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CADASIL

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Copyright 2009, 2013

NORD is very grateful to Dr. Dominique Herve, Reference Centre for Rare Vascular Diseases of the Central Nervous System and the Retina (CERVCO), Department of Neurology, Lariboisiere Hospital, APHP, Paris, France, for assistance in the preparation of this report.

Synonyms of CADASIL

Disorder Subdivisions

General Discussion

CADASIL is a rare genetic disorder affecting the small blood vessels in the brain.
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 (A)utosomal (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 arteries

(I)nfarcts - tissue loss in the brain caused by lack of oxygen to the brain, which occurs when blood flow in the small arteries is severly reduced or interupted

(L)eukoencephalopathy - refers to lesions in the brain white mattter caused by the disease and well observed on MRI

Symptoms

The symptoms of CADASIL 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 (approximatively three out of four patients) experience recurrent brain infarcts or transient ischemic attacks (TIAs). They usually occur between 40-50 years of age. They can be detected on MRI without any symptom (silent infarcts) or cause arm and leg weakness, loss of feeling of one part of the body, speech difficulties or lack of coordination in movements. These difficulties may regress in less than 24 hours but they may also become permanent as the disease develops. Repeated brain infacrts can cause progressive symptoms including cognitive disturbances, loss of bladder control (urinary incontinence) and loss of balance. As the disorder progresses, affected individuals may lose the ability to walk unassisted or become bedridden.

Although strokes are the most common symptom associated with CADASIL, some affected individuals never have a stroke.

Cognitive impairment eventually develops in many affected individuals, although the progression of the disease will vary. They do not significant until the age of 50 to 60. They may include difficulties with concentration, deficits in attention span or memory dyfunction, difficulties making decisions or solving problems and general loss of interest (apathy). With age, continued cognitive decline may result in dementia. Dementia is defined as the progressive loss of memory and decline in intellectual abilities that interferes with performing routine tasks of daily life.

Migraine with aura may be the predominant symptom in some affected individuals. Migraines are severe headaches that often cause excruciating pain and can be disabling. In individuals with CADASIL, these headaches are often preceded by abnormal feelings called "aura". These additional symptoms usually affect vision and may consist of the sudden appearance of a bright light in the centre of the field of vision (scintillating scotoma) or, less frequently, blurred vision in one half of the field of vision (hemianopsia). Other signs can occur: numbness, tingling or weakness on one side of the bosy, or speech difficulties. The signs preceding the migraine, the "aura", usually last 20 to 30 minutes but sometimes have an extended delay. A few patients suffer from severe attacks with unusual symptoms such as confusion, fever or coma. Although some individuals with CADASIL develop migraines with or without aura, other individuals never develop migraines.

Some individuals with CADASIL develop psychiatric abnormalities ranging from personality and behavioral changes to severe depression.

Causes

CADASIL is caused by mutations of the NOTCH3 gene. This mutation is inherited as an autosomal dominant trait. 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 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 regardless of the gender of the child.

NOTCH3 gene is located on the short arm (p) of chromosome 19 (19p). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y.

NOTCH3 gene contains instructions to create (encode) a protein that is predominantly expressed in smooth muscle cells on the walls of small arteries. Mutations to 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, reduced blood flow to the brain and tissue loss within the white matter and the deeper parts of the brain, by means of a mechanism not entirely understood.

Affected Populations

CADASIL affects males and females in equal numbers. The disorder is found worldwide. The incidence of the disorder is unknown. Researchers believe that the disorder often goes undiagnosed or misdiagnosed making it difficult to determine the true frequency of CADASIL in the general population.

Related Disorders

Symptoms of the following disorders can be similar to those of CADASIL. Comparisons may be useful for a differential diagnosis.

Cerebral small vessel disease (SVD) related to age and hypertension is a progressive and frequent neurological disorder characterized by an involvement of blood vessels supplying the white-matter and deep structures of the brain. Less frequently and later than in CADASIL, patients can experience progressive memory loss, deterioration of intellectual abilities and loss of balance with a progressive worsening of these symptoms.
A variety of rare genetic disorders, of known or yet unknown causes, may have symptoms similar to those found in CADASIL. These disorders include cerebral autosomal recessive arteriopathy with subcortical infarcts and leukodystrophy (CARASIL), mithochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), Fabry disease, and some of the leukodystrophies, which are a rare group of progressive metabolic disorders that affect the brain, spinal cord and often the peripheral nerves. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)

Multiple sclerosis is a chronic neuroimmunologic (both the nervous system and the immunological system are involved) disorder of the central nervous system involving the brain, spinal chord and optic nerves. By means of a mechanism not clearly understood, the protective fatty, insulating substance called myelin sheath that covers the nerve is destroyed. The inflammatory attacks that produce the characteristic scarring (plaques or patches) of the myelin sheath occur randomly at multiple sites and vary in intensity. The course of the disease may advance, relapse, remit, or stabilize. The randomness of the location of plaques or patches causes a wide range of neurological symptoms, which may vary from person to person. (For more information on this disorder, choose "multiple sclerosis" as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
A diagnosis of CADASIL is most often suspected upon identification of symptoms and MRI lesions compatible with the disease. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues including the brain. An MRI can identify characteristic changes in the brains of individuals with CADASIL. However, such changes are not unique to CADASIL and can occur with other disorders.
The CADASIL diagnosis is confirmed by taking blood sample and looking for characteristic mutations in the Notch 3 gene.

Treatment
At the present, there is no treatment that can cure the disease or prevent its onset. However, it is possible to treat symptoms as they occur, to improve the patient’s quality of life. For example, migraines can be treated with traditional analgesics such as paracetamol, ibuprofen, aspirin and NSAIDs. Other medicines commonly used to treat migraine such as vasoconstrictors (especially triptans) are not recommended for patients with CADASIL. Aspirin may be used as preventive treatment after the first stroke has occurred. Drug therapy for depression or other psychiatric abnormalities are sometimes needed. Psychological support is often essential and genetic counseling may be of benefit for affected individuals and their families.

Investigational Therapies

The drug donepezil has been evaluated for individuals with CADASIL who have cognitive impairment. In this trial, researchers were not able to establish an efficacy of this potential therapy. 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:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

CADASIL Resources

Organizations:

References

TEXTBOOKS
Chabriat H, Joutel A, Vahedi K, Tournier-Lasserve E, Bousser MG. CADASIL: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy. In: Mohr JP, Choi DW, Grotta JC, eds. Stroke: pathophysiology, diagnosis, and management. Churchill Livingstone. 2004:687-692.

Salloway S, Desbiens S. The CADASIL syndrome and other genetic causes of stroke and vascular dementia. In: Paul RH, Cohen R, Ott BR, Sal S, eds. Vascular dementia: cerebrovascular mechanisms and clinical management. Totowa, New Jersey. Humana Press. 2004:87-95.

Rimoin D, Connor JM, Pyeritz RP, Korf BR. Eds. Emory and Rimoin’s Principles and Practice of Medical Genetics, 4th ed. Churchill Livingstone. New York, NY. 2002:3210-3212.

JOURNAL ARTICLES
Hervé D, Chabriat H. CADASIL. J Geriatr Psychiatry Neurol. 2010
Dec;23(4):269-76. doi: 10.1177/0891988710383570. Review. PubMed PMID: 21045164.

Reyes S, Viswanathan A, Godin O, et al. Apathy: a major symptom in CADASIL. 2009;10:905-910.

Dichgans M, Markus HS, Salloway S, et al. Donepezil in patients with subcortical vascular cognitive impairment: a randomized double-blind trial in CADASIL. Lancet Neurol. 2008;7:310-318.

Valenti R, Poggesi A, Pescini F, Inzitari D, Pantoni L. Psychiatric disturbances in CADASIL: a brief review. Acta Neurol Scand. 2008;118:291-295.

Benisty S, Hernandez K, Viswanathan A, et al. Diagnostic criteria of vascular dementia in CADASIL. Stroke. 2008;39:838-844.

Schon F, Martin RJ, Prevett M, et al. "CADASIL coma": an underdiagnosed acute encephalopathy. J Neurol Neurosurg Psychiatry. 2003;74:249-252.

Lesnik Oberstein SA, Jukema JW, Van Duinen SG, et al. Myocardial infarction in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Medicine. 2003;82:251-256.

Joutel A, Favrole P, Labauge P, et al. Skin biopsy immunostaining with Notch3 monoclonal antibody for CADASIL diagnosis. Lancet. 2001;358:2049-2051.

Joutel A, Vahedi K, Corpechot C, et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997;350:1511-1515.

INTERNET
Lesnik Oberstein SAJ, Boon EMJ, Dichgans M. Updated:June 28, 2012. CADASIL. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2003. Available at http://www.genetests.org Accessed:February 6, 2013.

National Institute of Neurological Disorders and Stoke. CADASIL Information Page.March 2, 2012. Available at: http://www.ninds.nih.gov/disorders/cadasil/CADASIL.htm Accessed :February 6, 2013.

Labauge P. CADASIL syndrome. Orphanet encyclopedia, September 2004. Available at: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=136 Accessed:February 6, 2013.

Report last updated: 2013/02/07 00:00:00 GMT+0