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CADASIL

[Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy]

Summary

Disease characteristics.  CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is characterized by a history of migraine headaches (30%-40% of individuals), mid-adult (30s-60s) onset of cerebrovascular disease progressing to dementia, and diffuse white matter lesions and subcortical infarcts on neuroimaging.

Diagnosis/testing.  The pathologic hallmark of CADASIL is electron-dense granules in the media of arterioles that can often be identified by electron microscopic (EM) evaluation of skin biopsies. NOTCH3 is the only gene known to be associated with CADASIL. More than 90% of individuals have mutations in the NOTCH3 gene. Molecular genetic testing is available on a clinical basis.

Management.  Treatment of manifestations: 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.

Genetic counseling.  CADASIL is inherited in an autosomal dominant manner. Most affected individuals have an affected parent; de novo mutations are rare. Each child of an affected person is at a 50% risk of inheriting the mutation and developing signs of the disease. Prenatal testing is possible; however, requests for prenatal testing of typically adult-onset disorders are uncommon.

Diagnosis

Clinical Diagnosis

There are no generally accepted diagnostic criteria for CADASIL.

The presenting symptoms, age at onset, and disease progression in CADASIL vary. Typical signs and symptoms:

• Stroke-like episodes before age 60 years
• Cognitive disturbance (dysexecutive syndrome)
• Behavioral abnormalities
• Migraine with aura

Frequent and diagnostically important signs on brain magnetic resonance imaging (MRI) [Auer et al 2001 , O'Sullivan et al 2001]:

• T2-signal-abnormalities in the white matter of the temporal pole
• T2-signal-abnormalities in the external capsule

A family history consistent with autosomal dominant inheritance supports the diagnosis [Dichgans et al 1998 , Razvi et al 2005a] but is not required [Joutel et al 2000].

Brain imaging.  Imaging abnormalities in CADASIL evolve as the disease progresses [van den Boom et al 2003 , Singhal et al 2005]. MRI white matter hyperintensities, although sometimes very subtle, are consistently visualized from age 21 years onward [Lesnik Oberstein 2003]. In individuals age 20-30 years with a pathogenic mutation, distinctive white matter hyperintensities first appear in the anterior temporal lobes, when the rest of the white matter, except for periventricular caps, appears unaffected [Lesnik 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].

Additional findings:

• Subcortical lacunar lesions (SLLs).   Linearly arranged groups of rounded, circumscribed lesions at the junction of the grey and white matter with signal intensity identical to that of cerebrospinal fluid, SLLs are found in about two-thirds of affected individuals and may be a specific marker for CADASIL [Van den Boom et al 2002]. They are preferentially located in the basal ganglia, the thalamus, and the brain stem (in particular the pons).

• Cerebral microbleeds.   Located predominantly in the thalamus, cerebral microbleeds are best visualized with T2*-weighted gradient echo imaging [Lesnik Oberstein et al 2001 , Dichgans et al 2002].

Pathology.  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 osmiophilic material within the vascular media close to smooth muscle cells. These changes are highly specific for CADASIL but the sensitivity of biopsy is limited and depends on the quality of the sample and skills of the pathologist [Schultz et al 1999].

NOTCH3 immunostaining, a means of confirming the diagnosis, is quite sensitive, specific, and more straightforward than electronmicroscopy, but not yet commercially available [Joutel et al 2001 , Lesnik Oberstein 2003].

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.

Gene.   NOTCH3 is the only gene currently known to be associated with CADASIL.

Molecular genetic testing: Clinical uses

• Confirmatory diagnostic testing
• Predictive testing
• Prenatal diagnosis

Molecular genetic testing: Clinical method

Sequence analysis.  Most mutations in the NOTCH3 gene in individuals with CADASIL are located in exon 4, followed by exons 3, 5, 6, and 11 [Joutel et al 1997 ; Lesnik Oberstein et al 1999 ; Markus et al 2002 ; Peters, Opherk, Bergmann et al 2005]. Geographic variations have been described, showing exon 3 to be the second most common mutation site in French, British, and German persons [Joutel et al 1997 ; Markus et al 2002 ; Peters, Opherk, Bergmann et al 2005], while exon 11 is frequently affected in Dutch persons [Lesnik Oberstein 2003].

The mutation detection rate ranges from 57% to 96% in individuals with well-defined or biopsy-proven CADASIL [Markus et al 2002 ; Peters, Opherk, Bergmann et al 2005].

Possible explanations for the discrepancies between different studies in the location of the mutations and the mutation detection rate include the following:

• Study size
• Differences in molecular genetic testing methods (single-strand conformation polymorphism analysis vs direct sequencing)
• Population differences, including possible founder effects [Mykkanen et al 2004]
• Different inclusion criteria

Table 1. Molecular Genetic Testing Used in CADASIL Test Method Mutations Detected Mutation Detection Rate Test Availability Sequence analysis Sequence alteration in NOTCH3 Estimated >95%  1 Clinical

1. When all epidermal growth factor-like (EGFL) repeats are sequenced

Interpetation of test results.  Homozygous mutations have been described in CADASIL [Tuominen 2001 ; Lesnik Oberstein, unpublished observation].

For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy for a Proband

NOTCH3 molecular genetic testing should begin with exons 2-6 and 11, followed by complete sequencing of all EGFL repeats.

Genetically Related (Allelic) Disorders

No other phenotype is known to be caused by mutations in the NOTCH3 gene.

NOTCH3 over-expression has been described in ovarian cancer [Park et al 2006] and neuroblastoma [van Limpt et al 2005].

Clinical Description

Natural History

CADASIL is a microangiopathy mainly affecting the brain. The presenting symptoms, age at onset, and disease progression in CADASIL vary.

Stroke-like episodes.  Transient ischemic attacks (TIAs) and stroke, the most frequent presentation, are found in about 85% of symptomatic individuals [Chabriat, Vahedi et al 1995 ; Dichgans et al 1998]. Strokes related to small vessel pathology are clearly the main manifestation of the disease.

Mean age at onset for ischemic episodes is around 46 years (range: ~19-67 years) [Opherk et al 2004].

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 (brainstem 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 [Rubio et al 1997]. However, those observations may be coincidental.

Cognitive deficits and dementia.  Cognitive deficits, the second most frequent feature, are observed in about 60% of symptomatic individuals. They may start as early as age 35 years. About 75% of affected individuals develop dementia [Dichgans et al 1998 , Opherk et al 2004].

The pattern of cognitive dysfunction is characterized by deficits in executive function (timed measures and measures of error monitoring), verbal fluency, and memory with benefit from clues [Peters, Opherk, Danek et al 2005]. 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 mutations in the prestroke phase, and infer that cognitive decline may start insidiously before the onset of symptomatic ischemic episodes.

Migraine.  Migraine occurs in about 40% of individuals with CADASIL, with the first attack occurring at a mean age of 26 years. Ninety percent of individuals with migraine have migraine with aura [Dichgans et al 1998]. In some families with CADASIL, migraine with aura is the most prominent symptom.

Reversible acute encephalopathy.  Acute encephalopathy has been described in about a dozen individuals, with confusion, headache, pyrexia, seizures, and coma, sometimes leading to death [Chabriat, Vahedi et al 1995 ; Feuerhake et al 2002 ; Schon et al 2003].

Psychiatric disorders.  Thirty percent of individuals with CADASIL experience psychiatric disturbance, varying from personality changes to severe depression [Dichgans et al 1998]. Whether these disturbances are primary or reactive is not yet clear. However, individuals with CADASIL presenting with psychiatric problems have been described [Lalith-Kumar & Mahr 1997 , Leyhe et al 2005 , Nakamura et al 2005].

Epilepsy.  Epilepsy is present in 10% of individuals with CADASIL and presents at middle age [Dichgans et al 1998].

Pregnancy.  A retrospective study of 25 women found an increased frequency of ischemic symptoms (TIA and stroke) during pregnancy, particularly in those older than age 30 years [Roine et al 2005].

Other

• Cardiac involvement.  Controversity exists as to whether CADASIL is associated with cardiac involvement. In a study from The Netherlands, nearly 25% of individuals with NOTCH3 mutations 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 mutation. However, another study of 23 individuals with a NOTCH3 mutation found no signs of previous MI on ECG [Cumurciuc et al 2006].

• Subclinical peripheral neuropathy has been reported in some individuals [Schroder et al 2005 , Sicurelli et al 2005].

• Ocular findings.  Subclinical retinal lesions are also reported [Cumurciuc et al 2004]. Fundoscopy may reveal clinically silent retinal vascular abnormalities [Haritoglou et al 2004].

• Long-term prognosis and causes of death.  Data on the long-term prognosis come from a large study of 411 individuals [Opherk et al 2004]. According to that study the median age at onset for inability to walk without assistance was about 60 years and the median age at onset of being 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. At onset of the cause of death, 78% of individuals were completely dependent. Sixty-three percent were confined to bed. Pneumonia was the most frequent cause of death, followed by sudden unexpected death and asphyxia.

• 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 [Chabriat, Bousser et al 1995]. Cerebral blood flow, cerebral blood volume, and cerebral glucose utilization are significantly reduced [Chabriat et al 2000 , Bruning et al 2001 , Pfefferkorn et al 2001]. In addition, there is evidence for marked impairment of cerebral vasoreactivity, which agrees with the observed degeneration of vascular smooth muscle cells (VSMC) in small arteries and arterioles [Ruchoux & Maurage 1997]. An increased fragility of cerebral microvessels in individuals with CADASIL is suggested by a high frequency of cerebral microbleeds at autopsy and on gradient echo MR images [Dichgans et al 2002].

Genotype-Phenotype Correlations

Although some studies describe phenotype-genotype correlations, 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.

Dichgans et al (1999) found no influence of the NOTCH3 genotype on quantitative MRI variables.

Opherk et al (2004) found the p.C117F mutation associated with a lower age at death and the p.C174K mutation with a lower of age of onset for stroke and death.

Lesnik Oberstein et al (2001) detected an increased number of cerebral microbleeds in individuals with the p.R153C mutation.

Homozygous mutations have been described in CADASIL [Tuominen 2001 ; Lesnik Oberstein, unpublished observation]. The phenotype of individuals homozygous for NOTCH3 mutations falls within the CADASIL spectrum.

Penetrance

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

Anticipation

Anticipation, the phenomenon in which increasing disease severity or decreasing age of onset is observed in successive generations, was suggested in a family with a p.S180C mutation reported by Nakamura et al (2005). No other occurrence of anticipation in persons with CADASIL has been reported.

Nomenclature

Previous descriptions of families with "hereditary multi-infarct dementia," "chronic familial vascular encephalopathy," and "familial subcortical dementia" represent early reports of CADASIL [Sourander & Walinder 1977 , Stevens et al 1977 , Davous & Fallet-Bianco 1991].

Prevalence

Based on a small registry for CADASIL in the area of Glasgow, Razvi and colleagues (2005b) calculated a mutation carrier frequency of 1.98 per 100,000 adults.

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 [Mykkanen et al 2004].

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

The differential diagnosis of CADASIL includes multiple sclerosis (MS) [Vahedi et al 1996], sporadic small vessel disease including Binswanger's disease [Caplan 1995], and primary angiitis of the nervous system [Williamson et al 1999]. 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 include Fabry disease , CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy) [Yanagawa et al 2002], MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes), and some forms of leukodystrophy. 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 [Glastone & Dodick 2005].

Management

Evaluations at Initial Diagnosis to Establish the Extent of Disease

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

Treatment of Manifestations

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

No specific support group exists for individuals with CADASIL, but information relevant to Huntington disease and Alzheimer disease can well be applied to CADASIL.

Prevention of Primary Manifestations

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

Surveillance

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 [Dichgans & Petersen 1997 , Lesnik Oberstein et al 2001].

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

Therapies Under Investigation

A double-blind placebo-controlled trial evaluating the efficacy and safety of Donepezil HCL in individuals with CADASIL who have cognitive impairment has just been completed. The data of this trial are currently being analyzed.

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

Other

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

Based on the experience with stroke in general, many neurologists prescribe salicylates. Whether these have any effect on 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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.

Mode of Inheritance

CADASIL is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with CADASIL have an affected parent, although occasionally the family history is reported to be negative.
• A proband with CADASIL may have the disorder as the result of a new gene mutation. One such mutation has been reported [Joutel et al 2000].
• The recommended evaluation of apparently asymptomatic parents of an individual with CADASIL who has a known NOTCH3 mutation is molecular genetic testing. Note that genetic testing of asymptomatic parents should be performed in the context of formal genetic counseling as such testing constitutes predictive testing.
• In a proband with no known mutation and no family history of CADASIL, neuroimaging and/or skin biopsy of parents may be considered. If the parents are deceased, review of available neuroimaging and medical records may provide sufficient information to retrospectively diagnose the affected parent.
• An apparently negative family history cannot be confirmed until appropriate evaluations have been performed (see Note).
• Razvi et al (2005a) documented that a false-negative family history was common for individuals presenting with features of CADASIL. They conclude that restriction of family history to premature stroke alone is probably inadequate to identify affected CADASIL pedigrees.
• Homozygous mutations in NOTCH3 have been described in individuals with CADASIL [Tuominen 2001 ; Lesnik Oberstein, unpublished observation]. In such cases, both parents of a proband may have a NOTCH3 mutation.

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 upon the genetic status of the proband's parents.
• If a parent of the proband is affected, the risk to sibs is 50%.
• If the proband is homozygous for a NOTCH3 mutation and both parents are heterozygous, the risk to the sibs of the proband of having at least one NOTCH3 mutation is 75%.
• If the disease-causing mutation cannot be detected in the DNA extracted from leukocytes 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 mutation has a 50% chance of inheriting the mutation.
• Offspring of a proband who is homozygous or compound heterozygous for NOTCH3 mutations have a 100% chance of inheriting one of the mutations.

Related Genetic Counseling Issues

Testing of at-risk asymptomatic adults.  Testing of at-risk asymptomatic adults is available using the same techniques described in Molecular Genetic Testing . This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. Routine testing of asymptomatic at-risk individuals with nonspecific or equivocal symptoms is predictive testing, not diagnostic testing. When testing at-risk individuals, an affected family member should be tested first to confirm that the mutation is identifiable by currently available techniques.

It is appropriate to follow the guidelines published for presymptomatic testing for Huntington disease . At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations, including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pretest interviews in which the motives for requesting the test, the individual's knowledge of CADASIL, and the possible impact of positive and negative test results are assessed. Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow-up and evaluations.

Testing for at-risk asymptomatic individuals during childhood.  Consensus holds that individuals younger than age 18 years at risk for adult-onset disorders should not have testing in the absence of symptoms. The principal arguments against testing asymptomatic individuals during childhood are that it removes their choice to know or not know this information, it raises the possibility of stigmatization within the family and in other social settings, and it could have serious educational and career implications. Symptomatic individuals who are younger than age 18 years usually benefit from having a specific diagnosis established. (See also the National Society of Genetic Counselors resolution on genetic testing of children and the American Society of Human Genetics and American College of Medical Genetics points to consider : ethical, legal, and psychosocial implications of genetic testing in children and adolescents.)

Considerations in families with an apparent de novo mutation.  When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation 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 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. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.

DNA banking.  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, mutations, and diseases will improve in the future, consideration should be given to banking DNA, particularly in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

Prenatal testing for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The disease-causing mutation of an affected family member must be identified before prenatal testing can be performed. Prenatal diagnosis of CADASIL has been reported [Milunsky et al 2005 ; Lesnik Oberstein, unpublished data].

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering PGD, see .

Molecular Genetics

Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.

Normal allelic variants: The NOTCH3 gene consists of 33 exons spanning roughly 7 kb.

Pathologic allelic variants: The majority of sequence alterations in the NOTCH3 gene are missense mutations (95%), characteristically leading to the loss or gain of a cysteine residue in one of the EGF-like domains of the protein encoded by the NOTCH3 gene [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 [Joutel et al 1997]. A splice-site mutation and five small deletions, also resulting in an uneven number of cysteine residues, have been described [Joutel & Tournier-Lasserve 1998 , Federico et al 2005]. Almost 90% of mutations occurred in exons 2-6 [Peters, Opherk, Bergmann et al 2005], but there are regional differences [Federico et al 2005]. (For more information, see Genomic Databases table above.)

Normal gene product: Members of the NOTCH gene family encode evolutionarily conserved transmembrane receptors, which are involved in cell fate specification during development [Weinmaster 1997]. The protein encoded by the NOTCH3 gene consists of 2321 amino acids. It has an extracellular ligand-binding domain of 34 epidermal growth factor-like repeats, traverses the membrane once, and has an intracellular domain required for signal transduction [Weinmaster 1997].

Abnormal gene product: The functional consequences of NOTCH3 mutations in the abnormal protein are unknown. The mutations lead to loss or gain of a cysteine residue. This has led to the hypotheses that either the mutations affect folding by disrupting disulphide bonding of the cysteine residues or they could lead to increased reactivity of the NOTCH3 protein. Another proposal is that the receptor cannot be properly internalized resulting in enhanced ligand binding or, alternatively, toxic effects [Louvi et al 2006].

Resources

GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.

References

Published Statements and Policies Regarding Genetic Testing

• American Society of Human Genetics and American College of Medical Genetics (1995) Points to consider : ethical, legal, and psychosocial implications of genetic testing in children and adolescents.
  
  
• The National Society of Genetic Counselors (1995) Resolution on prenatal and childhood testing for adult-onset disorders.

Literature Cited

• Amberla K, Waljas M, Tuominen S, Almkvist O, Poyhonen M, Tuisku S, Kalimo H, Viitanen M (2004) Insidious cognitive decline in CADASIL. Stroke 35:1598-602 [Medline]
  
  
• Auer DP, Putz B, Gossl C, Elbel G, Gasser T, Dichgans M (2001) Differential lesion patterns in CADASIL and sporadic subcortical arteriosclerotic encephalopathy: MR imaging study with statistical parametric group comparison. Radiology 218:443-51 [Medline]
  
  
• Bruening R, Dichgans M, Berchtenbreiter C, Yousry T, Seelos KC, Wu RH, Mayer M, Brix G, Reiser M (2001) 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 22:1268-74 [Medline]
  
  
• Caplan LR (1995) Binswanger's disease--revisited. Neurology 45:626-33 [Medline]
  
  
• Chabriat H, Bousser MG, Pappata S (1995) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: a positron emission tomography study in two affected family members. Stroke 26:1729-30 [Medline]
  
  
• Chabriat H, Levy C, Taillia H, Iba-Zizen MT, Vahedi K, Joutel A, Tournier-Lasserve E, Bousser MG (1998) Patterns of MRI lesions in CADASIL. Neurology 51:452-7 [Medline]
  
  
• Chabriat H, Mrissa R, Levy C, Vahedi K, Taillia H, Iba-Zizen MT, Joutel A, Tournier-Lasserve E, Bousser MG (1999) Brain stem MRI signal abnormalities in CADASIL. Stroke 30:457-9 [Medline]
  
  
• Chabriat H, Pappata S, Ostergaard L, Clark CA, Pachot-Clouard M, Vahedi K, Jobert A, Le Bihan D, Bousser MG (2000) Cerebral hemodynamics in CADASIL before and after acetazolamide challenge assessed with MRI bolus tracking. Stroke 31:1904-12 [Medline]
  
  
• Chabriat H, Vahedi K, Iba-Zizen MT, Joutel A, Nibbio A, Nagy TG, Krebs MO, Julien J, Dubois B, Ducrocq X, et al (1995) Clinical spectrum of CADASIL: a study of 7 families. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Lancet 346:934-9 [Medline]
  
  
• Cumurciuc R, Henry P, Gobron C, Vicaut E, Bousser MG, Chabriat H, Vahedi K (2006) 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 37:1100-2 [Medline]
  
  
• Cumurciuc R, Massin P, Paques M, Krisovic V, Gaudric A, Bousser MG, Chabriat H (2004) Retinal abnormalities in CADASIL: a retrospective study of 18 patients. J Neurol Neurosurg Psychiatry 75:1058-60 [Medline]
  
  
• Davous P and Fallet-Bianco C (1991) [Familial subcortical dementia with arteriopathic leukoencephalopathy. A clinico-pathological case] Rev Neurol (Paris) 147:376-84 [Medline]
  
  
• Dichgans M and Petersen D (1997) Angiographic complications in CADASIL [letter]. Lancet 349:776-7 [Medline]
  
  
• Dichgans M, Filippi M, Bruning R, Iannucci G, Berchtenbreiter C, Minicucci L, Uttner I, Crispin A, Ludwig H, Gasser T, Yousry TA (1999) Quantitative MRI in CADASIL: correlation with disability and cognitive performance. Neurology 52:1361-7 [Medline]
  
  
• Dichgans M, Herzog J, Gasser T (2001) NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL. Neurology 57:1714-7 [Medline]
  
  
• Dichgans M, Holtmannspotter M, Herzog J, Peters N, Bergmann M, Yousry TA (2002) Cerebral microbleeds in CADASIL: a gradient-echo magnetic resonance imaging and autopsy study. Stroke 33:67-71 [Medline]
  
  
• Dichgans M, Mayer M, Uttner I, Bruning R, Muller-Hocker J, Rungger G, Ebke M, Klockgether T, Gasser T (1998) The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol 44:731-9 [Medline]
  
  
• Federico A, Bianchi S, Dotti MT (2005) The spectrum of mutations for CADASIL diagnosis. Neurol Sci 26:117-24 [Medline]
  
  
• Feuerhake F, Volk B, Ostertag CB, Jungling FD, Kassubek J, Orszagh M, Dichgans M (2002) Reversible coma with raised intracranial pressure: an unusual clinical manifestation of CADASIL. Acta Neuropathol (Berl) 103:188-92 [Medline]
  
  
• Gladstone JP and Dodick DW (2005) Migraine and cerebral white matter lesions: when to suspect cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Neurologist 11:19-29 [Medline]
  
  
• Goebel HH, Meyermann R, Rosin R, Schlote W (1997) Characteristic morphologic manifestation of CADASIL, cerebral autosomal- dominant arteriopathy with subcortical infarcts and leukoencephalopathy, in skeletal muscle and skin. Muscle Nerve 20:625-7 [Medline]
  
  
• Haritoglou C, Rudolph G, Hoops JP, Opherk C, Kampik A, Dichgans M (2004) Retinal vascular abnormalities in CADASIL. Neurology 62:1202-5 [Medline]
  
  
• Holtmannspotter M, Peters N, Opherk C, Martin D, Herzog J, Bruckmann H, Samann P, Gschwendtner A, Dichgans M (2005) Diffusion magnetic resonance histograms as a surrogate marker and predictor of disease progression in CADASIL: a two-year follow-up study. Stroke 36:2559-65 [Medline]
  
  
• Joutel A and Tournier-Lasserve E (1998) Notch signalling pathway and human diseases. Semin Cell Dev Biol 9:619-25 [Medline]
  
  
• Joutel A, Dodick DD, Parisi JE, Cecillon M, Tournier-Lasserve E, Bousser MG (2000) De novo mutation in the Notch3 gene causing CADASIL. Ann Neurol 47:388-91 [Medline]
  
  
• 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 (2001) Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. Lancet 358:2049-51 [Medline]
  
  
• 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 (1997) Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet 350:1511-5 [Medline]
  
  
• Kumar SK and Mahr G (1997) CADASIL presenting as bipolar disorder. [letter] Psychosomatics 38:397-8 [Medline]
  
  
• Lesnik Oberstein SA, Jukema JW, Van Duinen SG, Macfarlane PW, van Houwelingen HC, Breuning MH, Ferrari MD, Haan J (2003) Myocardial infarction in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Medicine (Baltimore) 82:251-6 [Medline]
  
  
• Lesnik Oberstein SA, van den Boom R, van Buchem MA, van Houwelingen HC, Bakker E, Vollebregt E, Ferrari MD, Breuning MH, Haan J (2001) Cerebral microbleeds in CADASIL. Neurology 57:1066-70 [Medline]
  
  
• Leyhe T, Wiendl H, Buchkremer G, Wormstall H (2005) CADASIL: underdiagnosed in psychiatric patients? Acta Psychiatr Scand 111:392-6 [Medline]
  
  
• Louvi A, Arboleda-Velasquez JF, Artavanis-Tsakonas S (2006) CADASIL: a critical look at a Notch disease. Dev Neurosci 28:5-12 [Medline]
  
  
• Markus HS, Martin RJ, Simpson MA, Dong YB, Ali N, Crosby AH, Powell JF (2002) Diagnostic strategies in CADASIL. Neurology 59:1134-8 [Medline]
  
  
• Milunsky A, Konialis C, Shim SH, Maher TA, Spengos K, Ito M, Pangalos C (2005) The prenatal diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) by mutation analysis. Prenat Diagn 25:1057-8 [Medline]
  
  
• Mykkanen K, Savontaus ML, Juvonen V, Sistonen P, Tuisku S, Tuominen S, Penttinen M, Lundkvist J, Viitanen M, Kalimo H, Poyhonen M (2004) Detection of the founder effect in Finnish CADASIL families. Eur J Hum Genet 12:813-9 [Medline]
  
  
• Nakamura T, Watanabe H, Hirayama M, Inukai A, Kabasawa H, Matsubara M, Mitake S, Nakamura M, Ando Y, Uchino M, Sobue G (2005) CADASIL with NOTCH3 S180C presenting anticipation of onset age and hallucinations. J Neurol Sci 238:87-91 [Medline]
  
  
• O'Sullivan M, Jarosz JM, Martin RJ, Deasy N, Powell JF, Markus HS (2001) MRI hyperintensities of the temporal lobe and external capsule in patients with CADASIL. Neurology 56:628-34 [Medline]
  
  
• O'Sullivan M, Jarosz JM, Martin RJ, Deasy N, Powell JF, Markus HS (2001) MRI hyperintensities of the temporal lobe and external capsule in patients with CADASIL. Neurology 56:628-34 [Medline]
  
  
• Oberstein SAJ (2003) Diagnostic strategies in CADASIL. Neurology 60:2020 [Medline]
  
  
• Oberstein SA, Ferrari MD, Bakker E, van Gestel J, Kneppers AL, Frants RR, Breuning MH, Haan J (1999) Diagnostic Notch3 sequence analysis in CADASIL: three new mutations in Dutch patients. Dutch CADASIL Research Group. Neurology 52:1913-5 [Medline]
  
  
• Opherk C, Peters N, Herzog J, Luedtke R, Dichgans M (2004) Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. Brain 127:2533-9 [Medline]
  
  
• Park JT, Li M, Nakayama K, Mao TL, Davidson B, Zhang Z, Kurman RJ, Eberhart CG, Shih IeM, Wang TL (2006) Notch3 gene amplification in ovarian cancer. Cancer Res 66:6312-8 [Medline]
  
  
• Peters N, Herzog J, Opherk C, Dichgans M (2004) A two-year clinical follow-up study in 80 CADASIL subjects: progression patterns and implications for clinical trials. Stroke 35:1603-8 [Medline]
  
  
• Peters N, Holtmannspotter M, Opherk C, Gschwendtner A, Herzog J, Samann P, Dichgans M (2006) Brain volume changes in CADASIL: a serial MRI study in pure subcortical ischemic vascular disease. Neurology 66:1517-22 [Medline]
  
  
• Peters N, Opherk C, Bergmann T, Castro M, Herzog J, Dichgans M (2005) Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies. Arch Neurol 62:1091-4 [Medline]
  
  
• Peters N, Opherk C, Danek A, Ballard C, Herzog J, Dichgans M (2005) The pattern of cognitive performance in CADASIL: a monogenic condition leading to subcortical ischemic vascular dementia. Am J Psychiatry 162:2078-85 [Medline]
  
  
• Pfefferkorn T, von Stuckrad-Barre S, Herzog J, Gasser T, Hamann GF, Dichgans M (2001) Reduced cerebrovascular CO(2) reactivity in CADASIL: A transcranial Doppler sonography study. Stroke 32:17-21 [Medline]
  
  
• Razvi SS, Davidson R, Bone I, Muir KW (2005a) Is inadequate family history a barrier to diagnosis in CADASIL? Acta Neurol Scand 112:323-6 [Medline]
  
  
• Razvi SS, Davidson R, Bone I, Muir KW (2005b) The prevalence of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) in the west of Scotland. J Neurol Neurosurg Psychiatry 76:739-41 [Medline]
  
  
• Roine S, Poyhonen M, Timonen S, Tuisku S, Marttila R, Sulkava R, Kalimo H, Viitanen M (2005) Neurologic symptoms are common during gestation and puerperium in CADASIL. Neurology 64:1441-3 [Medline]
  
  
• Rubio A, Rifkin D, Powers JM, Patel U, Stewart J, Faust P, Goldman JE, Mohr JP, Numaguchi Y, Jensen K (1997) Phenotypic variability of CADASIL and novel morphologic findings. Acta Neuropathol (Berl) 94:247-54 [Medline]
  
  
• Ruchoux MM and Maurage CA (1997) CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. J Neuropathol Exp Neurol 56:947-64 [Medline]
  
  
• Schon F, Martin RJ, Prevett M, Clough C, Enevoldson TP, Markus HS (2003) "CADASIL coma": an underdiagnosed acute encephalopathy. J Neurol Neurosurg Psychiatry 74:249-52 [Medline]
  
  
• Schroder JM, Zuchner S, Dichgans M, Nagy Z, Molnar MJ (2005) Peripheral nerve and skeletal muscle involvement in CADASIL. Acta Neuropathol (Berl) 110:587-99 [Medline]
  
  
• Schultz A, Santoianni R, Hewan-Lowe K (1999) Vasculopathic changes of CADASIL can be focal in skin biopsies. Ultrastruct Pathol 23:241-7 [Medline]
  
  
• Sicurelli F, Dotti MT, De Stefano N, Malandrini A, Mondelli M, Bianchi S, Federico A (2005) Peripheral neuropathy in CADASIL. J Neurol 252:1206-9 [Medline]
  
  
• Singhal S, Bevan S, Barrick T, Rich P, Markus HS (2004) The influence of genetic and cardiovascular risk factors on the CADASIL phenotype. Brain 127:2031-8 [Medline]
  
  
• Singhal S, Rich P, Markus HS (2005) 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 26:2481-7 [Medline]
  
  
• Sourander P and Walinder J (1977) Hereditary multi-infarct dementia. Morphological and clinical studies of a new disease. Acta Neuropathol (Berl) 39:247-54 [Medline]
  
  
• Stevens DL, Hewlett RH, Brownell B (1977) Chronic familial vascular encephalopathy. Lancet 1:1364-5 [Medline]
  
  
• Tuominen S, Juvonen V, Amberla K, Jolma T, Rinne JO, Tuisku S, Kurki T, Marttila R, Poyhonen M, Savontaus ML, Viitanen M, Kalimo H (2001) Phenotype of a homozygous CADASIL patient in comparison to 9 age-matched heterozygous patients with the same R133C Notch3 mutation. Stroke 32:1767-74 [Medline]
  
  
• Vahedi K, Tournier-Lasserve E, Vahedi K, Chabriat H, Bousser MG (1996) An additional monogenic disorder that masquerades as multiple sclerosis. [letter] Am J Med Genet 65:357-8 [Medline]
  
  
• van den Boom R, Lesnik Oberstein SA, Spilt A, Behloul F, Ferrari MD, Haan J, Westendorp RG, van Buchem MA (2003) Cerebral hemodynamics and white matter hyperintensities in CADASIL. J Cereb Blood Flow Metab 23:599-604 [Medline]
  
  
• van den Boom R, Lesnik Oberstein SA, van Duinen SG, Bornebroek M, Ferrari MD, Haan J, van Buchem MA (2002) Subcortical lacunar lesions: an MR imaging finding in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Radiology 224:791-6 [Medline]
  
  
• van Limpt V, Chan A, Schramm A, Eggert A, Versteeg R (2005) Phox2B mutations and the Delta-Notch pathway in neuroblastoma. Cancer Lett 228:59-63 [Medline]
  
  
• Weinmaster G (1997) The ins and outs of notch signaling. Mol Cell Neurosci 9:91-102 [Medline]
  
  
• Williamson EE, Chukwudelunzu FE, Meschia JF, Witte RJ, Dickson DW, Cohen MD (1999) 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 42:2243-8 [Medline]
  
  
• Yanagawa S, Ito N, Arima K, Ikeda S (2002) Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy. Neurology 58:817-20 [Medline]
  
  

Suggested Readings

• Bowler JV (2005) Vascular cognitive impairment. J Neurol Neurosurg Psychiatry 76 Suppl 5:35-44 [Medline]
  
  
• Kalaria RN, Viitanen M, Kalimo H, Dichgans M, Tabira T (2004) The pathogenesis of CADASIL: an update. J Neurol Sci 226:35-9 [Medline]
  
  
• Lesnik Oberstein SA and Haan J (2004) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Panminerva Med 46:265-76 [Medline]
  
  

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