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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.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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.
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. More than 90% of individuals have mutations in NOTCH3, the only gene known to be associated with CADASIL. 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 appear to be rare. Each child of an affected person is at a 50% risk of inheriting the mutation and developing signs of the disease. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation 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.
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, Liem et al 2008a].
MRI white matter hyperintensities, although sometimes very subtle, are consistently visualized from age 21 years onward [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 [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 approximately two-thirds of affected individuals and may be a specific marker for CADASIL [van den Boom et al 2002].
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 osmophilic 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 electron microscopy, but is not offered routinely in a diagnostic setting [Joutel et al 2001, Oberstein 2003].
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.
Clinical testing
Sequence analysis/mutation scanning of entire coding and flanking intronic regions. 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, Oberstein et al 1999, Markus et al 2002, Peters et al 2005a]. 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 et al 2005a], while exon 11 frequently harbors mutations in affected Dutch persons [Oberstein 2003].
The mutation detection rate is up to 96% in individuals with well-defined or biopsy-proven CADASIL [Markus et al 2002, Peters et al 2005a].
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 (mutation scanning by a method such as single-strand conformation polymorphism (SSCP) analysis vs direct sequence analysis)
Population differences, including possible founder effects [Mykkanen et al 2004]
Different inclusion criteria
| Gene Symbol | Test Method | Mutations Detected | Mutation Detection Frequency | Test Availability |
|---|---|---|---|---|
| NOTCH3 | Sequence analysis/mutation scanning | Sequence variants | Estimated >95% 1 | Clinical
 |
| Sequence analysis/mutation scanning of select exons 2 | Sequence variants | Unknown |
1. When all epidermal growth factor-like (EGFL) repeats are sequenced and stringent inclusion criteria are applied
2. Exons sequenced/scanned vary by laboratory.
Interpretation of test results
Homozygous mutations have been described in CADASIL [Tuominen et al 2001, Liem et al 2008b]. The phenotype of individuals homozygous for NOTCH3 mutations falls within the CADASIL spectrum.
For issues to consider in interpretation of sequence analysis results, click here.
Confirming/establishing the diagnosis in a proband. NOTCH3 molecular genetic testing should begin with exons 2-6 and 11, followed by complete sequencing of all EGFL repeats.
Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.
No other phenotype is known to be caused by mutations in the NOTCH3 gene.
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 approximately 85% of symptomatic individuals [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 approximately 46 years (age 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 (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, those observations may be coincidental.
Cognitive deficits and dementia. Cognitive deficits, the second most frequent feature, are observed in approximately 60% of symptomatic individuals. They may start as early as age 35 years. Approximately 75% of affected individuals develop dementia [Dichgans et al 1998, Opherk et al 2004, Dichgans 2009].
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 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 mutations 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 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 approximately a dozen individuals, with confusion, headache, pyrexia, seizures, and coma, sometimes leading to death [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 [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 and puerperium (the period between childbirth and the return of the uterus to its normal size), particularly in those older than age 30 years [Roine et al 2005].
Other
Cardiac involvement. Controversy 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 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 of inability to walk without assistance was approximately 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 and 63% 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. Cerebral blood flow, cerebral blood volume, and cerebral glucose utilization are significantly reduced [Chabriat et al 2000, Bruening et al 2001, Pfefferkorn et al 2001]. In addition, cerebral vasoreactivity is impaired, consistent with the observed degeneration of vascular smooth muscle cells in small arteries and arterioles. Increased fragility of cerebral microvessels is suggested by a high frequency of cerebral microbleeds at autopsy and on gradient echo MR images [Dichgans et al 2002].
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.
Homozygous mutations have been described in CADASIL [Tuominen et al 2001, Liem et al 2008b]. The phenotype of individuals homozygous for NOTCH3 mutations 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.
Based on a small registry for CADASIL in the area of Glasgow, Razvi et al [2005b] calculated a mutation 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].
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), sporadic small vessel disease including Binswanger's disease, 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 [Gladstone & Dodick 2005].
To establish the extent of disease 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)
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.
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.
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].
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
A double-blind placebo-controlled trial evaluating the efficacy and safety of donepezil HCL in individuals with CADASIL revealed that donepezil had no effect on the primary (cognitive) endpoint, the V-ADAS-cog score in patients with CADASIL who had cognitive impairment. Improvements were noted however on several secondary measures of executive function; the clinical relevance of these findings is not clear [Dichgans et al 2008].
Search ClinicalTrials.gov 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, 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.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
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.
CADASIL is inherited in an autosomal dominant manner.
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 below).
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 et al 2001, Liem et al 2008b]. 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 on 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.
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.
Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults is available using the 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 younger than age 18 years. Consensus holds that 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.
Genetic testing is always indicated in affected or symptomatic individuals in a family with established CADASIL regardless of age.
For more information, see 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 (pdf; Genetic Testing).
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 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. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made 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. 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 when the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
Prenatal testing for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately 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].
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. For laboratories offering PGD, see
.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name | Locus Specific | HGMD |
|---|---|---|---|---|
| NOTCH3 | 19p13.2-p13.1 | Neurogenic locus notch homolog protein 3 | Notch homolog 3 (NOTCH3) @ LOVD | NOTCH3 |
| 125310 | CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY; CADASIL |
| 600276 | NOTCH, DROSOPHILA, HOMOLOG OF, 3; NOTCH3 |
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. 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 occur in exons 2-6 [Peters et al 2005a], but there are regional differences [Federico et al 2005]. (For more information, see Table A.) There are some reports of possible cysteine-sparing NOTCH3 mutations in patients with a CADASIL or CADASIL-like phenotype [Kim et al 2006, Scheid et al 2008]. Note that there is still debate whether these mutations are really pathogenic and in the authors’ experience (unpublished data), for instance, the p.Ala1020Pro mutation described by Scheid and colleagues has been detected in conjunction with a typical cysteine-sparing mutation.
| DNANucleotide Change (Alias 1) | Protein Amino Acid Change | Reference Sequences |
|---|---|---|
| c.350G>T | p.Cys117Phe | NM_000435.2NP_000426.2 |
| c.457C>T | p.Arg153Cys | |
| c.521G>A | p.Cys174Tyr | |
| c.539C>G | p.Ser180Cys | |
| c.3058G>C | p.Ala1020Pro |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).
1. Variant designation that does not conform to current naming conventions
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 the control of vascular mechano-transduction [Belin de Chantemèle et al 2008]. 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.
Abnormal gene product. The functional consequences of NOTCH3 mutations in the abnormal protein are unknown. In almost all cases, 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].
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
Elles MJ Boon, PhD (2006-present)
Martijn H Breuning, MD, PhD; Leiden University Medical Center (2000-2006)
Martin Dichgans, MD, PhD (2006-present)
J Haan, MD, PhD; Leiden University Medical Center (2000-2006)
Saskia AJ Lesnik Oberstein, MD, PhD (2000-present)
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
