss your decision or questions about brain donation with your religious leader. Click here for a list of statements from various religions on tissue donation, .

What do I do if I decide to enroll?

If you choose to donate your brain, you must notify the Memory and Aging Program as well as your home doctor. You will fill out some forms stating your wishes. Your family members will also receive information on whom to contact at the time of your passing. It is important to make plans in advance because families have other important concerns to deal with at the time of a loved one's passing.

Who can give permission?

In most cases, the law lets a person give consent for autopsy (including brain autopsy) while still alive and also authorizes close relations to do so after death or if a person becomes incompetent.

What happens at the time of donation?

Your family must notify us of your death shortly beforehand or within two hours after. Your body will then be taken to Rhode Island Hospital and the brain will be removed. Afterwards your body will be brought back to the funeral home.

What if I don't live in or near Rhode Island?

If you live out of state, the brain will be removed at your local hospital and delivered to Rhode Island Hospital. It is important to discuss your plans with us and with your hospital ahead of time to make sure that the process will run smoothly.

Can I have an open casket funeral?

Absolutely. The brain is removed in such a way that your face and hair will not be affected. Funeral directors and morticians are familiar with the process and will know what to do to make you look your best.

Will brain donation be helpful to my family?

Your family will receive a written report on your autopsy. The report tells the diagnosis, summarizes other findings, and includes a number to call if there are any questions.

Is there any cost?

The autopsy is free, but certain transportation charges may apply.

Brochure

Click here to download our general brochure on brain donation (not specific to CADASIL).

If I have CADASIL, can I drive a car?

The answer to this question depends on your symptoms. The deciding factor is whether by driving you would endanger yourself and/or other people on the road. Symptoms that can impair driving ability include vision disorders, reduced coordination, paralysis, epileptic seizures, slow reaction times, etc. You should discuss this question with your doctor. You can also take a driving test with a driving simulator offered by occupational therapy..

Is it all right to play sports?

Yes. The best sports for you are endurance sports (e.g., swimming, jogging, hiking). Extreme sports should be avoided. There are no medical objections to taking vacations (including airline flights)

Is CADASIL contagious?

No, you cannot become “infected” with CADASIL. The only possible means of transmission is through genetic inheritance.

My physician has said that I have already had several strokes—but I haven’t noticed anything!

Your doctor’s statement is probably based on MRI or CT images. In CADASIL patients, these tests frequently show small “scars” indicating minor circulation disorders (strokes) that have already occurred. Small strokes, especially early in the disease, can occur without any symptoms.

How good are alternative treatment methods?

So far there have not been any reliable studies of alternative treatments for CADASIL. It does not appear that any such treatments influence the disease process itself. However, we do not actively discourage some alternative treatments such as acupuncture, natural homeopathic preparations, etc. for specific problems (e.g., stubborn headaches) as appropriate in the individual case (for example, relaxation exercises for headaches). However, you should inform your doctor before starting such treatments.

My father/mother who has CADASIL has become severely ill—should I expect the same experience if I have CADASIL?

No, not necessarily. The severity of the disease fluctuates greatly within a family.

Should we have our children tested?

It is generally not advisable for children who are minors to have genetic testing for CADASIL, particularly if they are not showing symptoms of the disease. There are a number of practical and psychological reasons why this is discouraged, the details of which can be discussed with your physician or a genetics counselor. If your child is an adult, you may wish to talk with him or her about your diagnosis and about the fact that CADASIL is inherited. Your child can then discuss this with his or her own treating physician and make a decision about whether or not to have a detailed neurological evaluation including MRI and genetic testing.

Should we talk to our children about the disease and the fact that it is hereditary? If so, when is the correct time to do this?

Our view is that it is appropriate and important at some point in time for your children to learn of your disease and the fact that it is hereditary. This information may be particularly important with respect to your adult children’s family planning. There is no “best time” to talk with your children about CADASIL, and the decision will depend on many factors such as their age, maturity, and typical psychological reactions to stressful news. Parents often have a better sense of this than do physicians. As a rule of thumb, we feel that the discussion should preferably occur before the start of family planning.