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Synonym: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

, MD and , MD, PhD.

Author Information
, MD
Department of Human Genetics
Leiden University Medical Center
Leiden, Netherlands
, MD, PhD
Department of Clinical Genetics
Leiden University Medical Center
Leiden, Netherlands

Initial Posting: ; Last Update: February 26, 2015.


Clinical characteristics.

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is characterized by mid-adult onset of recurrent ischemic stroke, cognitive decline progressing to dementia, a history of migraine with aura, mood disturbance, apathy, and diffuse white matter lesions and subcortical infarcts on neuroimaging.


More than 95% of individuals with CADASIL have pathogenic variants in NOTCH3, the only gene in which mutation is known to cause CADASIL. The pathologic hallmark of CADASIL is electron-dense granules in the media of arterioles, and increased NOTCH3 staining of the arterial wall, which can be evaluated in a skin biopsy.


Treatment of manifestations: There is no treatment of proven efficacy for CADASIL. Antiplatelet treatment is frequently used, but not proven effective in CADASIL. Migraine should be treated both symptomatically and prophylactically, depending on the frequency of manifestations. Co-occurrence of hypertension, diabetes or hypercholesterolemia should be treated. Supportive care (practical help, emotional support, and counseling) is appropriate for affected individuals and their families.

Agents to avoid: Angiography and anticoagulants may provoke cerebrovascular accidents; smoking increases the risk of stroke. Thrombolytic therapy (intravenous thrombolysis) is contraindicated because of the presumed increased risk for cerebral hemorrhage.

Genetic counseling.

CADASIL is inherited in an autosomal dominant manner. Most affected individuals have an affected parent; de novo mutations appear to be rare. Each child of an affected person is at a 50% risk of inheriting the pathogenic variant and developing signs of the disease. Prenatal testing or preimplantation genetic diagnosis (PGD) for couples at increased risk of having a child with CADASIL is possible if the pathogenic variant in the family is known; however, requests for prenatal testing of typically adult-onset disorders are uncommon.


There are no generally accepted diagnostic criteria for CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). A CADASIL diagnostic screening tool has been proposed by Pescini et al [2012].

Suggestive Findings

CADASIL should be suspected in individuals with the following:

Clinical signs. The clinical presentation of CADASIL varies among and within families. The disease is characterized by five main symptoms: subcortical ischemic events, cognitive impairment, migraine with aura, mood disturbances, and apathy.

  • Transient ischemic attacks and ischemic stroke occur at a mean age of 47 years (age range 20-70 years), in most cases without conventional vascular risk factors. Ischemic events are subcortical and present in most individuals as lacunar syndromes [Dichgans et al 1998, Adib-Samii et al 2010].
  • Cognitive decline usually manifests initially with executive dysfunction (mild cognitive impairment). This is progressive, with some preservation of recognition and semantic memory, with a concurrent stepwise deterioration due to recurrent strokes.
  • Migraine with aura occurs in 30%-40% of individuals with CADASIL. When present, it can be the first symptom, with a mean age of onset of 30 years (age range 6-48 years) [Dichgans et al 1998, Adib-Samii et al 2010]. Atypical attacks can occur, with prolonged, basilar or hemiplegic aura and confusion, fever, meningitis or coma.
  • Mood disturbances occur in about 30% of affected individuals [Dichgans et al 1998, Adib-Samii et al 2010].
  • Apathy has been described in 40% of individuals and may be independent of depression [Reyes et al 2009].

Brain imaging. Imaging abnormalities in CADASIL evolve as the disease progresses [van Den Boom et al 2003, Singhal et al 2005, Liem et al 2008a].

  • MRI white matter hyperintensities, although sometimes very subtle, can be visualized from age 21 years onward [Oberstein 2003]. Frequent and diagnostically important signs on brain MRI [Auer et al 2001, O'Sullivan et al 2001]:
    • White matter hyperintensities in the temporal poles
    • White matter hyperintensities in the external capsules
  • In individuals age 20-30 years, distinctive white matter hyperintensities often first appear in the anterior temporal lobes, when the rest of the white matter, except for periventricular caps, appears unaffected [Oberstein 2003, van Den Boom et al 2003].
  • In the course of the disease, the load of white matter hyperintensity lesions increases, eventually coalescing to the point where, in some elderly individuals, normal-appearing white matter is barely distinguishable [Chabriat et al 1998].
  • In symptomatic individuals, white matter hyperintensities are symmetrically distributed and located in the periventricular and deep white matter. Within the white matter, the frontal lobe is the site with the highest lesion load, followed by the temporal and parietal lobes [Chabriat et al 1999, Auer et al 2001, O'Sullivan et al 2001].
  • Dilated perivascular spaces are found in approximately 70%-80% of affected individuals [van Den Boom et al 2002, Cumurciuc et al 2006a, Yao et al 2014]. These MRI abnormalities have also been referred to as subcortical lacunar lesions [van Den Boom et al 2002].
  • Cerebral microbleeds, located predominantly in the thalamus, are best visualized with T2-weighted gradient echo imaging [Lesnik Oberstein et al 2001, Dichgans et al 2002].

Family history. A family history consistent with autosomal dominant inheritance supports the diagnosis but is not required [Dichgans et al 1998], as affected family members may have been misdiagnosed [Razvi et al 2005a]. Of note, the clinical presentation of CADASIL varies among and within families.

Establishing the Diagnosis

The diagnosis of CADASIL is established in a proband either by identification of a heterozygous NOTCH3 pathogenic variant (see Table 1) or, if molecular genetic testing is not definitive, by detection of characteristic findings by electron microscopy and immunohistochemistry of a skin biopsy.

Molecular testing approaches can include sequence analysis of exons 2-24 and intron-exon boundaries of NOTCH3 followed by deletion/duplication analysis if no pathogenic variant is found.

Note: Homozygosity for NOTCH3 pathogenic variants has been described in CADASIL [Tuominen et al 2001, Liem et al 2008b, Ragno et al 2013, Soong et al 2013, Vinciguerra et al 2014]. Of note, the phenotype of individuals homozygous for NOTCH3 pathogenic variants falls within the CADASIL spectrum.

Table 1.

Summary of Molecular Genetic Testing Used in CADASIL

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
NOTCH3Sequence analysis 2Estimated >95% 3
Deletion/duplication analysis 4Unknown 5

See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


When all exons coding for epidermal growth factor-like (EGFL) repeats (see Molecular Genetics) are sequenced (exons 2-24) and stringent inclusion criteria are applied [Markus et al 2002, Peters et al 2005a].


Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


Skin biopsy. The diagnosis can be confirmed by ultrastructural analysis of small arterioles obtained, for example, by skin biopsy [Goebel et al 1997, Ruchoux & Maurage 1997]. Electron microscopy shows characteristic granular osmophilic material (GOM) within the vascular media close to vascular smooth muscle cells. The detection of GOM is considered pathognomonic for CADASIL, but the reported sensitivity is variable [Ebke et al 1997, Markus et al 2002, Malandrini et al 2007,Tikka et al 2009, Morroni et al 2013].

NOTCH3 immunostaining of a skin biopsy shows a positive NOTCH3 staining of the vessel wall [Joutel et al 2001, Oberstein 2003].

The combined analysis by electron microscopy and immunohistochemistry, when interpreted by an experienced (neuro)pathologist, usually allows for a conclusive CADASIL diagnosis.

Clinical Characteristics

Clinical Description

CADASIL is a disease of the small to medium-sized arteries, mainly affecting the brain. The presenting symptoms, age at onset, and disease progression in CADASIL are variable.

Subcortical ischemic events. Transient ischemic attacks (TIAs) and stroke, the most frequent presentation, are found in approximately 85% of symptomatic individuals [Dichgans et al 1998]. Strokes related to cerebral small vessel pathology are clearly the main manifestation of the disease.

Mean age at onset for ischemic episodes is approximately 45-50 years [Opherk et al 2004], but the range of age at onset is broad (3rd-8th decade).

Ischemic episodes typically present as a classic lacunar syndrome (pure motor stroke, ataxic hemiparesis/dysarthria-clumsy hand syndrome, pure sensory stroke, sensorimotor stroke), but other lacunar syndromes (brain stem or hemispheric) are also observed. Ischemic episodes are often recurrent, leading to severe disability with gait disturbance, urinary incontinence, and pseudobulbar palsy.

Strokes involving the territory of a large artery have occasionally been reported. However, whether these are coincidental observations, or whether (certain sub-populations of) individuals with CADASIL are at increased risk for large vessel stroke, is unclear [Choi et al 2013, Yin et al 2014].

Cognitive deficits and dementia. Cognitive deficits, the second most frequent feature, may start as early as age 35 years. Approximately 75% of affected individuals develop dementia, often accompanied by apathy [Dichgans et al 1998, Opherk et al 2004, Dichgans 2009, Reyes et al 2009].

The pattern of cognitive dysfunction is initially characterized by deficits in executive function (timed measures and measures of error monitoring), verbal fluency, and memory with benefit from clues [Peters et al 2005b]. Cognitive dysfunction is accompanied by a narrowing of the field of interest. In most cases, cognitive decline is slowly progressive with additional stepwise deterioration. Amberla et al [2004] observed deterioration of working memory and executive function in individuals with NOTCH3 pathogenic variants in the prestroke phase, and infer that cognitive decline may start insidiously before the onset of symptomatic ischemic episodes.

Migraine. Migraine occurs in approximately 35% of individuals with CADASIL, with the first attack occurring at a mean age of 26-29 years [Dichgans et al 1998, Adib-Samii et al 2010]. The reported prevalence of migraine in CADASIL is variable between studies, and ranges from as low as 5% [Wang et al 2011], to up to 77% of patients [Singhal et al 2004, Adib-Samii et al 2010]; 90% of individuals with migraine have migraine with aura [Dichgans et al 1998, Adib-Samii et al 2010]. Atypical migraine attacks can occur with prolonged, basilar or hemiplegic aura and confusion, fever, meningitis or coma.

Psychiatric disorders. In most CADASIL cohorts, psychiatric disturbances are described in about one third of individuals [Dichgans et al 1998, Adib-Samii et al 2010]. The reported prevalence of psychiatric disturbances is variable: a small study in 23 Italian patients recorded a life time risk for depression of 74% [Valenti et al 2011], whereas in a Chinese cohort, psychiatric manifestations were recorded in only 7% of patients [Wang et al 2011]. The psychiatric manifestations vary from personality changes to severe depression. Whether these disturbances are primary or reactive is not yet clear. However, individuals with CADASIL presenting with psychiatric problems have been described [Leyhe et al 2005, Nakamura et al 2005, Park et al 2014].

Reversible acute encephalopathy. Acute encephalopathy has been described in some individuals, with confusion, headache, pyrexia, seizures, and coma, sometimes leading to death [Chabriat et al 1995, Feuerhake et al 2002, Schon et al 2003, Adib-Samii et al 2010, Ragno et al 2013].

Epilepsy. Epilepsy occurs in 10% of individuals with CADASIL and presents in middle age, usually secondary to stroke [Chabriat et al 1995, Dichgans et al 1998, Desmond et al 1999, Haan et al 2007].

Pregnancy. It has been suggested that during pregnancy, but especially during puerperium (the period between childbirth and the return of the uterus to its normal size), an increased risk for migraine with aura occurs. The symptoms are sometimes confused with transient ischemic symptoms [Roine et al 2005]. See Pregnancy Management.

Other findings

  • Cardiac. Controversy exists as to whether CADASIL is associated with cardiac involvement. In a study from The Netherlands, nearly 25% of individuals with NOTCH3 pathogenic variants had a history of acute myocardial infarction (MI) and/or current pathologic Q-waves on electrocardiogram [Lesnik Oberstein et al 2003]. This percentage was significantly higher than in controls without a NOTCH3 pathogenic variant. However, another study of 23 individuals with a NOTCH3 pathogenic variant found no signs of previous MI on ECG [Cumurciuc et al 2006b]. Two studies have suggested an increased risk for arrhythmias, based on increased QT variability on electrocardiogram recording [Rufa et al 2007, Piccirillo et al 2008].
  • Nerve. Nerve biopsies of some CADASIL patients have been shown to have abnormalities [Schröder et al 2005]. Sicurelli et al [2005] have suggested that peripheral neuropathy may be part of the CADASIL phenotype. Others did not find a clear association between CADASIL and peripheral neuropathy [Kang et al 2009].
  • Ocular. Subclinical retinal lesions are reported [Cumurciuc et al 2004]. Fundoscopy may reveal clinically silent retinal vascular abnormalities [Pretegiani et al 2013].
  • Renal. NOTCH3 accumulation and GOM deposits are also detected in renal arteries, and stenosis of renal arteries has been described [Ruchoux et al 1995, Guerrot et al 2008, Ragno et al 2012]. Although no large-scale studies have been published regarding kidney function in CADASIL, there is to date no evidence that kidney function is affected [Bergmann et al 1996].

Long-term prognosis and causes of death. Data on the long-term prognosis in CADASIL come from a large study of 411 individuals [Opherk et al 2004], which found that the median age at onset of inability to walk without assistance was approximately 60 years and the median age at which individuals became bedridden was 64 years. The median age at death was 68 years with a more rapid disease progression in men than in women. The median survival time of men was significantly shorter than expected from German life tables, whereas the median survival time of women was not significantly reduced. The reason for this difference is not known; possible explanations include sex hormones, sex differences in risk factor control; medical management, social support, and socio-economic factors.

Pneumonia was the most frequent cause of death, followed by sudden unexpected death and asphyxia. At onset of the cause of death, 78% of individuals were completely dependent and 63% were confined to bed.

Pathophysiology. Cerebral blood supply in individuals with CADASIL is reduced below demand, as demonstrated by an increased oxygen extraction rate in asymptomatic and demented individuals with CADASIL. Cerebral blood flow, cerebral blood volume, and cerebral glucose utilization are significantly reduced [Chabriat et al 2000, Bruening et al 2001, Tuominen et al 2004]. In addition, cerebral vasoreactivity is impaired [Pfefferkorn et al 2001], consistent with the observed degeneration of vascular smooth muscle cells in small arteries and arterioles [Kalimo et al 2002]. Increased fragility of cerebral microvessels is suggested by a high frequency of cerebral microbleeds at autopsy and on gradient echo MR images [Lesnik Oberstein et al 2001, Dichgans et al 2002].

Genotype-Phenotype Correlations

Although some studies describe phenotype-genotype correlations [Lesnik Oberstein et al 2001, Arboleda-Velasquez et al 2002, Opherk et al 2004, Bianchi et al 2010], the genotype cannot be used to predict the phenotype in individuals with CADASIL [Singhal et al 2004]. Even within a single family, the age of onset, disease severity, and disease progression can vary significantly.

Homozygous pathogenic variants have been described in CADASIL [Tuominen et al 2001, Liem et al 2008b, Ragno et al 2013, Soong et al 2013, Vinciguerra et al 2014]. The phenotype of individuals homozygous for NOTCH3 pathogenic variants falls within the CADASIL spectrum.


Penetrance of the disease is probably 100%, but expression varies in age of onset, severity of the clinical symptoms, and progression of the disease.


Previous descriptions of families with “hereditary multi-infarct dementia,” “chronic familial vascular encephalopathy,” and “familial subcortical dementia” represent early reports of CADASIL.


The exact prevalence of CADASIL is not known, and the disease is probably still underdiagnosed. Multiple small and national registries have estimated the minimum prevalence between two and four per 100,000 [Kalimo et al 2002, Razvi et al 2005b, Narayan et al 2012, Bianchi et al 2015].

While the majority of published data have come from Europe, CADASIL has been observed on all continents.

A founder effect has been reported for Finnish individuals with CADASIL [Mykkänen et al 2004] and for patients in the Marche region of Italy [Bianchi et al 2015].

Differential Diagnosis

The differential diagnosis of CADASIL includes the following:

The clinical characteristics and MRI abnormalities in these conditions may resemble those of CADASIL. The presence of temporopolar MRI lesions, the absence of optic nerve and spinal cord involvement, the absence of oligoclonal bands in the cerebrospinal fluid, and the absence of hypertension are critical in this regard [Dichgans et al 1999].

Other inherited disorders in the differential diagnosis:

These disorders can be distinguished from CADASIL by the associated clinical signs, MRI, mode of inheritance, and appropriate laboratory investigations.

CADASIL should also be considered in any young person who has migraine with aura in conjunction with multiple white matter lesions on MRI [Gladstone & Dodick 2005].


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CADASIL, the following evaluations are recommended:

  • Neurologic evaluation
  • Psychometrics with particular attention to executive function
  • Standard brain MRI (FLAIR sequence)
  • Medical genetics consultation

Psychiatric consultation should be considered

Treatment of Manifestations

There is no treatment of proven efficacy for CADASIL. Antiplatelet treatment is frequently used, but not proven effective in CADASIL.

Migraine should be treated symptomatically and prophylactically, depending on the frequency of manifestations. There is no evidence that triptans and ergot derivatives should be avoided, although some argue that vasoconstrictive medication should be used with prudence.

Co-occurrence of hypertension, diabetes, or hypercholesterolemia should be treated.

Supportive care in the form of practical help, emotional support, and counseling are appropriate for affected individuals and their families.

Further discussion of medical management options for individuals with CADASIL was published by del Río-Espínola et al [2009].

Prevention of Primary Manifestations

There are no preventive measures for stroke or vascular dementia.

Migraine attacks can be treated symptomatically and prophylactically according to migraine care standards.


There are no standard international surveillance guidelines for CADASIL. Several countries have developed CADASIL guidelines which can be referred to, such as the medical guideline for CADASIL published (in French) by the French Health Authority (HAS).

Yearly follow up by a neurologist with expertise in CADASIL is recommended from the time of diagnosis.

A consultation with a neuropsychiatrist is recommended when there are symptoms of depression or other psychiatric manifestations.

Consultation of other medical specialists (e.g., rehabilitation physician, physical therapist, and psychologist) is as required.

The interval at which individuals with CADASIL should be seen for follow up depends on the severity and type of symptoms and the needs of the patients and their care givers.

Agents/Circumstances to Avoid

Angiography and anticoagulants are contraindicated in CADASIL as they may provoke cerebrovascular accidents [Lesnik Oberstein et al 2001].

Smoking increases the risk of stroke in individuals with CADASIL and should be avoided [Singhal et al 2004].

Thrombolytic therapy (intravenous thrombolysis) is contraindicated because of the presumed increased risk for cerebral hemorrhage in view of the fact that patients with CADASIL have microbleeds on MRI [Lesnik Oberstein et al 2001, Dichgans et al 2002].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Although no formal studies have been performed, no evidence from clinical practice suggests that fetuses affected with CADASIL are at an increased risk for intrauterine complications or complications during/after delivery.

Women with a NOTCH3 pathogenic variant have been described as at increased risk for neurologic events in pregnancy during and shortly after delivery (puerperium) [Roine et al 2005]. However, it should be noted that this study was performed retrospectively. In the authors’ experience, most women with CADASIL have an uncomplicated pregnancy and delivery, but transient neurologic events are sometimes reported (mostly consistent with migraine aura) [Lesnik Oberstein, unpublished observation based on clinical practice].

Therapies Under Investigation

Small-scale observational studies have suggested a beneficial effect of acetazolamide on migraine [Donnini et al 2012]. Acetazolamide has also been shown to have a beneficial effect on cerebral blood flow in one case report [Park et al 2011]. Acetazolamide is not given to patients with CADASIL on a routine basis.

Search for access to information on clinical studies for a wide range of diseases and conditions.


Cross-sectional and longitudinal studies suggest that disease progression is faster in individuals with CADASIL who have increased blood pressure [Peters et al 2004, Holtmannspötter et al 2005, Peters et al 2006]. However, no controlled data are available regarding the effect of antihypertensive treatment on disease progression.

Based on experience with stroke in general, many neurologists prescribe salicylates. Whether these are of any efficacy in preventing stroke in individuals with CADASIL has not been studied.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

CADASIL is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

Note: Although most individuals diagnosed with CADASIL have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If one of the parents is affected, as is true for the vast majority of individuals with a NOTCH3 pathogenic variant, the risk to sibs is 50%.
  • If the proband is homozygous for a NOTCH3 pathogenic variant and both parents are heterozygous, the risk to the sibs of the proband of having at least one NOTCH3 pathogenic variant is 75%.
  • If the pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is reduced to almost zero, as the proband probably has a de novo mutation. Germline mosaicism is theoretically possible but has not been reported to date.

Offspring of a proband

  • Every child of an individual with a NOTCH3 pathogenic variant has a 50% chance of inheriting the pathogenic variant.
  • Offspring of a proband who is homozygous or compound heterozygous for NOTCH3 pathogenic variants will inherit one of the pathogenic variants.

Other family members of a proband

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

Testing of at-risk asymptomatic adult relatives of individuals with CADASIL is possible after molecular genetic testing has identified the specific NOTCH3 pathogenic variants in the family. Such testing should be performed in the context of formal genetic counseling, and is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. Testing of asymptomatic at-risk individuals with nonspecific or equivocal symptoms is predictive testing, not diagnostic testing.

Testing of asymptomatic individuals younger than age 18 years who are at risk for adult-onset disorders for which no treatment exists is not considered appropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.

In a family with an established diagnosis of CADASIL, testing is appropriate to consider in symptomatic individuals regardless of age.

For more information, see also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

Considerations in families with apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the NOTCH3 pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Requests for prenatal testing for typically adult-onset conditions such as CADASIL are not common. Differences in perspectives may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the NOTCH3 pathogenic variant has been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • CADASIL Association
    P. O. Box 124
    Helmetta NJ 08828
    Phone: 307-215-9840
  • CADASIL Together We Have Hope Nonprofit Organization
    3605 Monument Drive
    Round Rock TX 78681
    Phone: 800-617-8387
  • L’association CADASIL France
  • National Library of Medicine Genetics Home Reference
  • Stichting Platform CADASIL
  • United Leukodystrophy Foundation (ULF)
    224 North Second Street
    Suite 2
    DeKalb IL 60115
    Phone: 800-728-5483 (toll-free); 815-748-3211
    Fax: 815-748-0844
  • CADASIL Together We Have Hope Registry
    3605 Monument Drive
    Round Rock TX 78681
    Phone: 877-519-4673; 512-255-0209

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

CADASIL: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for CADASIL (View All in OMIM)


Gene structure. NOTCH3 consists of 33 exons spanning roughly 7 kb. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Pathogenic variants in CADASIL are detected in exons 2-24. The majority of sequence alterations in NOTCH3 are missense mutations (95%), characteristically leading to the loss or gain of a cysteine residue in one of the epidermal growth factor-like repeat (EGFr) domains of neurogenic locus notch homolog protein 3 (NOTCH3), the protein encoded by NOTCH3 [Dichgans et al 2001]. This results in an uneven number of cysteine residues in the given domain, most likely modifying the tertiary structure of the protein.

A few splice-site mutations, insertions, and deletions have been described, also resulting in an uneven number of cysteine residues within EGFr [Rutten et al 2014]. The majority of mutations occur in exons 2-6 [Rutten et al 2014], although regional differences are seen [Federico et al 2005, Bianchi et al 2015]. (For more information, see Table A.)

Normal gene product. The NOTCH signaling pathway is an evolutionarily conserved intercellular signaling mechanism that plays a central role during vascular development and physiology. NOTCH3 is primarily expressed in vascular smooth muscle cells and plays an important role in vascular smooth muscle cell differentiation and maturation [Domenga et al 2004], and in the control of vascular mechano-transduction [Belin de Chantemèle et al 2008]. NOTCH3 is a single pass transmembrane protein which consists of 2321 amino acids. It can bind to a ligand via the extracellular domain which is composed of 34 EGFr domains, and it has an intracellular domain required for signal transduction.

Variants of unknown significance. There are some reports of possible NOTCH3 mutations not involving a cysteine residue, in individuals with a CADASIL or CADASIL-like phenotype. With a few exceptions [Mizuno et al [2008], there is no convincing evidence that these mutations cause CADASIL [Rutten et al 2014]. These variants should therefore be interpreted with great caution, and additional investigations (segregation analysis, deletion/duplication analysis, pathologic analysis) are required to unravel a possible role of such variants.

NOTCH3 nonsense mutations have been described in healthy individuals, and therefore are most likely non-pathogenic [Rutten et al 2013]. In a Italian family, a NOTCH3 stop mutation was described in a family with brain MRI abnormalities and clinical symptoms suggestive of CADASIL [Moccia et al 2015], but the relation between the mutation and the phenotype has not been unequivocally confirmed [Cognat et al 2014b].

Abnormal gene product. NOTCH3 pathogenic variants in CADASIL lead to loss or gain of a cysteine residue. This results in an unpaired cysteine residue and disrupted disulphide bridge formation, causing aggregation of the mutated NOTCH3 extracellular domain. This, directly or indirectly, has a toxic effect, leading to degeneration of VSMC. Recent evidence indicates that the NOTCH3 aggregates cause sequestration of functionally important extracellular matrix proteins [Monet-Leprêtre et al 2013].

Overall, evidence from studies in human, mice, and cell models indicates that neomorphic properties of the mutated NOTCH3 protein drive CADASIL pathogenesis, whereas loss of NOTCH3 function does not play a pivotal role [Rutten et al 2013, Cognat et al 2014a].


Published Guidelines/Consensus Statements

  1. Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 2-18-15. [PubMed: 23428972]
  2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 2-18-15.

Literature Cited

  1. Adib-Samii P, Brice G, Martin RJ, Markus HS. Clinical spectrum of CADASIL and the effect of cardiovascular risk factors on phenotype: study in 200 consecutively recruited individuals. Stroke. 2010;41:630–4. [PubMed: 20167921]
  2. Amberla K, Waljas M, Tuominen S, Almkvist O, Poyhonen M, Tuisku S, Kalimo H, Viitanen M. Insidious cognitive decline in CADASIL. Stroke. 2004;35:1598–602. [PubMed: 15143298]
  3. Arboleda-Velasquez JF, Lopera F, Lopez E, Frosch MP, Sepulveda-Falla D, Gutierrez JE, Vargas S, Medina M, Martinez De Arrieta C, Lebo RV, Slaugenhaupt SA, Betensky RA, Villegas A, Arcos-Burgos M, Rivera D, Restrepo JC, Kosik KS. C455R notch3 mutation in a Colombian CADASIL kindred with early onset of stroke. Neurology. 2002;59:277–9. [PubMed: 12136071]
  4. Auer DP, Putz B, Gossl C, Elbel G, Gasser T, Dichgans M. Differential lesion patterns in CADASIL and sporadic subcortical arteriosclerotic encephalopathy: MR imaging study with statistical parametric group comparison. Radiology. 2001;218:443–51. [PubMed: 11161160]
  5. Belin de Chantemèle EJ, Retailleau K, Pinaud F, Vessières E, Bocquet A, Guihot AL, Lemaire B, Domenga V, Baufreton C, Loufrani L, Joutel A, Henrion D. Notch3 is a major regulator of vascular tone in cerebral and tail resistance arteries. Arterioscler Thromb Vasc Biol. 2008;28:2216–24. [PMC free article: PMC2658748] [PubMed: 18818417]
  6. Bergmann M, Ebke M, Yuan Y, Brück W, Mugler M, Schwendemann G. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): a morphological study of a German family. Acta Neuropathol. 1996;92:341–50. [PubMed: 8891065]
  7. Bianchi S, Rufa A, Ragno M, D'Eramo C, Pescini F, Pantoni L, Cappelli A, Perretti A, Zicari E, Zolo P, Inzitari D, Dotti MT, Federico A. High frequency of exon 10 mutations in the NOTCH3 gene in Italian CADASIL families: phenotypic peculiarities. J Neurol. 2010;257:1039–42. [PubMed: 20169447]
  8. Bianchi S, Zicari E, Carluccio A, Di Donato I, Pescini F, Nannucci S, Valenti R, Ragno M, Inzitari D, Pantoni L, Federico A, Dotti MT. CADASIL in central Italy: a retrospective clinical and genetic study in 229 patients. J Neurol. 2015;262:134–41. [PubMed: 25344745]
  9. Boelens MC, Wu TJ, Nabet BY, Xu B, Qiu Y, Yoon T, Azzam DJ, Twyman-Saint VC, Wiemann BZ, Ishwaran H, Ter Brugge PJ, Jonkers J, Slingerland J, Minn AJ. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell. 2014;159:499–513. [PMC free article: PMC4283810] [PubMed: 25417103]
  10. Bruening R, Dichgans M, Berchtenbreiter C, Yousry T, Seelos KC, Wu RH, Mayer M, Brix G, Reiser M. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: decrease in regional cerebral blood volume in hyperintense subcortical lesions inversely correlates with disability and cognitive performance. AJNR Am J Neuroradiol. 2001;22:1268–74. [PubMed: 11498413]
  11. Chabriat H, Levy C, Taillia H, Iba-Zizen MT, Vahedi K, Joutel A, Tournier-Lasserve E, Bousser MG. Patterns of MRI lesions in CADASIL. Neurology. 1998;51:452–7. [PubMed: 9710018]
  12. Chabriat H, Mrissa R, Levy C, Vahedi K, Taillia H, Iba-Zizen MT, Joutel A, Tournier-Lasserve E, Bousser MG. Brain stem MRI signal abnormalities in CADASIL. Stroke. 1999;30:457–9. [PubMed: 9933287]
  13. Chabriat H, Pappata S, Ostergaard L, Clark CA, Pachot-Clouard M, Vahedi K, Jobert A, Le Bihan D, Bousser MG. Cerebral hemodynamics in CADASIL before and after acetazolamide challenge assessed with MRI bolus tracking. Stroke. 2000;31:1904–12. [PubMed: 10926955]
  14. Chabriat H, Vahedi K, Iba-Zizen MT, Joutel A, Nibbio A, Nagy TG, Krebs MO, Julien J, Dubois B, Ducrocq X, et al. Clinical spectrum of CADASIL: a study of 7 families. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Lancet. 1995;346:934–9. [PubMed: 7564728]
  15. Choi JC, Song SK, Lee JS, Kang SY, Kang JH. Diversity of stroke presentation in CADASIL: study from patients harboring the predominant NOTCH3 mutation R544C. J Stroke Cerebrovasc Dis. 2013;22:126–31. [PubMed: 21852154]
  16. Cognat E, Baron-Menguy C, Domenga-Denier V, Cleophax S, Fouillade C, Monet-Leprêtre M, Dewerchin M, Joutel A. Archetypal Arg169Cys mutation in NOTCH3 does not drive the pathogenesis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy via a loss-of-function mechanism. Stroke. 2014a;45:842–9. [PubMed: 24425116]
  17. Cognat E, Hervé D, Joutel A. Response to letter regarding article, "Archetypal Arg169Cys mutation in NOTCH3 does not drive the pathogenesis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy via a loss-of-function mechanism. Stroke. 2014b;45:e129. [PubMed: 24867925]
  18. Coto E, Menendez M, Navarro R, Garcia-Castro M, Alvarez V. A new de novo Notch3 mutation causing CADASIL. Eur J Neurol. 2006;13:628–31. [PubMed: 16796587]
  19. Cumurciuc R, Guichard JP, Reizine D, Gray F, Bousser MG, Chabriat H. Dilation of Virchow-Robin spaces in CADASIL. Eur J Neurol. 2006a;13:187–90. [PubMed: 16490051]
  20. Cumurciuc R, Henry P, Gobron C, Vicaut E, Bousser MG, Chabriat H, Vahedi K. Electrocardiogram in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy patients without any clinical evidence of coronary artery disease: a case-control study. Stroke. 2006b;37:1100–2. [PubMed: 16514092]
  21. Cumurciuc R, Massin P, Paques M, Krisovic V, Gaudric A, Bousser MG, Chabriat H. Retinal abnormalities in CADASIL: a retrospective study of 18 patients. J Neurol Neurosurg Psychiatry. 2004;75:1058–60. [PMC free article: PMC1739116] [PubMed: 15201374]
  22. del Río-Espínola A, Mendióroz M, Domingues-Montanari S, Pozo-Rosich P, Solé E, Fernández-Morales J, Fernández-Cadenas I, Montaner J. CADASIL management or what to do when there is little one can do. Expert Rev Neurother. 2009;9:197–210. [PubMed: 19210195]
  23. Desmond DW, Moroney JT, Lynch T, Chan S, Chin SS, Mohr JP. The natural history of CADASIL: a pooled analysis of previously published cases. Stroke. 1999;30:1230–3. [PubMed: 10356105]
  24. Dichgans M. Cognition in CADASIL. Stroke. 2009;40:S45–7. [PubMed: 19064778]
  25. Dichgans M, Filippi M, Bruning R, Iannucci G, Berchtenbreiter C, Minicucci L, Uttner I, Crispin A, Ludwig H, Gasser T, Yousry TA. Quantitative MRI in CADASIL: correlation with disability and cognitive performance. Neurology. 1999;52:1361–7. [PubMed: 10227618]
  26. Dichgans M, Herzog J, Gasser T. NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL. Neurology. 2001;57:1714–7. [PubMed: 11706120]
  27. Dichgans M, Holtmannspotter M, Herzog J, Peters N, Bergmann M, Yousry TA. Cerebral microbleeds in CADASIL: a gradient-echo magnetic resonance imaging and autopsy study. Stroke. 2002;33:67–71. [PubMed: 11779891]
  28. Dichgans M, Mayer M, Uttner I, Bruning R, Muller-Hocker J, Rungger G, Ebke M, Klockgether T, Gasser T. The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol. 1998;44:731–9. [PubMed: 9818928]
  29. Domenga V, Fardoux P, Lacombe P, Monet M, Maciazek J, Krebs LT, Klonjkowski B, Berrou E, Mericskay M, Li Z, Tournier-Lasserve E, Gridley T, Joutel A. Notch3 is required for arterial identity and maturation of vascular smooth muscle cells. Genes Dev. 2004;18:2730–5. [PMC free article: PMC528893] [PubMed: 15545631]
  30. Donnini I, Nannucci S, Valenti R, Pescini F, Bianchi S, Inzitari D, Pantoni L. Acetazolamide for the prophylaxis of migraine in CADASIL: a preliminary experience. J Headache Pain. 2012;13:299–302. [PMC free article: PMC3356473] [PubMed: 22367627]
  31. Ebke M, Dichgans M, Bergmann M, Voelter HU, Rieger P, Gasser T, Schwendemann G. CADASIL: skin biopsy allows diagnosis in early stages. Acta Neurol Scand. 1997;95:351–7. [PubMed: 9228269]
  32. Federico A, Bianchi S, Dotti MT. The spectrum of mutations for CADASIL diagnosis. Neurol Sci. 2005;26:117–24. [PubMed: 15995828]
  33. Feuerhake F, Volk B, Ostertag CB, Jungling FD, Kassubek J, Orszagh M, Dichgans M. Reversible coma with raised intracranial pressure: an unusual clinical manifestation of CADASIL. Acta Neuropathol (Berl) 2002;103:188–92. [PubMed: 11810186]
  34. Gladstone JP, Dodick DW. Migraine and cerebral white matter lesions: when to suspect cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Neurologist. 2005;11:19–29. [PubMed: 15631641]
  35. Goebel HH, Meyermann R, Rosin R, Schlote W. Characteristic morphologic manifestation of CADASIL, cerebral autosomal- dominant arteriopathy with subcortical infarcts and leukoencephalopathy, in skeletal muscle and skin. Muscle Nerve. 1997;20:625–7. [PubMed: 9140375]
  36. Gripp KW, Robbins KM, Sobreira NL, Witmer PD, Bird LM, Avela K, Makitie O, Alves D, Hogue JS, Zackai EH, Doheny KF, Stabley DL, Sol-Church K. Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome. Am J Med Genet A. 2015;167:271–81. [PubMed: 25394726]
  37. Guerrot D, François A, Boffa JJ, Boulos N, Hanoy M, Legallicier B, Triquenot-Bagan A, Guyant-Marechal L, Laquerriere A, Freguin-Bouilland C, Ronco P, Godin M. Nephroangiosclerosis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: is NOTCH3 mutation the common culprit? Am J Kidney Dis. 2008;52:340–5. [PubMed: 18572291]
  38. Haan J, Lesnik Oberstein SA, Ferrari MD. Epilepsy in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Cerebrovasc Dis. 2007;24:316–7. [PubMed: 17675836]
  39. Holtmannspötter M, Peters N, Opherk C, Martin D, Herzog J, Bruckmann H, Samann P, Gschwendtner A, Dichgans M. Diffusion magnetic resonance histograms as a surrogate marker and predictor of disease progression in CADASIL: a two-year follow-up study. Stroke. 2005;36:2559–65. [PubMed: 16269644]
  40. Joutel A, Dodick DD, Parisi JE, Cecillon M, Tournier-Lasserve E, Bousser MG. De novo mutation in the Notch3 gene causing CADASIL. Ann Neurol. 2000;47:388–91. [PubMed: 10716263]
  41. Joutel A, Favrole P, Labauge P, Chabriat H, Lescoat C, Andreux F, Domenga V, Cecillon M, Vahedi K, Ducros A, Cave-Riant F, Bousser MG, Tournier-Lasserve E. Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. Lancet. 2001;358:2049–51. [PubMed: 11755616]
  42. Joutel A, Vahedi K, Corpechot C, Troesch A, Chabriat H, Vayssiere C, Cruaud C, Maciazek J, Weissenbach J, Bousser MG, Bach JF, Tournier-Lasserve E. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997;350:1511–5. [PubMed: 9388399]
  43. Jung JG, Stoeck A, Guan B, Wu RC, Zhu H, Blackshaw S, Shih I, Wang TL. Notch3 Interactome Analysis Identified WWP2 as a Negative Regulator of Notch3 Signaling in Ovarian Cancer. PLoS Genet. 2014;10:e1004751. [PMC free article: PMC4214668] [PubMed: 25356737]
  44. Kalimo H, Ruchoux MM, Viitanen M, Kalaria RN. CADASIL: a common form of hereditary arteriopathy causing brain infarcts and dementia. Brain Pathol. 2002;12:371–84. [PubMed: 12146805]
  45. Kang SY, Oh JH, Kang JH, Choi JC, Lee JS. Nerve conduction studies in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. J Neurol. 2009;256:1724–7. [PubMed: 19488673]
  46. Lesnik Oberstein SA, Jukema JW, Van Duinen SG, Macfarlane PW, van Houwelingen HC, Breuning MH, Ferrari MD, Haan J. Myocardial infarction in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Medicine (Baltimore) 2003;82:251–6. [PubMed: 12861102]
  47. Lesnik Oberstein SA, van Den Boom R, van Buchem MA, van Houwelingen HC, Bakker E, Vollebregt E, Ferrari MD, Breuning MH, Haan J. Cerebral microbleeds in CADASIL. Neurology. 2001;57:1066–70. [PubMed: 11571335]
  48. Leyhe T, Wiendl H, Buchkremer G, Wormstall H. CADASIL: underdiagnosed in psychiatric patients? Acta Psychiatr Scand. 2005;111:392–6. [PubMed: 15819734]
  49. Liem MK, Lesnik Oberstein SA, Haan J, van der Neut IL, van Den Boom R, Ferrari MD, van Buchem MA, van der Grond J. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: progression of MR abnormalities in prospective 7-year follow-up study. Radiology. 2008a;249:964–71. [PubMed: 18840792]
  50. Liem MK, Lesnik Oberstein SA, Vollebregt MJ, Middelkoop HA, van der Grond J, Helderman-van den Enden AT. Homozygosity for a NOTCH3 mutation in a 65-year-old CADASIL patient with mild symptoms: a family report. J Neurol. 2008b;255:1978–80. [PubMed: 19153638]
  51. Malandrini A, Gaudiano C, Gambelli S, Berti G, Serni G, Bianchi S, Federico A, Dotti MT. Diagnostic value of ultrastructural skin biopsy studies in CADASIL. Neurology. 2007;68:1430–2. [PubMed: 17452591]
  52. Markus HS, Martin RJ, Simpson MA, Dong YB, Ali N, Crosby AH, Powell JF. Diagnostic strategies in CADASIL. Neurology. 2002;59:1134–8. [PubMed: 12395806]
  53. Martignetti JA, Tian L, Li D, Ramirez MC, Camacho-Vanegas O, Camacho SC, Guo Y, Zand DJ, Bernstein AM, Masur SK, Kim CE, Otieno FG, Hou C, Abdel-Magid N, Tweddale B, Metry D, Fournet JC, Papp E, McPherson EW, Zabel C, Vaksmann G, Morisot C, Keating B, Sleiman PM, Cleveland JA, Everman DB, Zackai E, Hakonarson H. Mutations in PDGFRB Cause Autosomal-Dominant Infantile Myofibromatosis. Am J Hum Genet. 2013;92:1001–7. [PMC free article: PMC3675260] [PubMed: 23731542]
  54. Mizuno T, Muranishi M, Torugun T, Tango H, Nagakane Y, Kudeken T, Kawase Y, Kawabe K, Oshima F, Yaoi T, Itoh K, Fushiki S, Nakagawa M. Two Japanese CADASIL families exhibiting Notch3 mutation R75P not involving cysteine residue. Intern Med. 2008;47:2067–72. [PubMed: 19043263]
  55. Moccia M, Mosca L, Erro R, Cervasio M, Allocca R, Vitale C, Leonardi A, Caranci F, Del Basso-De Caro ML, Barone P, Penco S. Hypomorphic NOTCH3 mutation in an Italian family with CADASIL features. Neurobiol Aging. 2015;36:547.e5–11. [PubMed: 25260852]
  56. Monet-Leprêtre M, Haddad I, Baron-Menguy C, Fouillot-Panchal M, Riani M, Domenga-Denier V, Dussaule C, Cognat E, Vinh J, Joutel A. Abnormal recruitment of extracellular matrix proteins by excess Notch3 ECD: a new pathomechanism in CADASIL. Brain. 2013;136:1830–45. [PMC free article: PMC3673461] [PubMed: 23649698]
  57. Morroni M, Marzioni D, Ragno M, Di BP, Cartechini E, Pianese L, Lorenzi T, Castellucci M, Scarpelli M. Role of electron microscopy in the diagnosis of cadasil syndrome: a study of 32 patients. PLoS One. 2013;8:e65482. [PMC free article: PMC3684609] [PubMed: 23799017]
  58. Mykkänen K, Savontaus ML, Juvonen V, Sistonen P, Tuisku S, Tuominen S, Penttinen M, Lundkvist J, Viitanen M, Kalimo H, Poyhonen M. Detection of the founder effect in Finnish CADASIL families. Eur J Hum Genet. 2004;12:813–9. [PubMed: 15378071]
  59. Nakamura T, Watanabe H, Hirayama M, Inukai A, Kabasawa H, Matsubara M, Mitake S, Nakamura M, Ando Y, Uchino M, Sobue G. CADASIL with NOTCH3 S180C presenting anticipation of onset age and hallucinations. J Neurol Sci. 2005;238:87–91. [PubMed: 16111703]
  60. Narayan SK, Gorman G, Kalaria RN, Ford GA, Chinnery PF. The minimum prevalence of CADASIL in northeast England. Neurology. 2012;78:1025–7. [PMC free article: PMC3310314] [PubMed: 22422895]
  61. Oberstein SA, Ferrari MD, Bakker E, van Gestel J, Kneppers AL, Frants RR, Breuning MH, Haan J. Diagnostic Notch3 sequence analysis in CADASIL: three new mutations in Dutch patients. Dutch CADASIL Research Group. Neurology. 1999;52:1913–5. [PubMed: 10371548]
  62. Oberstein SAJ. Diagnostic strategies in CADASIL. Neurology. 2003;60:2020. [PubMed: 14710716]
  63. Opherk C, Peters N, Herzog J, Luedtke R, Dichgans M. Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. Brain. 2004;127:2533–9. [PubMed: 15364702]
  64. O'Sullivan M, Jarosz JM, Martin RJ, Deasy N, Powell JF, Markus HS. MRI hyperintensities of the temporal lobe and external capsule in patients with CADASIL. Neurology. 2001;56:628–34. [PubMed: 11245715]
  65. Park S, Park B, Koh MK, Joo YH. Case report: bipolar disorder as the first manifestation of CADASIL. BMC Psychiatry. 2014;14:175. [PMC free article: PMC4080756] [PubMed: 24929957]
  66. Park SA, Yang CY, Choi SS, Kim WH. Assessment of cerebral hemodynamics to acetazolamide using brain perfusion SPECT in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Clin Nucl Med. 2011;36:158–9. [PubMed: 21220990]
  67. Pescini F, Nannucci S, Bertaccini B, Salvadori E, Bianchi S, Ragno M, Sarti C, Valenti R, Zicari E, Moretti M, Chiti S, Stromillo ML, De SN, Dotti MT, Federico A, Inzitari D, Pantoni L. The Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) Scale: a screening tool to select patients for NOTCH3 gene analysis. Stroke. 2012;43:2871–6. [PubMed: 22996955]
  68. Peters N, Herzog J, Opherk C, Dichgans M. A two-year clinical follow-up study in 80 CADASIL subjects: progression patterns and implications for clinical trials. Stroke. 2004;35:1603–8. [PubMed: 15155961]
  69. Peters N, Holtmannspotter M, Opherk C, Gschwendtner A, Herzog J, Samann P, Dichgans M. Brain volume changes in CADASIL: a serial MRI study in pure subcortical ischemic vascular disease. Neurology. 2006;66:1517–22. [PubMed: 16717211]
  70. Peters N, Opherk C, Bergmann T, Castro M, Herzog J, Dichgans M. Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies. Arch Neurol. 2005a;62:1091–4. [PubMed: 16009764]
  71. Peters N, Opherk C, Danek A, Ballard C, Herzog J, Dichgans M. The pattern of cognitive performance in CADASIL: a monogenic condition leading to subcortical ischemic vascular dementia. Am J Psychiatry. 2005b;162:2078–85. [PubMed: 16263847]
  72. Pfefferkorn T, von Stuckrad-Barre S, Herzog J, Gasser T, Hamann GF, Dichgans M. Reduced cerebrovascular CO(2) reactivity in CADASIL: A transcranial Doppler sonography study. Stroke. 2001;32:17–21. [PubMed: 11136908]
  73. Piccirillo G, Magrì D, Mitra M, Rufa A, Zicari E, Stromillo ML, De Stefano N, Dotti MT. Increased QT variability in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Eur J Neurol. 2008;15:1216–21. [PubMed: 18803652]
  74. Pretegiani E, Rosini F, Dotti MT, Bianchi S, Federico A, Rufa A. Visual system involvement in CADASIL. J Stroke Cerebrovasc Dis. 2013;22:1377–84. [PubMed: 23635925]
  75. Ragno M, Berbellini A, Cacchiò G, Manca A, Di Marzio F, Pianese L, De Rosa A, Silvestri S, Scarcella M, De Michele G. Parkinsonism is a late, not rare, feature of CADASIL: a study on Italian patients carrying the R1006C mutation. Stroke. 2013;44:1147–9. [PubMed: 23412372]
  76. Ragno M, Trojano L, Pianese L, Boni MV, Silvestri S, Mambelli V, Lorenzi T, Scarpelli M, Morroni M. Renal involvement in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): report of a case with a six-year follow-up. Histol Histopathol. 2012;27:1307–14. [PubMed: 22936449]
  77. Razvi SS, Davidson R, Bone I, Muir KW. Is inadequate family history a barrier to diagnosis in CADASIL? Acta Neurol Scand. 2005a;112:323–6. [PubMed: 16218915]
  78. Razvi SS, Davidson R, Bone I, Muir KW. The prevalence of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) in the west of Scotland. J Neurol Neurosurg Psychiatry. 2005b;76:739–41. [PMC free article: PMC1739620] [PubMed: 15834040]
  79. Reyes S, Viswanathan A, Godin O, Dufouil C, Benisty S, Hernandez K, Kurtz A, Jouvent E, O'Sullivan M, Czernecki V, Bousser MG, Dichgans M, Chabriat H. Apathy: a major symptom in CADASIL. Neurology. 2009;72:905–10. [PubMed: 19273824]
  80. Roine S, Poyhonen M, Timonen S, Tuisku S, Marttila R, Sulkava R, Kalimo H, Viitanen M. Neurologic symptoms are common during gestation and puerperium in CADASIL. Neurology. 2005;64:1441–3. [PubMed: 15851739]
  81. Ruchoux MM, Guerouaou D, Vandenhaute B, Pruvo JP, Vermersch P, Leys D. Systemic vascular smooth muscle cell impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Acta Neuropathol. 1995;89:500–12. [PubMed: 7676806]
  82. Ruchoux MM, Maurage CA. CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. J Neuropathol Exp Neurol. 1997;56:947–64. [PubMed: 9291937]
  83. Rufa A, Guideri F, Acampa M, Cevenini G, Bianchi S, De Stefano N, Stromillo ML, Federico A, Dotti MT. Cardiac autonomic nervous system and risk of arrhythmias in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Stroke. 2007;38:276–80. [PubMed: 17218610]
  84. Rutten JW, Boon EM, Liem MK, Dauwerse JG, Pont MJ, Vollebregt E, Maat-Kievit AJ, Ginjaar HB, Lakeman P, van Duinen SG, Terwindt GM, Lesnik Oberstein SA. Hypomorphic NOTCH3 alleles do not cause CADASIL in humans. Hum Mutat. 2013;34:1486–9. [PubMed: 24000151]
  85. Rutten JW, Haan J, Terwindt GM, van Duinen SG, Boon EM, Lesnik Oberstein SA. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014;14:593–603. [PubMed: 24844136]
  86. Schon F, Martin RJ, Prevett M, Clough C, Enevoldson TP, Markus HS. "CADASIL coma": an underdiagnosed acute encephalopathy. J Neurol Neurosurg Psychiatry. 2003;74:249–52. [PMC free article: PMC1738281] [PubMed: 12531961]
  87. Schröder JM, Zuchner S, Dichgans M, Nagy Z, Molnar MJ. Peripheral nerve and skeletal muscle involvement in CADASIL. Acta Neuropathol (Berl) 2005;110:587–99. [PubMed: 16328531]
  88. Sicurelli F, Dotti MT, De Stefano N, Malandrini A, Mondelli M, Bianchi S, Federico A. Peripheral neuropathy in CADASIL. J Neurol. 2005;252:1206–9. [PubMed: 15827866]
  89. Singhal S, Bevan S, Barrick T, Rich P, Markus HS. The influence of genetic and cardiovascular risk factors on the CADASIL phenotype. Brain. 2004;127:2031–8. [PubMed: 15229130]
  90. Singhal S, Rich P, Markus HS. The spatial distribution of MR imaging abnormalities in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and their relationship to age and clinical features. AJNR Am J Neuroradiol. 2005;26:2481–7. [PubMed: 16286388]
  91. Soong BW, Liao YC, Tu PH, Tsai PC, Lee IH, Chung CP, Lee YC. A homozygous NOTCH3 mutation p.R544C and a heterozygous TREX1 variant p.C99MfsX3 in a family with hereditary small vessel disease of the brain. J Chin Med Assoc. 2013;76:319–24. [PubMed: 23602593]
  92. Tikka S, Mykkanen K, Ruchoux MM, Bergholm R, Junna M, Poyhonen M, Yki-Jarvinen H, Joutel A, Viitanen M, Baumann M, Kalimo H. Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients. Brain. 2009;132:933–9. [PMC free article: PMC2668941] [PubMed: 19174371]
  93. Tuominen S, Juvonen V, Amberla K, Jolma T, Rinne JO, Tuisku S, Kurki T, Marttila R, Poyhonen M, Savontaus ML, Viitanen M, Kalimo H. Phenotype of a homozygous CADASIL patient in comparison to 9 age-matched heterozygous patients with the same R133C Notch3 mutation. Stroke. 2001;32:1767–74. [PubMed: 11486103]
  94. Tuominen S, Miao Q, Kurki T, Tuisku S, Pöyhönen M, Kalimo H, Viitanen M, Sipilä HT, Bergman J, Rinne JO. Positron emission tomography examination of cerebral blood flow and glucose metabolism in young CADASIL patients. Stroke. 2004;35:1063–7. [PubMed: 15017012]
  95. Valenti R, Pescini F, Antonini S, Castellini G, Poggesi A, Bianchi S, Inzitari D, Pallanti S, Pantoni L. Major depression and bipolar disorders in CADASIL: a study using the DSM-IV semi-structured interview. Acta Neurol Scand. 2011;124:390–5. [PubMed: 21428968]
  96. van Den Boom R, Lesnik Oberstein SA, Spilt A, Behloul F, Ferrari MD, Haan J, Westendorp RG, van Buchem MA. Cerebral hemodynamics and white matter hyperintensities in CADASIL. J Cereb Blood Flow Metab. 2003;23:599–604. [PubMed: 12771575]
  97. van Den Boom R, Lesnik Oberstein SA, van Duinen SG, Bornebroek M, Ferrari MD, Haan J, van Buchem MA. Subcortical lacunar lesions: an MR imaging finding in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Radiology. 2002;224:791–6. [PubMed: 12202716]
  98. Vinciguerra C, Rufa A, Bianchi S, Sperduto A, De Santis M, Malandrini A, Dotti MT, Federico A. Homozygosity and severity of phenotypic presentation in a CADASIL family. Neurol Sci. 2014;35:91–3. [PubMed: 24277202]
  99. Wang Z, Yuan Y, Zhang W, Lv H, Hong D, Chen B, Liu Y, Luan X, Xie S, Wu S. NOTCH3 mutations and clinical features in 33 mainland Chinese families with CADASIL. J Neurol Neurosurg Psychiatry. 2011;82:534–9. [PubMed: 20935329]
  100. Williamson EE, Chukwudelunzu FE, Meschia JF, Witte RJ, Dickson DW, Cohen MD. Distinguishing primary angiitis of the central nervous system from cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: the importance of family history. Arthritis Rheum. 1999;42:2243–8. [PubMed: 10524700]
  101. Yanagawa S, Ito N, Arima K, Ikeda S. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy. Neurology. 2002;58:817–20. [PubMed: 11889251]
  102. Yao M, Herve D, Jouvent E, Duering M, Reyes S, Godin O, Guichard JP, Dichgans M, Chabriat H. Dilated perivascular spaces in small-vessel disease: a study in CADASIL. Cerebrovasc Dis. 2014;37:155–63. [PubMed: 24503815]
  103. Yin X, Wu D, Wan J, Yan S, Lou M, Zhao G, Zhang B. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: Phenotypic and mutational spectrum in patients from mainland China. Int J Neurosci. 2014 Sep 1 Epub ahead of print. [PubMed: 25105908]

Suggested Reading

  1. Bowler JV. Vascular cognitive impairment. J Neurol Neurosurg Psychiatry. 2005;76 Suppl 5:v35–44. [PMC free article: PMC1765709] [PubMed: 16291920]
  2. Kalaria RN, Viitanen M, Kalimo H, Dichgans M, Tabira T. The pathogenesis of CADASIL: an update. J Neurol Sci. 2004;226:35–9. [PubMed: 15537516]
  3. Lesnik Oberstein SA, Haan J. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Panminerva Med. 2004;46:265–76. [PubMed: 15876982]

Chapter Notes

Author History

Elles MJ Boon, PhD; Leiden University Medical Center (2006-2015)
Martijn H Breuning, MD, PhD; Leiden University Medical Center (2000-2006)
Martin Dichgans, MD, PhD; Ludwig-Maximilians-Universität München (2006-2012)
J Haan, MD, PhD; Leiden University Medical Center (2000-2006)
Saskia AJ Lesnik Oberstein, MD, PhD (2000-present)
Julie Rutten, MD (2015-present)
Gisela M Terwindt, MD, PhD; Leiden University Medical Center (2012-2015)

Revision History

  • 26 February 2015 (me) Comprehensive update posted live
  • 28 June 2012 (me) Comprehensive update posted live
  • 23 July 2009 (me) Comprehensive update posted live
  • 21 November 2006 (me) Comprehensive update posted to live Web site
  • 2 August 2004 (me) Comprehensive update posted to live Web site
  • 23 August 2002 (me) Comprehensive update posted to live Web site
  • 15 March 2000 (pb) Review posted to live Web site
  • January 2000 (slo) Original submission
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