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Disease Profile

CADASIL

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

1-9 / 100 000

US Estimated

Europe Estimated

Age of onset

Adult

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ICD-10

F01.1

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease.

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype.

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; Dementia, hereditary multi-infarct type; Familial vascular leukoencephalopathy;

Categories

Congenital and Genetic Diseases; Eye diseases; Nervous System Diseases

Summary

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy) is an inherited disease of the blood vessels that occurs when the thickening of blood vessel walls blocks the flow of blood to the brain. The disease primarily affects the small blood vessels in the white matter of the brain. CADASIL is characterized by migraine headaches and multiple strokes, which progresses to dementia. Other symptoms include white matter lesions throughout the brain, cognitive deterioration, seizures, vision problems, and psychiatric problems such as severe depression and changes in behavior and personality. Individuals may also be at higher risk of heart attack. Symptoms and disease onset vary widely, with signs typically appearing in the mid-30s. Some individuals may not show signs of the disease until later in life.[1]

CADASIL is caused by a variant (or mutation) in a gene called NOTCH3.  Inheritance is autosomal dominant.[1][2] There is no cure yet. Treatment is only supportive and depends on the symptoms.[1][3] Most people with CADASIL become bed-ridden and develop dementia over time. Life expectancy is also reduced in people with CADASIL due, especially, to lung and heart diseases. Because people who smoke or have high arterial pressure or have other vascular risk factors, control of any vascular risk factors is an important part of CADASIL management.[3][4][5]

Symptoms

The most common signs and symptoms of CADASIL are caused by damage to small blood vessels, especially those within the brain and include: stroke,  cognitive impairment,  migraine with aura, and  psychiatric disturbances. These symptoms are:[6] 

  • Recurrent ischemic strokes (transient ischemic attack/stroke) in adulthood that may lead to severe disability such as an inability to walk and urinary incontinence. The average age at onset for stroke-like episodes is 46 years. Transient ischemic attacks and stroke are reported in approximately 85% of symptomatic individuals 
  • Progressive cognitive decline with dementia developing in about 75% of affected people including significant difficulty with reasoning and memory
  • Migraine, usually with aura, as the first symptom in the third decade of life
  • Psychiatric problems such as mood disturbances (apathy and depression), presenting in about 30% of people with CADASIL 
  • Seizures with epilepsy is present in 10% of affected people and usually presents at middle age
  • Diffuse white matter lesions and subcortical infarcts on neuroimaging.

Less common signs and symptoms may include:[5] 

  • Other psychiatric issues such as gambling, a seizure lasting 30 minutes or longer, or a cluster of shorter seizures for 30 minutes or more with little or no recovery between episodes (recurrent status epilecticus), psychosis, and bipolar disease
  • Slow movements and tremors (parkisionism)
  • Memory loss (amnesia)
  • Dysfunction of one or more peripheral nerves, typically causing numbness or weakness (neuropathy)
  • Muscular weakness due to a muscular disease (myopathy)
  • Confusion, fever and coma (CADASIL coma)
  • Acute vestibular syndrome ( rapid onset (over seconds to hours) of vertigo, nausea/vomiting, and abnormal gait in association with head-motion intolerance and abnormal eye movements, lasting days to weeks)
  • Spinal cord involvement.

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Lacunar stroke
0032325
Leukoencephalopathy
0002352
Multifocal hyperintensity of cerebral white matter on MRI
0040329
30%-79% of people have these symptoms
Apathy
Lack of feeling, emotion, interest
0000741
Migraine with aura
0002077
Mood changes
Moody
0001575
Transient ischemic attack
Mini stroke
0002326
5%-29% of people have these symptoms
Anxiety
Excessive, persistent worry and fear
0000739
Bradyphrenia
Slowness of thought
0031843
Brain atrophy
Brain degeneration
Brain wasting

[ more ]

 0012444
Cerebral hemorrhage
Bleeding in brain
0001342
Confusion
Disorientation
Easily confused
Mental disorientation

[ more ]

 0001289
Dementia
Dementia, progressive
Progressive dementia

[ more ]

 0000726
Depressivity
Depression
0000716
Diabetes mellitus
0000819
Dysarthria
Difficulty articulating speech
0001260
Dysphagia
Poor swallowing
Swallowing difficulties
Swallowing difficulty

[ more ]

 0002015
Encephalopathy
0001298
Gait disturbance
Abnormal gait
Abnormal walk
Impaired gait

[ more ]

 0001288
Hemiplegia
Paralysis on one side of body
0002301
Hypertension
0000822
Impaired visuospatial constructive cognition
0010794
Language impairment
0002463
Loss of consciousness
Passing out
0007185
Memory impairment
Forgetfulness
Memory loss
Memory problems
Poor memory

[ more ]

 0002354
Motor deterioration
Progressive degeneration of movement
0002333
Parkinsonism
0001300
Peripheral neuropathy
0009830
Recurrent subcortical infarcts
0007236
Seizure
0001250
Spasticity
Involuntary muscle stiffness, contraction, or spasm
0001257
Stress urinary incontinence
0010992
Visual loss
Loss of vision
Vision loss

[ more ]

 0000572
1%-4% of people have these symptoms
Aphasia
Difficulty finding words
Losing words
Loss of words

[ more ]

 0002381
Behavioral abnormality
Behavioral changes
Behavioral disorders
Behavioral disturbances
Behavioral problems
Behavioral/psychiatric abnormalities
Behavioural/Psychiatric abnormality
Psychiatric disorders
Psychiatric disturbances

[ more ]

 0000708
Percent of people who have these symptoms is not available through HPO
Abnormal electroretinogram
0000512
Abnormality of the skin
0000951
Abnormality of visual evoked potentials
0000649
Adult onset
Symptoms begin in adulthood
0003581
Autosomal dominant inheritance
0000006
Migraine
Intermittent migraine headaches
Migraine headache
Migraine headaches

[ more ]

 0002076
Nonarteritic anterior ischemic optic neuropathy
0007634
Pseudobulbar paralysis
0007024
Stroke
0001297
Subcortical dementia
0007123
Urinary incontinence
Loss of bladder control
0000020
Varicose veins
0002619
Do you have updated information on this disease? We want to hear from you.

Cause

CADASIL is caused by a variant (mutation) in the NOTCH3 gene. The NOTCH3 gene gives the body instructions to make the Notch3 receptor protein, needed for normal function and survival of vascular smooth muscle cells. Mutations in NOTCH3 cause the body to make an abnormal protein, thus impairing the function and survival of vascular smooth muscle cells and causing these cells to self-destruct. The loss of vascular smooth muscle cells in the brain causes blood vessel damage that leads to the characteristic features of CADASIL.[2]

Diagnosis

Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The following resources provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare professional.

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

    Treatment

    There is no cure or effective treatment for CADASIL yet. While antiplatelet treatment is often used, it is also not proven to be useful and some professionals do not recommend using these because microbleeds in the brain may occur in people with CADASIL, and, for this reason, the safety of antiplatelet drugs in this disease is still unknown.[5][6] 

    Migraine should be treated both symptomatically and prophylactically (with preventative methods), depending on the frequency of symptoms. Some medication that have shown some efficacy in some studies, but have not being proven may include acetazolamide, and sodium valproate for the migraine, and acetylcholinesterase inhibitor for cognitive decline.[5]

    When hypertension, diabetes or hypercholesterolemia (high cholesterol) are also present, they should be treated. Supportive care, including practical help, emotional support, and counseling, is useful for affected people and their families.[5][6]

    Yearly follow up by a neurologist with expertise in CADASIL is recommended from the time of diagnosis, as well as other specialists as needed.[6]

    Smoking, angiography, anticoagulants and thrombolytic therapy are all to be avoided by those with CADASIL as they increase the risk of strokes and/or brain bleeding.[5]

    Management Guidelines

    • Project OrphanAnesthesia is a project whose aim is to create peer-reviewed, readily accessible guidelines for patients with rare diseases and for the anesthesiologists caring for them. The project is a collaborative effort of the German Society of Anesthesiology and Intensive Care, Orphanet, the European Society of Pediatric Anesthesia, anesthetists and rare disease experts with the aim to contribute to patient safety.

      Organizations

      Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

      Organizations Supporting this Disease

        Organizations Providing General Support

          Learn more

          These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

          Where to Start

            In-Depth Information

            • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
            • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
            • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
            • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
            • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
            • PubMed is a searchable database of medical literature and lists journal articles that discuss CADASIL. Click on the link to view a sample search on this topic.

              References

              1. NINDS CADASIL Information Page. National Institute of Neurological Disorders and Stroke (NINDS). 2017; https://www.ninds.nih.gov/disorders/cadasil/CADASIL.htm.
              2. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Genetics Home Reference (GHR). May 2013; https://ghr.nlm.nih.gov/condition/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy.
              3. Behrouz R. CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy). Medscape Reference. 2017; https://emedicine.medscape.com/article/1423170.
              4. CADASIL. Orphanet. 2013; https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=136.
              5. Donato ID, Bianchi S, Stefano N & cols. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) as a model of small vessel disease: update on clinical, diagnostic, and management aspects. BMC Medicine. February 24, 2017; 15:41:https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-017-0778-8#Sec14.
              6. Rutten J & Lesnik Oberstein SAJ. CADASIL. GeneReviews. 2016; https://www.ncbi.nlm.nih.gov/books/NBK1500/.

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