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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>CADASIL - GeneReviews® - NCBI Bookshelf</title>
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<meta name="citation_publisher" content="University of Washington, Seattle">
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<meta name="citation_date" content="2019/03/14">
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<meta name="citation_author" content="Remco J Hack">
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<meta name="citation_author" content="Julie Rutten">
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<meta name="citation_author" content="Saskia AJ Lesnik Oberstein">
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<meta name="citation_keywords" content="Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy">
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<meta name="citation_keywords" content="Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy">
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<meta name="citation_keywords" content="Neurogenic locus notch homolog protein 3">
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<meta name="DC.Contributor" content="Saskia AJ Lesnik Oberstein">
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class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK1500_"><span class="title" itemprop="name">CADASIL</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonym: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy</div><p class="contribs">Hack RJ, Rutten J, Lesnik Oberstein SAJ.</p><p class="fm-aai"><a href="#_NBK1500_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 41 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="cadasil.Summary" itemprop="description"><h2 id="_cadasil_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>CADASIL (<i>c</i>erebral <i>a</i>utosomal <i>d</i>ominant <i>a</i>rteriopathy with <i>s</i>ubcortical <i>i</i>nfarcts and <i>l</i>eukoencephalopathy) 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.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of CADASIL is established in a proband either by identification of a heterozygous pathogenic variant in <i>NOTCH3</i> by molecular genetic testing or, if molecular genetic testing is not definitive, by detection of characteristic findings by electron microscopy and immunohistochemistry of a skin biopsy.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> There is no treatment of proven efficacy for CADASIL. Standard supportive treatment for stroke; the effect of thrombolytic therapy for the treatment of stroke remains unknown. Migraine should be treated symptomatically. Standard treatment for psychiatric disturbance. Supportive care (practical help, emotional support, and counseling) is appropriate for affected individuals and their families.</p><p><i>Prevention of primary manifestations</i>: Antiplatelet therapy may be considered for prevention of stroke/TIA, but efficacy has not been proven. Anticoagulants should be avoided if possible. Control of vascular risk factors (hypertension, diabetes, hypercholesterolemia, smoking). Prophylactic treatment of migraines, depending on the frequency.</p><p><i>Surveillance:</i> Routine evaluation by a neurologist with expertise in CADASIL; consultation with a neuropsychiatrist if symptoms of depression, apathy, or psychiatric manifestations; consultation with other medical specialists (e.g., rehabilitation physician, clinical geneticist, physical therapist, and psychologist) as needed.</p><p><i>Agents to avoid:</i> Thrombolytic therapy (intravenous thrombolysis) and oral anticoagulants probably increase the risk of intracerebral hemorrhage in individuals with CADASIL. These agents should therefore only be used carefully and on a case-by-case basis. Smoking increases the risk of stroke.</p><p><i>Pregnancy management</i>: There may be an increased risk for neurologic events in pregnancy during and shortly after delivery (puerperium); transient neurologic events (migraine with aura) have most commonly been reported.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>CADASIL is inherited in an autosomal dominant manner. Most affected individuals have an affected parent; <i>de novo</i> pathogenic variants 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 for a pregnancy at increased risk and preimplantation genetic testing are possible if the pathogenic variant in the family is known.</p></div></div><div id="cadasil.Diagnosis"><h2 id="_cadasil_Diagnosis_">Diagnosis</h2><p>There are no generally accepted diagnostic criteria for CADASIL (<i>c</i>erebral <i>a</i>utosomal <i>d</i>ominant <i>a</i>rteriopathy with <i>s</i>ubcortical <i>i</i>nfarcts and <i>l</i>eukoencephalopathy). A CADASIL diagnostic screening tool has been proposed by <a class="bibr" href="#cadasil.REF.pescini.2012.2871" rid="cadasil.REF.pescini.2012.2871">Pescini et al [2012]</a>, <a class="bibr" href="#cadasil.REF.mizuta.2017.62" rid="cadasil.REF.mizuta.2017.62">Mizuta et al [2017]</a>, and <a class="bibr" href="#cadasil.REF.bersano.2018.2934" rid="cadasil.REF.bersano.2018.2934">Bersano et al [2018]</a>.</p><div id="cadasil.Suggestive_Findings"><h3>Suggestive Findings</h3><p>CADASIL <b>should be suspected</b> in individuals with unexplained white matter hyperintensities and a family history of stroke and/or vascular dementia; however, lack of an apparent family history of CADASIL does not preclude the diagnosis (see <b>Family history</b>). The following clinical signs and neuroimaging findings can be observed in CADASIL.</p><p>
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<b>Clinical signs</b>
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</p><ul><li class="half_rhythm"><div>Transient ischemic attacks and ischemic stroke</div></li><li class="half_rhythm"><div>Cognitive impairment, manifesting initially with executive dysfunction, with a concurrent stepwise deterioration due to recurrent strokes to vascular dementia</div></li><li class="half_rhythm"><div>Migraine with aura, with a mean age of onset of 30 years</div></li><li class="half_rhythm"><div>Psychiatric disturbances, most frequently mood disturbances and apathy</div></li></ul><p>
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<b>Brain imaging</b>
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</p><ul><li class="half_rhythm"><div>Symmetric and progressive white matter hyperintensities, often involving the anterior temporal lobes and external capsules</div></li><li class="half_rhythm"><div>Lacunes of presumed vascular origin</div></li><li class="half_rhythm"><div>Recent subcortical infarcts</div></li><li class="half_rhythm"><div>Dilated perivascular spaces, sometimes referred to as subcortical lacunar lesions</div></li><li class="half_rhythm"><div>Brain atrophy</div></li><li class="half_rhythm"><div>Cerebral microbleeds</div></li></ul><p><b>Family history</b> consistent with autosomal dominant inheritance is suggestive. Note, however, that lack of an apparent family history of CADASIL does not preclude the diagnosis, as affected family members may have been misdiagnosed [<a class="bibr" href="#cadasil.REF.razvi.2005a.323" rid="cadasil.REF.razvi.2005a.323">Razvi et al 2005a</a>] and <i>de novo</i> cases have been described [<a class="bibr" href="#cadasil.REF.joutel.2000.388" rid="cadasil.REF.joutel.2000.388">Joutel et al 2000</a>, <a class="bibr" href="#cadasil.REF.coto.2006.628" rid="cadasil.REF.coto.2006.628">Coto et al 2006</a>].</p></div><div id="cadasil.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of CADASIL <b>is established</b> in a proband either by identification of a heterozygous pathogenic (or likely pathogenic) variant in <i>NOTCH3</i> by molecular genetic testing (see <a href="/books/NBK1500/table/cadasil.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figobcadasilTmoleculargenetictestingused">Table 1</a>) or, if molecular genetic testing is not definitive, by detection of characteristic findings by electron microscopy and immunohistochemistry of a <a href="#cadasil.Skin_Biopsy">skin biopsy</a>.</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [<a class="bibr" href="#cadasil.REF.richards.2015.405" rid="cadasil.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous <i>NOTCH3</i> variant of uncertain significance does not establish or rule out the diagnosis.</p><p>Molecular genetic testing approaches can include a combination of <b>gene-targeted testing</b> (single-gene testing, multigene panel) and <b>comprehensive</b>
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<b>genomic testing</b> (exome sequencing, exome array, genome sequencing) depending on the phenotype.</p><p>Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of CADASIL is broad, individuals with the distinctive findings described in <a href="#cadasil.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using gene-targeted testing (see <a href="#cadasil.Option_1">Option 1</a>), whereas those with a phenotype indistinguishable from many other inherited disorders with recurrent stroke and/or dementia are more likely to be diagnosed using genomic testing (see <a href="#cadasil.Option_2">Option 2</a>).</p><div id="cadasil.Option_1"><h4>Option 1</h4><p>When the phenotypic and laboratory findings suggest the diagnosis of CADASIL, molecular genetic testing approaches can include <b>single-gene testing</b> or use of a <b>multigene panel</b>:</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Single-gene testing.</b> Sequence analysis of <i>NOTCH3</i> (to include, at a minimum, exons 2-24) detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.</div><div class="half_rhythm">Perform sequence analysis first. If a biallelic pathogenic variant is identified, consider gene-targeted deletion/duplication analysis to determine if an unidentified exon deletion or duplication is present.</div><div class="half_rhythm">Note: Biallelic <i>NOTCH3</i> pathogenic variants have been described in individuals with CADASIL (see <a href="#cadasil.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a>).</div></li><li class="half_rhythm"><div class="half_rhythm"><b>A</b>
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<b>multigene panel</b> that includes <i>NOTCH3</i> and other genes of interest (see <a href="#cadasil.Differential_Diagnosis">Differential Diagnosis</a>) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.</div><div class="half_rhythm">For an introduction to multigene panels click <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels_FAQs">here</a>.</div></li></ul></div><div id="cadasil.Option_2"><h4>Option 2</h4><p>When the phenotype is indistinguishable from many other inherited disorders characterized by stroke and/or dementia, <b>comprehensive</b>
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<b>genomic testing</b> (which does not require the clinician to determine which gene[s] are likely involved) is the best option. <b>Exome sequencing</b> is most commonly used; <b>genome sequencing</b> is also possible.</p><p>For an introduction to comprehensive genomic testing click <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figcadasilTmoleculargenetictestingused"><a href="/books/NBK1500/table/cadasil.T.molecular_genetic_testing_used/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobcadasilTmoleculargenetictestingused"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="cadasil.T.molecular_genetic_testing_used"><a href="/books/NBK1500/table/cadasil.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figobcadasilTmoleculargenetictestingused">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in CADASIL </p></div></div></div><div id="cadasil.Skin_Biopsy"><h4>Skin Biopsy</h4><p>The diagnosis can be confirmed by ultrastructural analysis of small arterioles obtained, for example, by skin biopsy [<a class="bibr" href="#cadasil.REF.goebel.1997.625" rid="cadasil.REF.goebel.1997.625">Goebel et al 1997</a>, <a class="bibr" href="#cadasil.REF.ruchoux.1997.947" rid="cadasil.REF.ruchoux.1997.947">Ruchoux & Maurage 1997</a>]. Electron microscopy shows characteristic granular osmiophilic 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 [<a class="bibr" href="#cadasil.REF.tikka.2009.933" rid="cadasil.REF.tikka.2009.933">Tikka et al 2009</a>, <a class="bibr" href="#cadasil.REF.morroni.2013.e65482" rid="cadasil.REF.morroni.2013.e65482">Morroni et al 2013</a>].</p><p><i>NOTCH3</i> immunostaining of a skin biopsy shows a positive granular NOTCH3 staining of the vessel wall [<a class="bibr" href="#cadasil.REF.joutel.2001.2049" rid="cadasil.REF.joutel.2001.2049">Joutel et al 2001</a>, <a class="bibr" href="#cadasil.REF.oberstein.2003.2020" rid="cadasil.REF.oberstein.2003.2020">Oberstein 2003</a>].</p><p>The combined analysis by electron microscopy and immunohistochemistry, when interpreted by an experienced (neuro)pathologist, usually allows for a conclusive CADASIL diagnosis [<a class="bibr" href="#cadasil.REF.rutten.2014.593" rid="cadasil.REF.rutten.2014.593">Rutten et al 2014</a>].</p></div></div></div><div id="cadasil.Clinical_Characteristics"><h2 id="_cadasil_Clinical_Characteristics_">Clinical Characteristics</h2><div id="cadasil.Clinical_Description"><h3>Clinical Description</h3><p>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, both between and within families. The disease is characterized by five main symptoms: transient ischemic attacks and recurrent ischemic strokes; cognitive decline; migraine with aura; mood disturbance; and apathy.</p><p><b>Subcortical ischemic events.</b> Transient ischemic attacks (TIAs) and stroke, the most frequent presentation, are found in approximately 85% of symptomatic individuals [<a class="bibr" href="#cadasil.REF.dichgans.1998.731" rid="cadasil.REF.dichgans.1998.731">Dichgans et al 1998</a>]. Mean age at onset for ischemic episodes is 47 years (age range 20-70 years) [<a class="bibr" href="#cadasil.REF.opherk.2004.2533" rid="cadasil.REF.opherk.2004.2533">Opherk et al 2004</a>].</p><p>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 [<a class="bibr" href="#cadasil.REF.adibsamii.2010.630" rid="cadasil.REF.adibsamii.2010.630">Adib-Samii et al 2010</a>]. Ischemic episodes are often recurrent, leading to severe disability with gait disturbance, urinary incontinence, and pseudobulbar palsy.</p><p>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 [<a class="bibr" href="#cadasil.REF.choi.2013.126" rid="cadasil.REF.choi.2013.126">Choi et al 2013</a>, <a class="bibr" href="#cadasil.REF.yin.2015.585" rid="cadasil.REF.yin.2015.585">Yin et al 2015</a>, <a class="bibr" href="#cadasil.REF.kang.2015.347" rid="cadasil.REF.kang.2015.347">Kang & Kim 2015</a>].</p><p><b>Cognitive deficits and dementia.</b> Cognitive decline may start as early as age 35 years. Up to 75% of affected individuals develop dementia, often accompanied by apathy [<a class="bibr" href="#cadasil.REF.dichgans.2009.s45" rid="cadasil.REF.dichgans.2009.s45">Dichgans 2009</a>, <a class="bibr" href="#cadasil.REF.reyes.2009.905" rid="cadasil.REF.reyes.2009.905">Reyes et al 2009</a>].</p><p>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 [<a class="bibr" href="#cadasil.REF.peters.2005b.2078" rid="cadasil.REF.peters.2005b.2078">Peters et al 2005b</a>]. Cognitive dysfunction is accompanied by a narrowing of the field of interest. In most cases, cognitive decline is slowly progressive, with some preservation of recognition and semantic memory, with additional stepwise deterioration. Visuospatial abilities and reasoning decline, especially after age 60. Cognitive decline becomes more apparent with aging and disease progression, ultimately leading to significant alterations in all cognitive domains at an older age [<a class="bibr" href="#cadasil.REF.buffon.2006.175" rid="cadasil.REF.buffon.2006.175">Buffon et al 2006</a>]. <a class="bibr" href="#cadasil.REF.amberla.2004.1598" rid="cadasil.REF.amberla.2004.1598">Amberla et al [2004]</a> observed deterioration of working memory and executive function in individuals with <i>NOTCH3</i> pathogenic variants in the pre-stroke phase and inferred that cognitive decline may start insidiously before the onset of symptomatic ischemic episodes.</p><p><b>Migraine,</b> when present, can be the first symptom of CADASIL. Migraine occurs in 30%-75% of individuals with CADASIL, with the first attack occurring at a mean age of 26-29 years [<a class="bibr" href="#cadasil.REF.adibsamii.2010.630" rid="cadasil.REF.adibsamii.2010.630">Adib-Samii et al 2010</a>, <a class="bibr" href="#cadasil.REF.tan.2016.e0157613" rid="cadasil.REF.tan.2016.e0157613">Tan & Markus 2016</a>, <a class="bibr" href="#cadasil.REF.guey.2016.1038" rid="cadasil.REF.guey.2016.1038">Guey et al 2016</a>]. Eighty to ninety percent of those with migraine have migraine with aura [<a class="bibr" href="#cadasil.REF.guey.2016.1038" rid="cadasil.REF.guey.2016.1038">Guey et al 2016</a>, <a class="bibr" href="#cadasil.REF.tan.2016.e0157613" rid="cadasil.REF.tan.2016.e0157613">Tan & Markus 2016</a>]. Migraine auras are sometimes confused with transient ischemic symptoms, since aura may include focal neurologic deficits [<a class="bibr" href="#cadasil.REF.di_donato.2017.41" rid="cadasil.REF.di_donato.2017.41">Di Donato et al 2017</a>]. Sixty percent of those with migraine with aura have experienced an atypical migraine attack: prolonged, basilar or hemiplegic aura, confusion, fever, or coma [<a class="bibr" href="#cadasil.REF.guey.2016.1038" rid="cadasil.REF.guey.2016.1038">Guey et al 2016</a>].</p><p><b>Psychiatric disorders.</b> In most CADASIL cohorts, psychiatric disturbances are described in about one third of individuals [<a class="bibr" href="#cadasil.REF.adibsamii.2010.630" rid="cadasil.REF.adibsamii.2010.630">Adib-Samii et al 2010</a>]. The reported prevalence of psychiatric disturbances is variable: a small study in 23 Italian patients recorded a lifetime risk for depression of 74% and a lifetime risk for a manic episode of 26% [<a class="bibr" href="#cadasil.REF.valenti.2011.390" rid="cadasil.REF.valenti.2011.390">Valenti et al 2011</a>], whereas in a Chinese cohort, psychiatric manifestations were recorded in only 7% of affected individuals [<a class="bibr" href="#cadasil.REF.wang.2011.534" rid="cadasil.REF.wang.2011.534">Wang et al 2011</a>]. Apathy has been described in 40% of individuals [<a class="bibr" href="#cadasil.REF.reyes.2009.905" rid="cadasil.REF.reyes.2009.905">Reyes et al 2009</a>]. The psychiatric manifestations vary from personality changes to severe depression. The pathogenesis of psychiatric disturbances in CADASIL is incompletely understood. Psychiatric problems as a presenting symptom of CADASIL have been described [<a class="bibr" href="#cadasil.REF.leyhe.2005.392" rid="cadasil.REF.leyhe.2005.392">Leyhe et al 2005</a>, <a class="bibr" href="#cadasil.REF.nakamura.2005.87" rid="cadasil.REF.nakamura.2005.87">Nakamura et al 2005</a>, <a class="bibr" href="#cadasil.REF.park.2014.175" rid="cadasil.REF.park.2014.175">Park et al 2014</a>].</p><p><b>Reversible acute encephalopathy.</b> Acute encephalopathy has been described in some individuals, with confusion, headache, pyrexia, seizures, and coma, sometimes leading to death [<a class="bibr" href="#cadasil.REF.adibsamii.2010.630" rid="cadasil.REF.adibsamii.2010.630">Adib-Samii et al 2010</a>, <a class="bibr" href="#cadasil.REF.ragno.2013.1147" rid="cadasil.REF.ragno.2013.1147">Ragno et al 2013</a>, <a class="bibr" href="#cadasil.REF.tan.2016.e0157613" rid="cadasil.REF.tan.2016.e0157613">Tan & Markus 2016</a>]. Migraine with aura (especially confusional aura) is associated with increased risk of acute encephalopathy, suggesting that they may share pathophysiologic mechanisms [<a class="bibr" href="#cadasil.REF.tan.2016.e0157613" rid="cadasil.REF.tan.2016.e0157613">Tan & Markus 2016</a>].</p><p><b>Epilepsy.</b> Epilepsy occurs in 10% of individuals with CADASIL and presents in middle age, usually secondary to stroke [<a class="bibr" href="#cadasil.REF.haan.2007.316" rid="cadasil.REF.haan.2007.316">Haan et al 2007</a>]. In a pooled analysis of previous published cases, three of 105 individuals with CADASIL had a seizure as the initial presenting symptom [<a class="bibr" href="#cadasil.REF.desmond.1999.1230" rid="cadasil.REF.desmond.1999.1230">Desmond et al 1999</a>].</p><p><b>Pregnancy.</b> It has been suggested that the risk for migraine with aura is increased during pregnancy, but especially during puerperium (the period between childbirth and the return of the uterus to its normal size) [<a class="bibr" href="#cadasil.REF.roine.2005.1441" rid="cadasil.REF.roine.2005.1441">Roine et al 2005</a>]. Another study found no association between pregnancy and risk for neurologic events or problems during pregnancy [<a class="bibr" href="#cadasil.REF.donnini.2017.668" rid="cadasil.REF.donnini.2017.668">Donnini et al 2017</a>]. See <a href="#cadasil.Pregnancy_Management">Pregnancy Management</a>.</p><p>
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<b>Other findings</b>
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</p><ul><li class="half_rhythm"><div><b>Cardiac.</b> Controversy exists as to whether CADASIL is associated with cardiac involvement. In a study from The Netherlands, nearly 25% of individuals with CADASIL had a history of acute myocardial infarction (MI) and/or current pathologic Q-waves on electrocardiogram (EKG) [<a class="bibr" href="#cadasil.REF.lesnik_oberstein.2003.251" rid="cadasil.REF.lesnik_oberstein.2003.251">Lesnik Oberstein et al 2003</a>]. This percentage was significantly higher than in controls without a heterozygous <i>NOTCH3</i> pathogenic variant. However, another study of 23 individuals with CADASIL found no signs of previous MI on EKG [<a class="bibr" href="#cadasil.REF.cumurciuc.2006b.1100" rid="cadasil.REF.cumurciuc.2006b.1100">Cumurciuc et al 2006b</a>]. Two studies have suggested an increased risk for arrhythmias, based on increased QT variability on EKG recording [<a class="bibr" href="#cadasil.REF.rufa.2007.276" rid="cadasil.REF.rufa.2007.276">Rufa et al 2007</a>, <a class="bibr" href="#cadasil.REF.piccirillo.2008.1216" rid="cadasil.REF.piccirillo.2008.1216">Piccirillo et al 2008</a>].</div></li><li class="half_rhythm"><div><b>Nerve.</b> Nerve biopsies may demonstrate signs of axonal damage, demyelination, and ultrastructural changes of the endoneurial blood vessels [<a class="bibr" href="#cadasil.REF.schr_der.2005.587" rid="cadasil.REF.schr_der.2005.587">Schröder et al 2005</a>, <a class="bibr" href="#cadasil.REF.sicurelli.2005.1206" rid="cadasil.REF.sicurelli.2005.1206">Sicurelli et al 2005</a>, <a class="bibr" href="#cadasil.REF.lackovic.2012.325" rid="cadasil.REF.lackovic.2012.325">Lackovic et al 2012</a>]. Punch skin biopsies from individuals with CADASIL showed cutaneous somatic and autonomic nerve involvement [<a class="bibr" href="#cadasil.REF.nolano.2016.1039" rid="cadasil.REF.nolano.2016.1039">Nolano et al 2016</a>]. Clinically, however, there is no clear evidence that peripheral neuropathy is part of the CADASIL clinical spectrum [<a class="bibr" href="#cadasil.REF.kang.2009.1724" rid="cadasil.REF.kang.2009.1724">Kang et al 2009</a>].</div></li><li class="half_rhythm"><div><b>Ocular.</b> Subclinical retinal lesions are reported [<a class="bibr" href="#cadasil.REF.cumurciuc.2004.1058" rid="cadasil.REF.cumurciuc.2004.1058">Cumurciuc et al 2004</a>, <a class="bibr" href="#cadasil.REF.haritoglou.2004.302" rid="cadasil.REF.haritoglou.2004.302">Haritoglou et al 2004</a>]. Fundoscopy may reveal clinically silent retinal vascular abnormalities [<a class="bibr" href="#cadasil.REF.pretegiani.2013.1377" rid="cadasil.REF.pretegiani.2013.1377">Pretegiani et al 2013</a>]. Optical coherence tomography imaging techniques may show reduced subfoveal choroidal thickness, retinal arterial luminal narrowing, retinal venous luminal enlargement, and reduced vessel density of the deep retinal plexus [<a class="bibr" href="#cadasil.REF.alten.2014.e112311" rid="cadasil.REF.alten.2014.e112311">Alten et al 2014</a>, <a class="bibr" href="#cadasil.REF.fang.2017.1042" rid="cadasil.REF.fang.2017.1042">Fang et al 2017</a>, <a class="bibr" href="#cadasil.REF.nelis.2018.8148" rid="cadasil.REF.nelis.2018.8148">Nelis et al 2018</a>].</div></li><li class="half_rhythm"><div><b>Renal.</b> NOTCH3 accumulation and granular osmiophilic material (GOM) are also detected in renal arteries, and stenosis of renal arteries has been described [<a class="bibr" href="#cadasil.REF.ragno.2012.1307" rid="cadasil.REF.ragno.2012.1307">Ragno et al 2012</a>, <a class="bibr" href="#cadasil.REF.lorenzi.2017.e00624" rid="cadasil.REF.lorenzi.2017.e00624">Lorenzi et al 2017</a>]. Although no large-scale studies have been published regarding kidney function in individuals with CADASIL, to date there is no evidence that kidney function is affected [<a class="bibr" href="#cadasil.REF.bergmann.1996.341" rid="cadasil.REF.bergmann.1996.341">Bergmann et al 1996</a>].</div></li></ul><p><b>Long-term prognosis and causes of death.</b> Onset of symptoms and overall survival may vary based on the type of pathogenic variant and its location within <i>NOTCH3</i> (see <a href="#cadasil.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a>).</p><p>Data on the long-term prognosis in CADASIL come from a large study of 411 individuals [<a class="bibr" href="#cadasil.REF.opherk.2004.2533" rid="cadasil.REF.opherk.2004.2533">Opherk et al 2004</a>], 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. Pneumonia was the most frequent cause of death, followed by sudden unexpected death and asphyxia. In the final stages of disease, 78% of individuals were completely dependent and 63% were confined to bed.</p><p>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 socioeconomic factors.</p><p><b>Brain imaging.</b> Imaging abnormalities in CADASIL evolve as the disease progresses [<a class="bibr" href="#cadasil.REF.van_den_boom.2003.683" rid="cadasil.REF.van_den_boom.2003.683">van den Boom et al 2003</a>, <a class="bibr" href="#cadasil.REF.singhal.2005.2481" rid="cadasil.REF.singhal.2005.2481">Singhal et al 2005</a>, <a class="bibr" href="#cadasil.REF.liem.2008a.964" rid="cadasil.REF.liem.2008a.964">Liem et al 2008a</a>]:</p><ul><li class="half_rhythm"><div>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 [<a class="bibr" href="#cadasil.REF.oberstein.2003.2020" rid="cadasil.REF.oberstein.2003.2020">Oberstein 2003</a>, <a class="bibr" href="#cadasil.REF.van_den_boom.2003.683" rid="cadasil.REF.van_den_boom.2003.683">van den Boom et al 2003</a>].</div></li><li class="half_rhythm"><div>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 [<a class="bibr" href="#cadasil.REF.chabriat.1998.452" rid="cadasil.REF.chabriat.1998.452">Chabriat et al 1998</a>].</div></li><li class="half_rhythm"><div>White matter hyperintensities in the temporal lobe and external capsule are characteristic for CADASIL but not always present [<a class="bibr" href="#cadasil.REF.osullivan.2001.628" rid="cadasil.REF.osullivan.2001.628">O'Sullivan et al 2001</a>, <a class="bibr" href="#cadasil.REF.markus.2002.1134" rid="cadasil.REF.markus.2002.1134">Markus et al 2002</a>]. Involvement of the anterior temporal lobe is highly suggestive for CADASIL; this finding, however, is not sensitive or specific for the diagnosis of CADASIL [<a class="bibr" href="#cadasil.REF.sureka.2012.e782" rid="cadasil.REF.sureka.2012.e782">Sureka &Jakkani 2012</a>].</div></li><li class="half_rhythm"><div>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 [<a class="bibr" href="#cadasil.REF.auer.2001.443" rid="cadasil.REF.auer.2001.443">Auer et al 2001</a>, <a class="bibr" href="#cadasil.REF.osullivan.2001.628" rid="cadasil.REF.osullivan.2001.628">O'Sullivan et al 2001</a>].</div></li><li class="half_rhythm"><div>The majority of lacunes develop at the edge of white matter hyperintensities and proximal to white matter hyperintensities along the course of perforating vessels supplying the respective brain region [<a class="bibr" href="#cadasil.REF.duering.2013.2717" rid="cadasil.REF.duering.2013.2717">Duering et al 2013</a>].</div></li><li class="half_rhythm"><div>Brain atrophy appears to result from accumulation of lacunes and widespread microstructural alterations within the brain [<a class="bibr" href="#cadasil.REF.jouvent.2007.1786" rid="cadasil.REF.jouvent.2007.1786">Jouvent et al 2007</a>].</div></li><li class="half_rhythm"><div>Lacunes and brain atrophy are strongly correlated with clinical severity and clinical worsening in individuals with CADASIL [<a class="bibr" href="#cadasil.REF.ling.2018" rid="cadasil.REF.ling.2018">Ling et al 2018</a>, <a class="bibr" href="#cadasil.REF.jouvent.2016.1787" rid="cadasil.REF.jouvent.2016.1787">Jouvent et al 2016</a>].</div></li><li class="half_rhythm"><div>Dilated perivascular spaces are found in approximately 70%-80% of affected individuals [<a class="bibr" href="#cadasil.REF.van_den_boom.2002.791" rid="cadasil.REF.van_den_boom.2002.791">van Den Boom et al 2002</a>, <a class="bibr" href="#cadasil.REF.cumurciuc.2006a.187" rid="cadasil.REF.cumurciuc.2006a.187">Cumurciuc et al 2006a</a>, <a class="bibr" href="#cadasil.REF.yao.2014.155" rid="cadasil.REF.yao.2014.155">Yao et al 2014</a>].</div></li><li class="half_rhythm"><div>Cerebral microbleeds (CMB) are reported in approximately one third of affected individuals [<a class="bibr" href="#cadasil.REF.puy.2017.2699" rid="cadasil.REF.puy.2017.2699">Puy et al 2017</a>, <a class="bibr" href="#cadasil.REF.nannucci.2018.e0190878" rid="cadasil.REF.nannucci.2018.e0190878">Nannucci et al 2018</a>]. Cerebral microbleeds do not have a clear predominant location in individuals with CADASIL. In a study of 125 affected individuals, cerebral microbleeds were present in 34%. Of these, 29% had CMB in the deep subcortical region (most frequently in the thalamus), 22% in the lobar region (especially the temporal lobe), and 18% in the infratentorial region [<a class="bibr" href="#cadasil.REF.nannucci.2018.e0190878" rid="cadasil.REF.nannucci.2018.e0190878">Nannucci et al 2018</a>].</div></li></ul><p><b>Other imaging studies</b>. Positron emission tomography, transcranial Doppler sonography, and perfusion MRI may show decreased cerebral blood flow, decreased cerebral blood volume, impaired cerebral metabolism, decreased vasoreactivity, and altered neurovascular coupling [<a class="bibr" href="#cadasil.REF.tatsch.2003.862" rid="cadasil.REF.tatsch.2003.862">Tatsch et al 2003</a>, <a class="bibr" href="#cadasil.REF.tuominen.2004.1063" rid="cadasil.REF.tuominen.2004.1063">Tuominen et al 2004</a>, <a class="bibr" href="#cadasil.REF.huneau.2018.788" rid="cadasil.REF.huneau.2018.788">Huneau et al 2018</a>, <a class="bibr" href="#cadasil.REF.moreton.2018.1085" rid="cadasil.REF.moreton.2018.1085">Moreton et al 2018</a>].</p><p><b>Pathophysiology.</b> 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 [<a class="bibr" href="#cadasil.REF.bruening.2001.1268" rid="cadasil.REF.bruening.2001.1268">Bruening et al 2001</a>, <a class="bibr" href="#cadasil.REF.tuominen.2004.1063" rid="cadasil.REF.tuominen.2004.1063">Tuominen et al 2004</a>]. In addition, cerebral vasoreactivity is impaired [<a class="bibr" href="#cadasil.REF.pfefferkorn.2001.17" rid="cadasil.REF.pfefferkorn.2001.17">Pfefferkorn et al 2001</a>], consistent with the observed degeneration of vascular smooth muscle cells in small arteries and arterioles [<a class="bibr" href="#cadasil.REF.kalimo.2002.371" rid="cadasil.REF.kalimo.2002.371">Kalimo et al 2002</a>]. Increased fragility of cerebral microvessels is suggested by a high frequency of cerebral microbleeds at autopsy and on gradient echo MRI [<a class="bibr" href="#cadasil.REF.lesnik_oberstein.2001.1066" rid="cadasil.REF.lesnik_oberstein.2001.1066">Lesnik Oberstein et al 2001</a>, <a class="bibr" href="#cadasil.REF.dichgans.2002.67" rid="cadasil.REF.dichgans.2002.67">Dichgans et al 2002</a>].</p></div><div id="cadasil.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>Smaller studies have described genotype-phenotype correlations for specific pathogenic variants [<a class="bibr" href="#cadasil.REF.lesnik_oberstein.2001.1066" rid="cadasil.REF.lesnik_oberstein.2001.1066">Lesnik Oberstein et al 2001</a>, <a class="bibr" href="#cadasil.REF.arboledavelasquez.2002.277" rid="cadasil.REF.arboledavelasquez.2002.277">Arboleda-Velasquez et al 2002</a>, <a class="bibr" href="#cadasil.REF.opherk.2004.2533" rid="cadasil.REF.opherk.2004.2533">Opherk et al 2004</a>, <a class="bibr" href="#cadasil.REF.bianchi.2010.1039" rid="cadasil.REF.bianchi.2010.1039">Bianchi et al 2010</a>]; however, none of these associations have been firmly established.</p><p>In general, affected individuals with cysteine-altering pathogenic variants in epidermal growth-factor like repeat (EGFr) domains 1-6 of NOTCH3 have a 12-year earlier onset of stroke, lower survival, and increased white matter hyperintensity volume, consistent with the more severe classic CADASIL presentation, compared to those with a cysteine-altering pathogenic variant in EGFr domains 7-34. The mean survival time was 68.5 and 76.9 years, respectively [<a class="bibr" href="#cadasil.REF.rutten.2019.676" rid="cadasil.REF.rutten.2019.676">Rutten et al 2019</a>].</p><p>There is conflicting evidence about the effect of pathogenic variants in the ligand-binding domain of <i>NOTCH3</i> (EGFr domains 10 and 11). Both a more severe and a milder phenotype have been described in small series [<a class="bibr" href="#cadasil.REF.arboledavelasquez.2002.277" rid="cadasil.REF.arboledavelasquez.2002.277">Arboleda-Velasquez et al 2002</a>, <a class="bibr" href="#cadasil.REF.monetlepr_tre.2009.1601" rid="cadasil.REF.monetlepr_tre.2009.1601">Monet-Leprêtre et al 2009</a>, <a class="bibr" href="#cadasil.REF.rutten.2019.676" rid="cadasil.REF.rutten.2019.676">Rutten et al 2019</a>] (see also <a href="#cadasil.Penetrance">Penetrance</a>).</p><p><b>Biallelic pathogenic variants</b> in <i>NOTCH3</i> have been described in individuals with CADASIL [<a class="bibr" href="#cadasil.REF.tuominen.2001.1767" rid="cadasil.REF.tuominen.2001.1767">Tuominen et al 2001</a>, <a class="bibr" href="#cadasil.REF.liem.2008b.1978" rid="cadasil.REF.liem.2008b.1978">Liem et al 2008b</a>, <a class="bibr" href="#cadasil.REF.ragno.2013.1147" rid="cadasil.REF.ragno.2013.1147">Ragno et al 2013</a>, <a class="bibr" href="#cadasil.REF.soong.2013.319" rid="cadasil.REF.soong.2013.319">Soong et al 2013</a>, <a class="bibr" href="#cadasil.REF.vinciguerra.2014.91" rid="cadasil.REF.vinciguerra.2014.91">Vinciguerra et al 2014</a>, <a class="bibr" href="#cadasil.REF.abou_alshaar.2016.239" rid="cadasil.REF.abou_alshaar.2016.239">Abou Al-Shaar et al 2016</a>]. The phenotype of individuals with biallelic <i>NOTCH3</i> pathogenic variants falls within the CADASIL spectrum.</p></div><div id="cadasil.Penetrance"><h3>Penetrance</h3><p>Pathogenic variants in EGFr domains 1-6 appear to be fully penetrant and are usually associated with the classic CADASIL phenotype. However, there is variability in disease severity.</p><p>Pathogenic variants in EGFr domains 7-34 have a much higher population frequency (~1:300) [<a class="bibr" href="#cadasil.REF.rutten.2016a.844" rid="cadasil.REF.rutten.2016a.844">Rutten et al 2016a</a>, <a class="bibr" href="#cadasil.REF.rutten.2019.676" rid="cadasil.REF.rutten.2019.676">Rutten et al 2019</a>] and therefore likely predispose to a milder small-vessel disease and may even be non-penetrant.</p></div><div id="cadasil.Nomenclature"><h3>Nomenclature</h3><p>Previous descriptions of families with "hereditary multi-infarct dementia," "chronic familial vascular encephalopathy," and "familial subcortical dementia" represent early reports of CADASIL.</p></div><div id="cadasil.Prevalence"><h3>Prevalence</h3><p>While most published information on individuals with CADASIL originates from Europe, CADASIL has been observed on all continents. Multiple small and national European registries have estimated the minimum prevalence at between two and four per 100,000 [<a class="bibr" href="#cadasil.REF.kalimo.2002.371" rid="cadasil.REF.kalimo.2002.371">Kalimo et al 2002</a>, <a class="bibr" href="#cadasil.REF.razvi.2005b.739" rid="cadasil.REF.razvi.2005b.739">Razvi et al 2005b</a>, <a class="bibr" href="#cadasil.REF.narayan.2012.1025" rid="cadasil.REF.narayan.2012.1025">Narayan et al 2012</a>, <a class="bibr" href="#cadasil.REF.bianchi.2015.134" rid="cadasil.REF.bianchi.2015.134">Bianchi et al 2015</a>].</p><p>Recently, it was found that the frequency of <i>NOTCH3</i> cysteine-altering pathogenic variants is 1:300 in the general population worldwide (gnomAD), with the highest frequency in people who are from Asian descent (1:100) [<a class="bibr" href="#cadasil.REF.rutten.2016a.844" rid="cadasil.REF.rutten.2016a.844">Rutten et al 2016a</a>, <a class="bibr" href="#cadasil.REF.rutten.2019.676" rid="cadasil.REF.rutten.2019.676">Rutten et al 2019</a>]. This is approximately 100-fold higher than current estimates of the minimum prevalence of CADASIL, suggesting that CADASIL is much more prevalent than previously suspected and that the <i>NOTCH3</i> clinical spectrum must be considerably broader, ranging from classic CADASIL to a much milder small-vessel disease, or possibly even non-penetrance.</p></div></div><div id="cadasil.Genetically_Related_Allelic_Diso"><h2 id="_cadasil_Genetically_Related_Allelic_Diso_">Genetically Related (Allelic) Disorders</h2><p>Heterozygous truncating pathogenic variants in <i>NOTCH3</i> exon 33 (encoding the PEST domains of the intracellular part of the protein) have been described in <a href="/books/n/gene/lms/?report=reader">Lateral Meningocele Syndrome</a> (Lehman syndrome). These pathogenic variants are presumed to act via a gain of NOTCH3 signaling function and are distinct from <i>NOTCH3</i> pathogenic variants in CADASIL [<a class="bibr" href="#cadasil.REF.gripp.2015.271" rid="cadasil.REF.gripp.2015.271">Gripp et al 2015</a>].</p><p>A <i>NOTCH3</i> heterozygous exon 25 variant has been described in autosomal dominant infantile myofibromatosis (OMIM <a href="https://omim.org/entry/615293" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">615293</a>) [<a class="bibr" href="#cadasil.REF.martignetti.2013.1001" rid="cadasil.REF.martignetti.2013.1001">Martignetti et al 2013</a>].</p></div><div id="cadasil.Differential_Diagnosis"><h2 id="_cadasil_Differential_Diagnosis_">Differential Diagnosis</h2><p>The differential diagnosis of CADASIL includes <a href="#cadasil.SporadicMultifactorial_Disorders">sporadic/multifactorial disorders</a> and <a href="#cadasil.Inherited_Disorders">inherited disorders</a>.</p><div id="cadasil.SporadicMultifactorial_Disorders"><h3>Sporadic/Multifactorial Disorders</h3><p>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 [<a class="bibr" href="#cadasil.REF.dichgans.1999.1361" rid="cadasil.REF.dichgans.1999.1361">Dichgans et al 1999</a>] (see <a href="/books/NBK1500/table/cadasil.T.clinical_signs_and_mri_abnorma/?report=objectonly" target="object" rid-ob="figobcadasilTclinicalsignsandmriabnorma">Table 2</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figcadasilTclinicalsignsandmriabnorma"><a href="/books/NBK1500/table/cadasil.T.clinical_signs_and_mri_abnorma/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobcadasilTclinicalsignsandmriabnorma"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="cadasil.T.clinical_signs_and_mri_abnorma"><a href="/books/NBK1500/table/cadasil.T.clinical_signs_and_mri_abnorma/?report=objectonly" target="object" rid-ob="figobcadasilTclinicalsignsandmriabnorma">Table 2. </a></h4><p class="float-caption no_bottom_margin">Clinical Signs and MRI Abnormalities of Sporadic/Multifactorial Disorders in the Differential Diagnosis of CADASIL </p></div></div></div><div id="cadasil.Inherited_Disorders"><h3>Inherited Disorders</h3><p>Several inherited disorders are associated with acute ischemic events (or stroke-like episodes in the case of MELAS) and cerebral white matter hyperintensities on MRI. These disorders can be distinguished from CADASIL by the associated clinical signs, MRI, mode of inheritance, and appropriate laboratory investigations (particularly, molecular genetic testing) (see <a href="/books/NBK1500/table/cadasil.T.clinical_signs_and_mri_abnorma_1/?report=objectonly" target="object" rid-ob="figobcadasilTclinicalsignsandmriabnorma1">Table 3</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figcadasilTclinicalsignsandmriabnorma1"><a href="/books/NBK1500/table/cadasil.T.clinical_signs_and_mri_abnorma_1/?report=objectonly" target="object" title="Table 3. " class="img_link icnblk_img" rid-ob="figobcadasilTclinicalsignsandmriabnorma1"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="cadasil.T.clinical_signs_and_mri_abnorma_1"><a href="/books/NBK1500/table/cadasil.T.clinical_signs_and_mri_abnorma_1/?report=objectonly" target="object" rid-ob="figobcadasilTclinicalsignsandmriabnorma1">Table 3. </a></h4><p class="float-caption no_bottom_margin">Clinical Signs and MRI Abnormalities of Inherited Disorders to Consider in the Differential Diagnosis of CADASIL </p></div></div></div></div><div id="cadasil.Management"><h2 id="_cadasil_Management_">Management</h2><div id="cadasil.Evaluations_Following_Initial_Di"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with CADASIL, the following evaluations are recommended, if they have not already been completed.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figcadasilTrecommendedevaluationsfollow"><a href="/books/NBK1500/table/cadasil.T.recommended_evaluations_follow/?report=objectonly" target="object" title="Table 4. " class="img_link icnblk_img" rid-ob="figobcadasilTrecommendedevaluationsfollow"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="cadasil.T.recommended_evaluations_follow"><a href="/books/NBK1500/table/cadasil.T.recommended_evaluations_follow/?report=objectonly" target="object" rid-ob="figobcadasilTrecommendedevaluationsfollow">Table 4. </a></h4><p class="float-caption no_bottom_margin">Recommended Evaluations Following Initial Diagnosis in Individuals with CADASIL </p></div></div></div><div id="cadasil.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Discussion of medical management options for individuals with CADASIL have been published [<a class="bibr" href="#cadasil.REF.del_r_oesp_nola.2009.197" rid="cadasil.REF.del_r_oesp_nola.2009.197">del Río-Espínola et al 2009</a>, <a class="bibr" href="#cadasil.REF.di_donato.2017.41" rid="cadasil.REF.di_donato.2017.41">Di Donato et al 2017</a>].</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figcadasilTtreatmentofmanifestationsin"><a href="/books/NBK1500/table/cadasil.T.treatment_of_manifestations_in/?report=objectonly" target="object" title="Table 5. " class="img_link icnblk_img" rid-ob="figobcadasilTtreatmentofmanifestationsin"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="cadasil.T.treatment_of_manifestations_in"><a href="/books/NBK1500/table/cadasil.T.treatment_of_manifestations_in/?report=objectonly" target="object" rid-ob="figobcadasilTtreatmentofmanifestationsin">Table 5. </a></h4><p class="float-caption no_bottom_margin">Treatment of Manifestations in Individuals with CADASIL </p></div></div></div><div id="cadasil.Prevention_of_Primary_Manifestat"><h3>Prevention of Primary Manifestations</h3><p>No treatment is of proven efficacy in preventing stroke, vascular dementia, or CADASIL disease progression.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figcadasilTpreventionofprimarymanifest"><a href="/books/NBK1500/table/cadasil.T.prevention_of_primary_manifest/?report=objectonly" target="object" title="Table 6. " class="img_link icnblk_img" rid-ob="figobcadasilTpreventionofprimarymanifest"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="cadasil.T.prevention_of_primary_manifest"><a href="/books/NBK1500/table/cadasil.T.prevention_of_primary_manifest/?report=objectonly" target="object" rid-ob="figobcadasilTpreventionofprimarymanifest">Table 6. </a></h4><p class="float-caption no_bottom_margin">Prevention of Primary Manifestations in Individuals with CADASIL </p></div></div></div><div id="cadasil.Surveillance"><h3>Surveillance</h3><p>No standard international surveillance guidelines for CADASIL exist. Several countries have developed CADASIL guidelines, such as the medical guideline for CADASIL published (in French) by the French Health Authority (HAS).</p><p>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 patients and their care givers.</p><ul><li class="half_rhythm"><div>Follow up by a neurologist with expertise in CADASIL is recommended from the time of diagnosis onward.</div></li><li class="half_rhythm"><div>A consultation with a neuropsychiatrist is recommended when there are symptoms of depression, apathy, or other psychiatric manifestations.</div></li><li class="half_rhythm"><div>Consultation of other medical specialists (e.g., rehabilitation physician, clinical geneticist, physical therapist, and psychologist) is as required.</div></li></ul></div><div id="cadasil.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>The treatment effect of thrombolytic therapy (intravenous thrombolysis) is unknown in individuals with CADASIL. Studies performed in non-CADASIL populations show that increasing cerebral microbleed burden and increasing white matter hyperintensity lesion load is associated with an increased risk of intracerebral hemorrhage after thrombolytic therapy [<a class="bibr" href="#cadasil.REF.charidimou.2016.2364" rid="cadasil.REF.charidimou.2016.2364">Charidimou et al 2016</a>, <a class="bibr" href="#cadasil.REF.charidimou.2017b.2084" rid="cadasil.REF.charidimou.2017b.2084">Charidimou et al 2017b</a>]; therefore, individuals with CADASIL may be at increased risk for intracerebral hemorrhage. In case of a thromboembolic large vessel stroke (i.e., unrelated to CADASIL), the benefit of thrombolysis outweighs the potential risk of intracerebral hemorrhage.</p><p>Oral anticoagulants could lead to an increased risk of intracerebral hemorrhage in individuals with CADASIL due to the presence of microbleeds [<a class="bibr" href="#cadasil.REF.charidimou.2017a.2317" rid="cadasil.REF.charidimou.2017a.2317">Charidimou et al 2017a</a>]; the prescription of anticoagulants should therefore be carefully weighed. In case of a clear indication for anticoagulant therapy, such as atrial fibrillation or deep venous thrombosis, the benefit of the treatment likely outweighs the potential risk of intracerebral hemorrhage.</p><p>Smoking increases the risk of stroke in individuals with CADASIL and should be avoided [<a class="bibr" href="#cadasil.REF.singhal.2004.2031" rid="cadasil.REF.singhal.2004.2031">Singhal et al 2004</a>].</p></div><div id="cadasil.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#cadasil.Related_Genetic_Counseling_Issue">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="cadasil.Pregnancy_Management"><h3>Pregnancy Management</h3><p>Fetuses affected with CADASIL are not at an increased risk for intrauterine complications or complications during/after delivery [<a class="bibr" href="#cadasil.REF.donnini.2017.668" rid="cadasil.REF.donnini.2017.668">Donnini et al 2017</a>].</p><p>In a retrospective study, women with CADASIL were at increased risk for neurologic events in pregnancy during and shortly after delivery (puerperium) [<a class="bibr" href="#cadasil.REF.roine.2005.1441" rid="cadasil.REF.roine.2005.1441">Roine et al 2005</a>]. However, another retrospective study of 50 affected women and prospectively collected data of six women showed no association between CADASIL and risk for neurologic events or problems during pregnancy [<a class="bibr" href="#cadasil.REF.donnini.2017.668" rid="cadasil.REF.donnini.2017.668">Donnini et al 2017</a>]. In the authorsʹ 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].</p></div><div id="cadasil.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Case reports and small-scale observational studies have suggested a beneficial effect of acetazolamide on migraine [<a class="bibr" href="#cadasil.REF.weller.1998.1505" rid="cadasil.REF.weller.1998.1505">Weller et al 1998</a>, <a class="bibr" href="#cadasil.REF.forteza.2001.2144" rid="cadasil.REF.forteza.2001.2144">Forteza et al 2001</a>, <a class="bibr" href="#cadasil.REF.donnini.2012.299" rid="cadasil.REF.donnini.2012.299">Donnini et al 2012</a>]. Acetazolamide has also been shown to have a beneficial effect on cerebral perfusion [<a class="bibr" href="#cadasil.REF.chabriat.2000.1904" rid="cadasil.REF.chabriat.2000.1904">Chabriat et al 2000</a>, <a class="bibr" href="#cadasil.REF.huang.2010.77" rid="cadasil.REF.huang.2010.77">Huang et al 2010</a>, <a class="bibr" href="#cadasil.REF.park.2011.158" rid="cadasil.REF.park.2011.158">Park et al 2011</a>, <a class="bibr" href="#cadasil.REF.fujiwara.2012.128" rid="cadasil.REF.fujiwara.2012.128">Fujiwara et al 2012</a>]. Acetazolamide is not given to individuals with CADASIL on a routine basis, as no large studies have been performed.</p><p>Several therapeutic approaches are in pre-clinical development: testing in cells and mouse models including immunotherapy [<a class="bibr" href="#cadasil.REF.machucaparra.2017.2271" rid="cadasil.REF.machucaparra.2017.2271">Machuca-Parra et al 2017</a>, <a class="bibr" href="#cadasil.REF.ghezali.2018.246" rid="cadasil.REF.ghezali.2018.246">Ghezali et al 2018</a>], antisense mediated <i>NOTCH3</i> exon skipping [<a class="bibr" href="#cadasil.REF.rutten.2016b.1123" rid="cadasil.REF.rutten.2016b.1123">Rutten et al 2016b</a>], and treatment with stem cell factor and granulocyte colony-stimulating factor [<a class="bibr" href="#cadasil.REF.liu.2015.189" rid="cadasil.REF.liu.2015.189">Liu et al 2015</a>].</p><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions.</p></div><div id="cadasil.Other"><h3>Other</h3><p>Cross-sectional and longitudinal studies suggest that disease progression is faster in individuals with CADASIL who have increased blood pressure [<a class="bibr" href="#cadasil.REF.peters.2004.1603" rid="cadasil.REF.peters.2004.1603">Peters et al 2004</a>, <a class="bibr" href="#cadasil.REF.holtmannsp_tter.2005.2559" rid="cadasil.REF.holtmannsp_tter.2005.2559">Holtmannspötter et al 2005</a>, <a class="bibr" href="#cadasil.REF.peters.2006.1517" rid="cadasil.REF.peters.2006.1517">Peters et al 2006</a>, <a class="bibr" href="#cadasil.REF.ling.2017.283" rid="cadasil.REF.ling.2017.283">Ling et al 2017</a>]. However, no controlled data regarding the effect of antihypertensive treatment on disease progression are available.</p></div></div><div id="cadasil.Genetic_Counseling"><h2 id="_cadasil_Genetic_Counseling_">Genetic Counseling</h2><p>
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<i>Genetic counseling is the process of providing individuals and families with
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information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
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make informed medical and personal decisions. The following section deals with genetic
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risk assessment and the use of family history and genetic testing to clarify genetic
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status for family members; it is not meant to address all personal, cultural, or
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ethical issues that may arise or to substitute for consultation with a genetics
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professional</i>. —ED.</p><div id="cadasil.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>CADASIL is inherited in an autosomal dominant manner.</p></div><div id="cadasil.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
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<b>Parents of a proband</b>
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</p><ul><li class="half_rhythm"><div>Most individuals diagnosed with CADASIL have an affected parent, although a negative family history is occasionally reported.</div></li><li class="half_rhythm"><div>A proband with CADASIL may have the disorder as the result of a new pathogenic variant. Two individuals with <i>de novo</i> pathogenic variants have been reported [<a class="bibr" href="#cadasil.REF.joutel.2000.388" rid="cadasil.REF.joutel.2000.388">Joutel et al 2000</a>, <a class="bibr" href="#cadasil.REF.coto.2006.628" rid="cadasil.REF.coto.2006.628">Coto et al 2006</a>]; the authors have seen four individuals with <i>de novo</i> pathogenic variants in clinical practice [Authors, personal observations].</div></li><li class="half_rhythm"><div>The recommended evaluation of apparently asymptomatic parents of an individual with CADASIL who has a known <i>NOTCH3</i> pathogenic variant 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.)</div></li><li class="half_rhythm"><div>An apparently negative family history cannot be confirmed until appropriate evaluations have been performed:</div><ul><li class="half_rhythm"><div>A 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.</div></li><li class="half_rhythm"><div>A review of family histories by <a class="bibr" href="#cadasil.REF.razvi.2005a.323" rid="cadasil.REF.razvi.2005a.323">Razvi et al [2005a]</a> found 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.</div></li></ul></li><li class="half_rhythm"><div>Biallelic pathogenic variants in <i>NOTCH3</i> have been described in individuals with CADASIL [<a class="bibr" href="#cadasil.REF.tuominen.2001.1767" rid="cadasil.REF.tuominen.2001.1767">Tuominen et al 2001</a>, <a class="bibr" href="#cadasil.REF.liem.2008b.1978" rid="cadasil.REF.liem.2008b.1978">Liem et al 2008b</a>, <a class="bibr" href="#cadasil.REF.ragno.2013.1147" rid="cadasil.REF.ragno.2013.1147">Ragno et al 2013</a>, <a class="bibr" href="#cadasil.REF.soong.2013.319" rid="cadasil.REF.soong.2013.319">Soong et al 2013</a>, <a class="bibr" href="#cadasil.REF.vinciguerra.2014.91" rid="cadasil.REF.vinciguerra.2014.91">Vinciguerra et al 2014</a>, <a class="bibr" href="#cadasil.REF.abou_alshaar.2016.239" rid="cadasil.REF.abou_alshaar.2016.239">Abou Al-Shaar et al 2016</a>, <a class="bibr" href="#cadasil.REF.mukai.2018.38" rid="cadasil.REF.mukai.2018.38">Mukai et al 2018</a>]. In such cases, both parents of a proband may have a <i>NOTCH3</i> pathogenic variant.</div></li></ul><p>
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<b>Sibs of a proband</b>
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</p><ul><li class="half_rhythm"><div>The risk to the sibs of the proband depends on the genetic status of the proband's parents.</div></li><li class="half_rhythm"><div>If one of the parents is affected, as is true for the vast majority of individuals with a <i>NOTCH3</i> pathogenic variant, the risk to sibs is 50%.</div></li><li class="half_rhythm"><div>If the proband has biallelic <i>NOTCH3</i> pathogenic variants and both parents are heterozygous, the risk to the sibs of the proband of having at least one <i>NOTCH3</i> pathogenic variant and being affected is 75%.</div></li><li class="half_rhythm"><div>If the <i>NOTCH3</i> pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism.</div></li><li class="half_rhythm"><div>If both parents are clinically unaffected but have not been tested for the <i>NOTCH3</i> pathogenic variant, the sibs of a proband are still at increased risk for CADASIL because of the possibility of late onset of CADASIL in a heterozygous parent or the theoretic possibility of parental germline mosaicism.</div></li></ul><p>
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<b>Offspring of a proband</b>
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</p><ul><li class="half_rhythm"><div>Each child of an individual with a <i>NOTCH3</i> pathogenic variant has a 50% chance of inheriting the pathogenic variant.</div></li><li class="half_rhythm"><div>Each child of an individual who has biallelic <i>NOTCH3</i> pathogenic variants will inherit one of the pathogenic variants.</div></li></ul><p><b>Other family members.</b> The risk to other family members depends on the status of the proband's parents: if a parent is affected, the parent's family members may be at risk.</p></div><div id="cadasil.Related_Genetic_Counseling_Issue"><h3>Related Genetic Counseling Issues</h3><p>
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<b>Predictive testing (i.e., testing of asymptomatic at-risk individuals)</b>
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</p><ul><li class="half_rhythm"><div>Predictive testing for at-risk relatives is possible once the <i>NOTCH3</i> pathogenic variant has been identified in an affected family member.</div></li><li class="half_rhythm"><div>Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.</div></li></ul><p>
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<b>Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years)</b>
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</p><ul><li class="half_rhythm"><div>For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, 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.</div></li><li class="half_rhythm"><div>For more information, see the National Society of Genetic Counselors <a href="https://www.nsgc.org/Policy-Research-and-Publications/Position-Statements/Position-Statements/Post/genetic-testing-of-minors-for-adult-onset-conditions" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">position statement</a> on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics <a href="http://pediatrics.aappublications.org/content/131/3/620.full.pdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">policy statement</a>: ethical and policy issues in genetic testing and screening of children.</div></li></ul><p>In a family with an established diagnosis of CADASIL, it is appropriate to consider testing of symptomatic individuals regardless of age.</p><p><b>Considerations in families with an apparent <i>de novo</i> pathogenic variant</b>. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely <i>de novo</i>. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.</p><p>
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<b>Family planning</b>
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</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.</div></li><li class="half_rhythm"><div>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.</div></li></ul><p><b>DNA banking.</b> Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see <a class="bibr" href="#cadasil.REF.huang.2022.389" rid="cadasil.REF.huang.2022.389">Huang et al [2022]</a>.</p></div><div id="cadasil.Prenatal_Testing_and_Preimplanta"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>NOTCH3</i> pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for CADASIL are possible.</p><p>Differences in perspectives may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="cadasil.Resources"><h2 id="_cadasil_Resources_">Resources</h2><p>
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<i>GeneReviews staff has selected the following disease-specific and/or umbrella
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support organizations and/or registries for the benefit of individuals with this disorder
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and their families. GeneReviews is not responsible for the information provided by other
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organizations. For information on selection criteria, click <a href="/books/n/gene/app4/?report=reader">here</a>.</i></p>
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<ul><li class="half_rhythm"><div>
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<b>CADASIL Support UK</b>
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</div><div>110 Heathmoor Park Road</div><div>Halifax West Yorkshire HX2 9LP</div><div>United Kingdom</div><div><b>Email:</b> info@cadasilsupport.co.uk</div><div>
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<a href="http://www.cadasilsupportuk.co.uk/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.cadasilsupportuk.co.uk</a>
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</div></li><li class="half_rhythm"><div>
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<b>CADASIL Together We Have Hope Nonprofit Organization</b>
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</div><div>3605 Monument Drive</div><div>Round Rock TX 78681</div><div><b>Phone:</b> 800-617-8387</div><div><b>Email:</b> info@cadasilfoundation.org</div><div>
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<a href="http://www.cadasilfoundation.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.cadasilfoundation.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>Cambridge Stroke</b>
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</div><div>
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<a href="http://www.cambridgestroke.com/cadasil.php" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">CADASIL website</a>
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</div></li><li class="half_rhythm"><div>
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<b>cureCADASIL Association</b>
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</div><div>10 Schalks Crossing Road</div><div>Suite 501A-133</div><div>Plainsboro NJ 08536</div><div>
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<a href="https://curecadasil.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.curecadasil.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>L’association CADASIL France</b>
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</div><div>France</div><div>
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<a href="http://www.cadasil.fr/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.cadasil.fr</a>
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</div></li><li class="half_rhythm"><div>
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<b>MedlinePlus</b>
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</div><div>
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<a href="https://medlineplus.gov/genetics/condition/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">CADASIL</a>
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</div></li><li class="half_rhythm"><div>
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<b>Stichting Platform CADASIL</b>
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</div><div>
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<a href="http://www.cadasil.eu/index.php/nl/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.cadasil.eu</a>
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</div></li><li class="half_rhythm"><div>
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<b>United Leukodystrophy Foundation</b>
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</div><div><b>Phone:</b> 815-748-0844</div><div><b>Email:</b> office@ulf.org</div><div>
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<a href="https://ulf.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ulf.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>CADASIL Family Registry</b>
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</div><div><b>Email:</b> registry@cadasilassociation.org</div><div>
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<a href="https://connect.patientcrossroads.org/?org=cadasil" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.curecadasilfamilyregistry.com</a>
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</div></li><li class="half_rhythm"><div>
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<b>CADASIL Together We Have Hope Registry</b>
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</div><div>3605 Monument Drive</div><div>Round Rock TX 78681</div><div><b>Phone:</b> 877-519-4673; 512-255-0209</div><div><b>Email:</b> info@cadasilfoundation.org</div><div>
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<a href="http://www.cadasilfoundation.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.cadasilfoundation.org</a>
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</div></li></ul>
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</div><div id="cadasil.Molecular_Genetics"><h2 id="_cadasil_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figcadasilmolgenTA"><a href="/books/NBK1500/table/cadasil.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobcadasilmolgenTA"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="cadasil.molgen.TA"><a href="/books/NBK1500/table/cadasil.molgen.TA/?report=objectonly" target="object" rid-ob="figobcadasilmolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">CADASIL: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figcadasilmolgenTB"><a href="/books/NBK1500/table/cadasil.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobcadasilmolgenTB"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="cadasil.molgen.TB"><a href="/books/NBK1500/table/cadasil.molgen.TB/?report=objectonly" target="object" rid-ob="figobcadasilmolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for CADASIL (View All in OMIM) </p></div></div><p><b>Gene structure.</b>
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<i>NOTCH3</i> (<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000435.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000435.2</a>) consists of 33 exons spanning about 7 kb. For a detailed summary of gene and protein information, see <a href="/books/NBK1500/?report=reader#cadasil.molgen.TA">Table A</a>, <b>Gene</b>.</p><p><b>Pathogenic variants.</b> Pathogenic variants in CADASIL are detected in exons 2-24. The majority of sequence alterations in <i>NOTCH3</i> are missense variants (95%), characteristically leading to the loss or gain of a cysteine residue in one of the 34 epidermal growth factor-like repeat (EGFr) domains of neurogenic locus notch homolog protein 3 (NOTCH3), the protein encoded by <i>NOTCH3</i> [<a class="bibr" href="#cadasil.REF.dichgans.2001.1714" rid="cadasil.REF.dichgans.2001.1714">Dichgans et al 2001</a>]. This results in an uneven number of cysteine residues in the given EGFr domain, most likely modifying the tertiary structure of the protein.</p><p>Approximately 70% of European individuals with a clinical CADASIL diagnosis have a pathogenic variant in one of the exons encoding EGFr domains 1-6 [<a class="bibr" href="#cadasil.REF.rutten.2019.676" rid="cadasil.REF.rutten.2019.676">Rutten et al 2019</a>], although regional differences are seen [<a class="bibr" href="#cadasil.REF.federico.2005.117" rid="cadasil.REF.federico.2005.117">Federico et al 2005</a>, <a class="bibr" href="#cadasil.REF.bianchi.2015.134" rid="cadasil.REF.bianchi.2015.134">Bianchi et al 2015</a>, <a class="bibr" href="#cadasil.REF.yin.2015.585" rid="cadasil.REF.yin.2015.585">Yin et al 2015</a>, <a class="bibr" href="#cadasil.REF.chen.2017.707" rid="cadasil.REF.chen.2017.707">Chen et al 2017</a>, <a class="bibr" href="#cadasil.REF.rutten.2019.676" rid="cadasil.REF.rutten.2019.676">Rutten et al 2019</a>]. Pathogenic variants in EGFr domains 7-34 are less frequently seen in diagnosed individuals (~30%) but have a high frequency in the general population (gnomAD) [<a class="bibr" href="#cadasil.REF.rutten.2019.676" rid="cadasil.REF.rutten.2019.676">Rutten et al 2019</a>] – suggesting that only a small proportion of individuals with a pathogenic variant in EGFr 7-34 develop a classic CADASIL phenotype.</p><p>Of note, with a few exceptions [<a class="bibr" href="#cadasil.REF.mizuno.2008.2067" rid="cadasil.REF.mizuno.2008.2067">Mizuno et al 2008</a>, <a class="bibr" href="#cadasil.REF.wollenweber.2015.786" rid="cadasil.REF.wollenweber.2015.786">Wollenweber et al 2015</a>], there is no convincing evidence that missense variants not involving a cysteine residue cause CADASIL [<a class="bibr" href="#cadasil.REF.rutten.2014.593" rid="cadasil.REF.rutten.2014.593">Rutten et al 2014</a>].</p><p>A few splice site variants, insertions, and deletions, predicted to result in an uneven number of cysteine residues within EGFr, have been associated with disease [<a class="bibr" href="#cadasil.REF.rutten.2014.593" rid="cadasil.REF.rutten.2014.593">Rutten et al 2014</a>].</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figcadasilTnotablenotch3pathogenicvari"><a href="/books/NBK1500/table/cadasil.T.notable_notch3_pathogenic_vari/?report=objectonly" target="object" title="Table 7. " class="img_link icnblk_img" rid-ob="figobcadasilTnotablenotch3pathogenicvari"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="cadasil.T.notable_notch3_pathogenic_vari"><a href="/books/NBK1500/table/cadasil.T.notable_notch3_pathogenic_vari/?report=objectonly" target="object" rid-ob="figobcadasilTnotablenotch3pathogenicvari">Table 7. </a></h4><p class="float-caption no_bottom_margin">Notable <i>NOTCH3</i> Pathogenic Variants </p></div></div><p><b>Normal gene product.</b> 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 [<a class="bibr" href="#cadasil.REF.domenga.2004.2730" rid="cadasil.REF.domenga.2004.2730">Domenga et al 2004</a>], and in the control of vascular mechano-transduction [<a class="bibr" href="#cadasil.REF.belin_de_chantem_le.2008.2216" rid="cadasil.REF.belin_de_chantem_le.2008.2216">Belin de Chantemèle et al 2008</a>]. NOTCH3 is a single pass transmembrane protein which consists of 2321 amino acids (<a href="https://www.ncbi.nlm.nih.gov/protein/NP_000426.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000426.2</a>). The extracellular domain is composed of 34 EGFr domains and three Lin/Notch (LNR) repeats. It can bind to a ligand via the ligand binding domain, which consists of EGFr domain 10 and 11. The NOTCH3 protein also has an intracellular domain required for signal transduction.</p><p><b>Abnormal gene product.</b>
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<i>NOTCH3</i> pathogenic variants in CADASIL lead to loss or gain of a cysteine residue in one of the protein’s 34 EGFr domains. This results in an unpaired cysteine residue and disrupted disulphide bridge formation, causing aggregation of the mutant NOTCH3 extracellular domain. This, directly or indirectly, has a toxic effect, leading to degeneration of VSMC. It has been proposed that VSMC degeneration is due increased VSMC death [<a class="bibr" href="#cadasil.REF.gray.2007.597" rid="cadasil.REF.gray.2007.597">Gray et al 2007</a>]. However, studies also showed that CADASIL VSMCs have a lower proliferation rate than control VSMCs [<a class="bibr" href="#cadasil.REF.viitanen.2013.134" rid="cadasil.REF.viitanen.2013.134">Viitanen et al 2013</a>], due to increased transforming growth factor-β (TGFβ) expression [<a class="bibr" href="#cadasil.REF.panahi.2018.3016" rid="cadasil.REF.panahi.2018.3016">Panahi et al 2018</a>]. Recent evidence indicates that the NOTCH3 aggregates cause sequestration of functionally important extracellular matrix proteins, such as vitronectin and tissue inhibitor of metalloproteinase-3 (TIMP3) [<a class="bibr" href="#cadasil.REF.monetlepr_tre.2013.1830" rid="cadasil.REF.monetlepr_tre.2013.1830">Monet-Leprêtre et al 2013</a>].</p><p>Whether and which hypomorphic <i>NOTCH3</i> variants may cause a CADASIL-like phenotype is still unclear as these variants have been described in individuals both with and without small vessel disease. [<a class="bibr" href="#cadasil.REF.rutten.2013.1486" rid="cadasil.REF.rutten.2013.1486">Rutten et al 2013</a>, <a class="bibr" href="#cadasil.REF.moccia.2015.547.e5" rid="cadasil.REF.moccia.2015.547.e5">Moccia et al 2015</a>].</p><p>Overall, evidence from studies in human, mice, and cell models indicates that neomorphic properties of mutant NOTCH3 protein drive CADASIL pathogenesis, whereas loss of NOTCH3 function does not play a pivotal role [<a class="bibr" href="#cadasil.REF.rutten.2013.1486" rid="cadasil.REF.rutten.2013.1486">Rutten et al 2013</a>, <a class="bibr" href="#cadasil.REF.cognat.2014.842" rid="cadasil.REF.cognat.2014.842">Cognat et al 2014</a>].</p><p><b>Cancer and benign tumors.</b>
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<i>NOTCH3</i> amplification and rearrangement has been observed in cancerous tissues obtained from normal individuals suggesting NOTCH3 plays a role in tumorigenesis [<a class="bibr" href="#cadasil.REF.boelens.2014.499" rid="cadasil.REF.boelens.2014.499">Boelens et al 2014</a>, <a class="bibr" href="#cadasil.REF.jung.2014.e1004751" rid="cadasil.REF.jung.2014.e1004751">Jung et al 2014</a>].</p></div><div id="cadasil.Chapter_Notes"><h2 id="_cadasil_Chapter_Notes_">Chapter Notes</h2><div id="cadasil.Author_History"><h3>Author History</h3><p>Elles MJ Boon, PhD; Leiden University Medical Center (2006-2015)<br />Martijn H Breuning, MD, PhD; Leiden University Medical Center (2000-2006)<br />Martin Dichgans, MD, PhD; Ludwig-Maximilians-Universität München (2006-2012)<br />J Haan, MD, PhD; Leiden University Medical Center (2000-2006)<br />Remco J Hack, MD, PhD student; Leiden University Medical Center (2019-present)<br />Saskia AJ Lesnik Oberstein, MD, PhD (2000-present)<br />Julie Rutten, MD (2015-present)<br />Gisela M Terwindt, MD, PhD; Leiden University Medical Center (2012-2015)</p></div><div id="cadasil.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>14 March 2019 (ma) Comprehensive update posted live</div></li><li class="half_rhythm"><div>14 July 2016 (aa) Revision: Addition to <a href="#cadasil.Differential_Diagnosis">Differential Diagnosis</a></div></li><li class="half_rhythm"><div>26 February 2015 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>28 June 2012 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>23 July 2009 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>21 November 2006 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>2 August 2004 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>23 August 2002 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>15 March 2000 (pb) Review posted live</div></li><li class="half_rhythm"><div>January 2000 (slo) Original submission</div></li></ul></div></div><div id="cadasil.References"><h2 id="_cadasil_References_">References</h2><div id="cadasil.Published_Guidelines__Consensus"><h3>Published Guidelines / Consensus Statements</h3><ul><li class="half_rhythm"><div>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 <a href="https://pediatrics.aappublications.org/content/131/3/620.full.pdf" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">online</a>. 2013. Accessed 3-30-23.</div></li><li class="half_rhythm"><div>National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available <a href="https://www.nsgc.org/Policy-Research-and-Publications/Position-Statements/Position-Statements/Post/genetic-testing-of-minors-for-adult-onset-conditions" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">online</a>. 2018. Accessed 3-30-23.</div></li></ul></div><div id="cadasil.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.abou_alshaar.2016.239">Abou Al-Shaar H, Qadi N, Al-Hamed MH, Meyer BF, Bohlega S. Phenotypic comparison of individuals with homozygous or heterozygous mutation of NOTCH3 in a large CADASIL family. <span><span class="ref-journal">J Neurol Sci. </span>2016;<span class="ref-vol">367</span>:239–43.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/27423596" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27423596</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.adibsamii.2010.630">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. <span><span class="ref-journal">Stroke. </span>2010;<span class="ref-vol">41</span>:630–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20167921" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20167921</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.alten.2014.e112311">Alten F, Motte J, Ewering C, Osada N, Clemens CR, Kadas EM, Eter N, Paul F, Marziniak M. Multimodal retinal vessel analysis in CADASIL patients. <span><span class="ref-journal">PLoS One. </span>2014;<span class="ref-vol">9</span>:e112311. </span> [<a href="/pmc/articles/PMC4221286/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4221286</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25372785" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25372785</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.amberla.2004.1598">Amberla K, Waljas M, Tuominen S, Almkvist O, Poyhonen M, Tuisku S, Kalimo H, Viitanen M. Insidious cognitive decline in CADASIL. <span><span class="ref-journal">Stroke. </span>2004;<span class="ref-vol">35</span>:1598–602.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15143298" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15143298</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.arboledavelasquez.2002.277">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. <span><span class="ref-journal">Neurology. </span>2002;<span class="ref-vol">59</span>:277–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12136071" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12136071</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.auer.2001.443">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. <span><span class="ref-journal">Radiology. </span>2001;<span class="ref-vol">218</span>:443–51.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11161160" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11161160</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.belin_de_chantem_le.2008.2216">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. <span><span class="ref-journal">Arterioscler Thromb Vasc Biol. </span>2008;<span class="ref-vol">28</span>:2216–24.</span> [<a href="/pmc/articles/PMC2658748/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2658748</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18818417" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18818417</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.bergmann.1996.341">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. <span><span class="ref-journal">Acta Neuropathol. </span>1996;<span class="ref-vol">92</span>:341–50.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8891065" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8891065</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.bersano.2018.2934">Bersano A, Bedini G, Markus HS, Vitali P, Colli-Tibaldi E, Taroni F, Gellera C, Baratta S, Mosca L, Carrera P, Ferrari M, Cereda C, Grieco G, Lanfranconi S, Mazucchelli F, Zarcone D, De Lodovici ML, Bono G, Boncoraglio GB, Parati EA, Calloni MV, Perrone P, Bordo BM, Motto C, Agostoni E, Pezzini A, Padovani A, Micieli G, Cavallini A, Molini G, Sasanelli F, Sessa M, Comi G, Checcarelli N, Carmerlingo M, Corato M, Marcheselli S, Fusi L, Grampa G, Uccellini D, Beretta S, Ferrarese C, Incorvaia B, Tadeo CS, Adobbati L, Silani V, Faragò G, Trobia N, Grond-Ginsbach C, Candelise L. Lombardia GENS-group. The role of clinical and neuroimaging features in the diagnosis of CADASIL. <span><span class="ref-journal">J Neurol. </span>2018;<span class="ref-vol">265</span>:2934–43.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/30311053" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30311053</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.bianchi.2010.1039">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. <span><span class="ref-journal">J Neurol. </span>2010;<span class="ref-vol">257</span>:1039–42.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20169447" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20169447</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.bianchi.2015.134">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. <span><span class="ref-journal">J Neurol. </span>2015;<span class="ref-vol">262</span>:134–41.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/25344745" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25344745</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.boelens.2014.499">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. <span><span class="ref-journal">Cell. </span>2014;<span class="ref-vol">159</span>:499–513.</span> [<a href="/pmc/articles/PMC4283810/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4283810</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25417103" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25417103</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.bruening.2001.1268">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. <span><span class="ref-journal">AJNR Am J Neuroradiol. </span>2001;<span class="ref-vol">22</span>:1268–74.</span> [<a href="/pmc/articles/PMC7975190/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7975190</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/11498413" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11498413</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.buffon.2006.175">Buffon F, Porcher R, Hernandez K, Kurtz A, Pointeau S, Vahedi K, Bousser MG, Chabriat H. Cognitive profile in CADASIL. <span><span class="ref-journal">J Neurol Neurosurg Psychiatry. </span>2006;<span class="ref-vol">77</span>:175–80.</span> [<a href="/pmc/articles/PMC2077584/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2077584</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16421118" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16421118</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.bugiani.2016.1777">Bugiani M, Kevelam SH, Bakels HS, Waisfisz Q, Ceuterick-de Groote C, Niessen HW, Abbink TE, Lesnik Oberstein SA, van der Knaap MS. Cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL). <span><span class="ref-journal">Neurology. </span>2016;<span class="ref-vol">87</span>:1777–86.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/27664989" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27664989</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.chabriat.1998.452">Chabriat H, Levy C, Taillia H, Iba-Zizen MT, Vahedi K, Joutel A, Tournier-Lasserve E, Bousser MG. Patterns of MRI lesions in CADASIL. <span><span class="ref-journal">Neurology. </span>1998;<span class="ref-vol">51</span>:452–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9710018" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9710018</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.chabriat.2000.1904">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. <span><span class="ref-journal">Stroke. </span>2000;<span class="ref-vol">31</span>:1904–12.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10926955" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10926955</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.charidimou.2017a.2317">Charidimou A, Karayiannis C, Song TJ, Orken DN, Thijs V, Lemmens R, Kim J, Goh SM, Phan TG, Soufan C, Chandra RV, Slater LA, Haji S, Mok V, Horstmann S, Leung KT, Kawamura Y, Sato N, Hasebe N, Saito T, Wong LKS, Soo Y, Veltkamp R, Flemming KD, Imaizumi T, Srikanth V, Heo JH., International META-MICROBLEEDS Initiative. 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Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. <span><span class="ref-journal">Expert Rev Mol Diagn. </span>2014;<span class="ref-vol">14</span>:593–603.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24844136" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24844136</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.rutten.2019.676">Rutten JW, Van Eijsden BJ, Duering M, Jouvent E, Opherk C, Pantoni L, Federico A, Dichgans M, Markus HS, Chabriat H, Lesnik Oberstein SAJ. The effect of NOTCH3 pathogenic variant position on CADASIL disease severity: NOTCH3 EGFr 1-6 pathogenic variant are associated with a more severe phenotype and lower survival compared with EGFr 7-34 pathogenic variant. <span><span class="ref-journal">Genet Med. </span>2019;<span class="ref-vol">21</span>:676–82.</span> [<a href="/pmc/articles/PMC6752295/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6752295</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30032161" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30032161</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.schr_der.2005.587">Schröder JM, Zuchner S, Dichgans M, Nagy Z, Molnar MJ. Peripheral nerve and skeletal muscle involvement in CADASIL. <span><span class="ref-journal">Acta Neuropathol (Berl). </span>2005;<span class="ref-vol">110</span>:587–99.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16328531" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16328531</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.sicurelli.2005.1206">Sicurelli F, Dotti MT, De Stefano N, Malandrini A, Mondelli M, Bianchi S, Federico A. Peripheral neuropathy in CADASIL. <span><span class="ref-journal">J Neurol. </span>2005;<span class="ref-vol">252</span>:1206–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15827866" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15827866</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.singhal.2004.2031">Singhal S, Bevan S, Barrick T, Rich P, Markus HS. The influence of genetic and cardiovascular risk factors on the CADASIL phenotype. <span><span class="ref-journal">Brain. </span>2004;<span class="ref-vol">127</span>:2031–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15229130" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15229130</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.singhal.2005.2481">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. <span><span class="ref-journal">AJNR Am J Neuroradiol. </span>2005;<span class="ref-vol">26</span>:2481–7.</span> [<a href="/pmc/articles/PMC7976180/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7976180</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16286388" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16286388</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.soong.2013.319">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. <span><span class="ref-journal">J Chin Med Assoc. </span>2013;<span class="ref-vol">76</span>:319–24.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23602593" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23602593</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.sureka.2012.e782">Sureka J, Jakkani RK. Clinico-radiological spectrum of bilateral temporal lobe hyperintensity: a retrospective review. <span><span class="ref-journal">Br J Radiol. </span>2012;<span class="ref-vol">85</span>:e782–92.</span> [<a href="/pmc/articles/PMC3487100/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3487100</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22422381" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22422381</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.tan.2016.e0157613">Tan RYY, Markus HS. CADASIL: Migraine, Encephalopathy, Stroke and Their Inter-Relationships. <span><span class="ref-journal">PLoS One. </span>2016;<span class="ref-vol">11</span>:e0157613. </span> [<a href="/pmc/articles/PMC4911105/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4911105</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27309730" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27309730</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.tatsch.2003.862">Tatsch K, Koch W, Linke R, Poepperl G, Peters N, Holtmannspoetter M, Dichgans M. Cortical hypometabolism and crossed cerebellar diaschisis suggest subcortically induced disconnection in CADASIL: an 18F-FDG PET study. <span><span class="ref-journal">J Nucl Med. </span>2003;<span class="ref-vol">44</span>:862–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12791811" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12791811</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.tikka.2009.933">Tikka S, Mykkänen 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. <span><span class="ref-journal">Brain. </span>2009;<span class="ref-vol">132</span>:933–9.</span> [<a href="/pmc/articles/PMC2668941/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2668941</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19174371" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19174371</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.tuominen.2001.1767">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. <span><span class="ref-journal">Stroke. </span>2001;<span class="ref-vol">32</span>:1767–74.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11486103" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11486103</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.tuominen.2004.1063">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. <span><span class="ref-journal">Stroke. </span>2004;<span class="ref-vol">35</span>:1063–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15017012" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15017012</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.valenti.2011.390">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. <span><span class="ref-journal">Acta Neurol Scand. </span>2011;<span class="ref-vol">124</span>:390–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21428968" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21428968</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.van_den_boom.2003.683">van den Boom R, Lesnik Oberstein SA, Ferrari MD, Haan J, van Buchem MA. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: MR imaging findings at different ages--3rd-6th decades. <span><span class="ref-journal">Radiology. </span>2003;<span class="ref-vol">229</span>:683–90.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14593195" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14593195</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.van_den_boom.2002.791">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. <span><span class="ref-journal">Radiology. </span>2002;<span class="ref-vol">224</span>:791–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12202716" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12202716</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.vinciguerra.2014.91">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. <span><span class="ref-journal">Neurol Sci. </span>2014;<span class="ref-vol">35</span>:91–3.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24277202" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24277202</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.viitanen.2013.134">Viitanen M, Sundström E, Baumann M, Poyhonen M, Tikka S, Behbahani H. Experimental studies of mitochondrial function in CADASIL vascular smooth muscle cells. <span><span class="ref-journal">Exp Cell Res. </span>2013;<span class="ref-vol">319</span>:134–43.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23036509" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23036509</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.wang.2011.534">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. <span><span class="ref-journal">J Neurol Neurosurg Psychiatry. </span>2011;<span class="ref-vol">82</span>:534–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20935329" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20935329</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.weller.1998.1505">Weller M, Dichgans J, Klockgether T. Acetazolamide-responsive migraine in CADASIL. <span><span class="ref-journal">Neurology. </span>1998;<span class="ref-vol">50</span>:1505.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9596023" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9596023</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.williamson.1999.2243">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. <span><span class="ref-journal">Arthritis Rheum. </span>1999;<span class="ref-vol">42</span>:2243–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10524700" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10524700</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.wollenweber.2015.786">Wollenweber FA, Hanecker P, Bayer-Karpinska A, Malik R, Bäzner H, Moreton F, Muir KW, Müller S, Giese A, Opherk C, Dichgans M, Haffner C, Duering M. Cysteine-sparing CADASIL mutations in NOTCH3 show proaggregatory properties in vitro. <span><span class="ref-journal">Stroke. </span>2015;<span class="ref-vol">46</span>:786–92.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/25604251" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25604251</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.yao.2014.155">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. <span><span class="ref-journal">Cerebrovasc Dis. </span>2014;<span class="ref-vol">37</span>:155–63.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24503815" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24503815</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cadasil.REF.yin.2015.585">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. <span><span class="ref-journal">Int J Neurosci. </span>2015;<span class="ref-vol">125</span>:585–92.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/25105908" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25105908</span></a>]</div></p></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK1500_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Remco J Hack</span>, MD<div class="affiliation small">Department of Clinical Genetics<br />Leiden University Medical Center<br />Leiden, The Netherlands<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ln.cmul@kcah.j.r" class="oemail">ln.cmul@kcah.j.r</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Julie Rutten</span>, MD, PhD<div class="affiliation small">Department of Clinical Genetics<br />Leiden University Medical Center<br />Leiden, The Netherlands<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ln.cmul@nettur.w.j" class="oemail">ln.cmul@nettur.w.j</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Saskia AJ Lesnik Oberstein</span>, MD, PhD<div class="affiliation small">Department of Clinical Genetics<br />Leiden University Medical Center<br />Leiden, The Netherlands<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ln.cmul@kinsel" class="oemail">ln.cmul@kinsel</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">March 15, 2000</span>; Last Update: <span itemprop="dateModified">March 14, 2019</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 1993-2025, University of Washington, Seattle. GeneReviews is
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contact: <a href="mailto:dev@null" data-email="ude.wu@tssamda" class="oemail">ude.wu@tssamda</a>.</p></div></div><h3>Publisher</h3><p><a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>, Seattle (WA)</p><h3>NLM Citation</h3><p>Hack RJ, Rutten J, Lesnik Oberstein SAJ. CADASIL. 2000 Mar 15 [Updated 2019 Mar 14]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/gene/timothy/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/gene/cask-dis/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figobcadasilTmoleculargenetictestingused"><div id="cadasil.T.molecular_genetic_testing_used" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in CADASIL</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1500/table/cadasil.T.molecular_genetic_testing_used/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cadasil.T.molecular_genetic_testing_used_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_cadasil.T.molecular_genetic_testing_used_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_cadasil.T.molecular_genetic_testing_used_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_cadasil.T.molecular_genetic_testing_used_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Probands with a Pathogenic Variant <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_cadasil.T.molecular_genetic_testing_used_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>NOTCH3</i>
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</td><td headers="hd_h_cadasil.T.molecular_genetic_testing_used_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_cadasil.T.molecular_genetic_testing_used_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Estimated >95% <sup>4</sup></td></tr><tr><td headers="hd_h_cadasil.T.molecular_genetic_testing_used_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>5</sup></td><td headers="hd_h_cadasil.T.molecular_genetic_testing_used_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown <sup>6</sup></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="cadasil.TF.1.1"><p class="no_margin">See <a href="/books/NBK1500/?report=reader#cadasil.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="cadasil.TF.1.2"><p class="no_margin">See <a href="#cadasil.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this gene.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="cadasil.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click <a href="/books/n/gene/app2/?report=reader">here</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="cadasil.TF.1.4"><p class="no_margin">When all exons coding for epidermal growth factor-like repeats (see <a href="#cadasil.Molecular_Genetics">Molecular Genetics</a>) are sequenced (exons 2-24) and stringent inclusion criteria are applied [<a class="bibr" href="#cadasil.REF.markus.2002.1134" rid="cadasil.REF.markus.2002.1134">Markus et al 2002</a>, <a class="bibr" href="#cadasil.REF.peters.2005a.1091" rid="cadasil.REF.peters.2005a.1091">Peters et al 2005a</a>]</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="cadasil.TF.1.5"><p class="no_margin">Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.</p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="cadasil.TF.1.6"><p class="no_margin">
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<a class="bibr" href="#cadasil.REF.rutten.2013.1486" rid="cadasil.REF.rutten.2013.1486">Rutten et al [2013]</a>
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</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobcadasilTclinicalsignsandmriabnorma"><div id="cadasil.T.clinical_signs_and_mri_abnorma" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Clinical Signs and MRI Abnormalities of Sporadic/Multifactorial Disorders in the Differential Diagnosis of CADASIL</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1500/table/cadasil.T.clinical_signs_and_mri_abnorma/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cadasil.T.clinical_signs_and_mri_abnorma_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing Clinical Characteristics</th><th id="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing MRI Abnormalities</th><th id="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Temporopolar MRI Lesions</th><th id="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Optic Nerve & Spinal Cord Involvement</th><th id="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_6" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Oligoclonal Bands in CSF</th><th id="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_7" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hypertension</th></tr></thead><tbody><tr><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Multiple sclerosis <sup>1</sup></td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Optic neuritis</div></li><li class="half_rhythm"><div>Spinal cord involvement</div></li><li class="half_rhythm"><div>Internuclear ophthalmoplegia</div></li><li class="half_rhythm"><div>Lhermitte sign</div></li><li class="half_rhythm"><div>Heat sensitivity</div></li><li class="half_rhythm"><div>Age of onset: 15-50 yrs</div></li></ul>
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</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Juxtacortical WMH</div></li><li class="half_rhythm"><div>Dawson fingers</div></li><li class="half_rhythm"><div>Spinal cord, corpus callosum & U-fibers involvement</div></li><li class="half_rhythm"><div>Gadolinium enhancement of lesions</div></li></ul>
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</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Common</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Typical</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Yes</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Not associated</td></tr><tr><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sporadic small vessel disease incl Binswanger's disease</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Hypertension</div></li><li class="half_rhythm"><div>Absence of AD or AR inheritance in family history</div></li><li class="half_rhythm"><div>Age of onset: >65 yrs</div></li></ul>
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</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Involvement of temporal pole is rare</div></li><li class="half_rhythm"><div>Involvement of external capsule occurs less frequently</div></li></ul>
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</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">No</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">No</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Associated</td></tr><tr><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Primary angiitis of the nervous system <sup>2</sup></td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Subacute headache</div></li><li class="half_rhythm"><div>Multifocal neurologic deficits</div></li><li class="half_rhythm"><div>Signs & symptoms suggestive of systemic vaculitis (peripheral neuropathy, fever, weight loss, rash, & night sweats)</div></li><li class="half_rhythm"><div>May occur at any age; median age at diagnosis: 50 yrs</div></li></ul>
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</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Multifocal infarcts in different vascular territories</div></li><li class="half_rhythm"><div>Diffuse gadolinium enhanced lesions</div></li></ul>
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</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Uncommon</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Involvement of:
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<ul><li class="half_rhythm"><div>Spinal cord: 5% of affected individuals</div></li><li class="half_rhythm"><div>Optic nerve: rare</div></li></ul>
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</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Occasionally</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Not associated</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">AD = autosomal dominant; AR = autosomal recessive; CSF = cerebrospinal fluid; WMH = white matter hyperintensities</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="cadasil.TF.2.1"><p class="no_margin">
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<a class="bibr" href="#cadasil.REF.joshi.2017.75" rid="cadasil.REF.joshi.2017.75">Joshi et al [2017]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="cadasil.TF.2.2"><p class="no_margin">
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<a class="bibr" href="#cadasil.REF.williamson.1999.2243" rid="cadasil.REF.williamson.1999.2243">Williamson et al [1999]</a>
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</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobcadasilTclinicalsignsandmriabnorma1"><div id="cadasil.T.clinical_signs_and_mri_abnorma_1" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Clinical Signs and MRI Abnormalities of Inherited Disorders to Consider in the Differential Diagnosis of CADASIL</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1500/table/cadasil.T.clinical_signs_and_mri_abnorma_1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cadasil.T.clinical_signs_and_mri_abnorma_1_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing Clinical Signs</th><th id="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing MRI Abnormalities</th></tr></thead><tbody><tr><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/fabry/?report=reader">Fabry disease</a>
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</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>GLA</i>
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</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XL</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Classic Fabry disease phenotype:
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<ul><li class="half_rhythm"><div>Onset in childhood & adolescence</div></li><li class="half_rhythm"><div>Periodic severe pain in extremities</div></li><li class="half_rhythm"><div>Angiokeratoma</div></li><li class="half_rhythm"><div>Renal insufficiency</div></li><li class="half_rhythm"><div>Hypohidrosis</div></li><li class="half_rhythm"><div>Cardiac involvement</div></li><li class="half_rhythm"><div>Corneal opacities</div></li></ul>
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Late-onset Fabry disease phenotype:
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<ul><li class="half_rhythm"><div>Onset in adulthood & later</div></li><li class="half_rhythm"><div>Cardiomyopathy</div></li><li class="half_rhythm"><div>Renal disease</div></li><li class="half_rhythm"><div>Cerebrovascular disease</div></li></ul>
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</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Exclusive involvement of pulvinar thought to be characteristic</div></li><li class="half_rhythm"><div>Ischemic strokes predominantly located in vertebrobasilar system</div></li><li class="half_rhythm"><div>Vertebrobasilar dolichoectasia</div></li></ul>
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</td></tr><tr><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/carasil/?report=reader">CARASIL</a> <sup>1</sup></td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_2" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>HTRA1</i>
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</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Onset age: 20-30 yrs (spastic gait)</div></li><li class="half_rhythm"><div>Spastic gait</div></li><li class="half_rhythm"><div>Premature alopecia</div></li><li class="half_rhythm"><div>Severe low back pain & deforming spondylosis</div></li></ul>
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</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Spinal spondylosis</div></li><li class="half_rhythm"><div>In advanced stage: "arc" sign (involvement of pontocerebellar tract)</div></li></ul>
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</td></tr><tr><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/carasil/?report=reader"><i>HTRA1</i> cerebral small vessel disease</a> (CADASIL type 2)</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_3" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Onset age: 50-70 yrs (stroke)</div></li><li class="half_rhythm"><div>Alopecia, spondylosis, & low back pain reported (less frequently than in CARASIL)</div></li></ul>
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</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Spinal spondylosis</td></tr><tr><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<p><a href="/books/n/gene/melas/?report=reader">MELAS</a> <sup>2</sup></p>
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</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MT-TL1</i>
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<br />
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<p><i>MT-ND5</i> <sup>3</sup></p>
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</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mat</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Onset age: 2-10 yrs</div></li><li class="half_rhythm"><div>Anorexia</div></li><li class="half_rhythm"><div>Recurrent vomiting</div></li><li class="half_rhythm"><div>Short stature</div></li><li class="half_rhythm"><div>Generalized tonic-clonic seizures</div></li><li class="half_rhythm"><div>Proximal limb weakness</div></li><li class="half_rhythm"><div>Sensorineural hearing loss</div></li><li class="half_rhythm"><div>Stroke-like episodes of cortical blindness and/or altered consciousness from age ~40 yrs</div></li></ul>
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</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>↑ T<sub>2</sub> signal, involving the posterior cerebrum, not conforming to the distribution of major arteries</div></li><li class="half_rhythm"><div>Swollen gyri</div></li><li class="half_rhythm"><div>Gadolinium enhancement of lesions</div></li><li class="half_rhythm"><div>Slow spreading of stroke-like lesions</div></li></ul>
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</td></tr><tr><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CARASAL <sup>4</sup></td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>CTSA</i>
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</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Age of onset: 40-60 yrs</div></li><li class="half_rhythm"><div>Intracerebral hemorrhage</div></li><li class="half_rhythm"><div>Muscle cramps</div></li><li class="half_rhythm"><div>Xerostomia</div></li><li class="half_rhythm"><div>Keratoconjuctivitis sicca</div></li><li class="half_rhythm"><div>Therapy-resistant hypertension</div></li></ul>
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</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Intracerebral hemorrhages</td></tr><tr><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>COL4A1</i>- & <i>COL4A2-</i> related small vessel disease<br />(see <a href="/books/n/gene/col4a1-dis/?report=reader"><i>COL4A1</i>-Related Disorders</a> & OMIM <a href="https://omim.org/phenotypicSeries/PS175780" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PS175780</a>) <sup>5</sup></td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>COL4A1</i>
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<br />
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<i>COL4A2</i>
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</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Highly variable clinical spectrum; onset range: infantile to (late) adult. Infantile onset:
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<ul><li class="half_rhythm"><div>Psychomotor retardation</div></li><li class="half_rhythm"><div>Infantile hemiplegia</div></li><li class="half_rhythm"><div>Intracerebral hemorrhage</div></li><li class="half_rhythm"><div>Seizures</div></li></ul>
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Adult onset:
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<ul><li class="half_rhythm"><div>Intracerebral hemorrhage</div></li><li class="half_rhythm"><div>Opthalmologic abnormalities</div></li><li class="half_rhythm"><div>Renal abnormalities</div></li><li class="half_rhythm"><div>Cardiovascular abnormalties</div></li><li class="half_rhythm"><div>Muscle cramps</div></li></ul>
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</td><td headers="hd_h_cadasil.T.clinical_signs_and_mri_abnorma_1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Porencephaly</div></li><li class="half_rhythm"><div>Schizencephaly</div></li><li class="half_rhythm"><div>Deep & lobar intracerebral hemorrhage</div></li><li class="half_rhythm"><div>Cerebral calcification</div></li><li class="half_rhythm"><div>Cerebellar atrophy</div></li><li class="half_rhythm"><div>Intracranial aneurysms</div></li></ul>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">AD = autosomal dominant; AR = autosomal recessive; Mat = maternal; MOI = mode of inheritance; WMH = white matter hyperintensities; XL = X-linked</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="cadasil.TF.3.1"><p class="no_margin">CARASIL = <i>c</i>erebral <i>a</i>utosomal <i>r</i>ecessive <i>a</i>rteriopathy with <i>s</i>ubcortical <i>i</i>nfarcts and <i>l</i>eukoencephalopathy</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="cadasil.TF.3.2"><p class="no_margin"><a href="/books/n/gene/melas/?report=reader">MELAS</a> = <i>m</i>itochondrial <i>e</i>ncephalomyopathy, <i>l</i>actic <i>a</i>cidosis, and <i>s</i>troke-like episodes</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="cadasil.TF.3.3"><p class="no_margin">Pathogenic variants known to cause MELAS have been identified in other mtDNA tRNA genes including <i>MT-TC</i>, <i>MT-TK</i>, <i>MT-TV, MT-TF</i>, <i>MT-TQ</i>, <i>MT-TS1</i>, <i>MT-TS2</i>, and <i>MT-TW</i>, and in the protein-encoding genes <i>MT-CO1</i>, <i>MT-CO2</i>, <i>MT-CO3</i>, <i>MT-CYB</i>, <i>MT-ND1</i>, <i>MT-ND3</i>, and <i>MT-ND6</i>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="cadasil.TF.3.4"><p class="no_margin">CARASAL = cathepsin A–related arteriopathy with strokes and leukoencephalopathy [<a class="bibr" href="#cadasil.REF.bugiani.2016.1777" rid="cadasil.REF.bugiani.2016.1777">Bugiani et al 2016</a>]</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="cadasil.TF.3.5"><p class="no_margin">
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<a class="bibr" href="#cadasil.REF.meuwissen.2015.843" rid="cadasil.REF.meuwissen.2015.843">Meuwissen et al [2015]</a>
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</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobcadasilTrecommendedevaluationsfollow"><div id="cadasil.T.recommended_evaluations_follow" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with CADASIL</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1500/table/cadasil.T.recommended_evaluations_follow/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cadasil.T.recommended_evaluations_follow_lrgtbl__"><table><thead><tr><th id="hd_h_cadasil.T.recommended_evaluations_follow_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_cadasil.T.recommended_evaluations_follow_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_cadasil.T.recommended_evaluations_follow_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_cadasil.T.recommended_evaluations_follow_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neurologic</b>
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</td><td headers="hd_h_cadasil.T.recommended_evaluations_follow_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Complete neurologic eval</td><td headers="hd_h_cadasil.T.recommended_evaluations_follow_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_cadasil.T.recommended_evaluations_follow_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Standard brain MRI incl FLAIR sequence & T<sub>2</sub>-weighted gradient echo imaging</td><td headers="hd_h_cadasil.T.recommended_evaluations_follow_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To determine extent of disease & establish baseline measure for follow up</td></tr><tr><td headers="hd_h_cadasil.T.recommended_evaluations_follow_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neurodevelopmental</b>
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</td><td headers="hd_h_cadasil.T.recommended_evaluations_follow_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Psychometrics</td><td headers="hd_h_cadasil.T.recommended_evaluations_follow_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">W/particular attention to executive function</td></tr><tr><td headers="hd_h_cadasil.T.recommended_evaluations_follow_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Psychiatric/</b>
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<br />
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<b>Behavioral</b>
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</td><td headers="hd_h_cadasil.T.recommended_evaluations_follow_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider referral to a psychiatrist.</td><td headers="hd_h_cadasil.T.recommended_evaluations_follow_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">For treatment of mood disorders & eval of apathy</td></tr><tr><td headers="hd_h_cadasil.T.recommended_evaluations_follow_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Miscellaneous/</b>
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<br />
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<b>Other</b>
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</td><td headers="hd_h_cadasil.T.recommended_evaluations_follow_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consultation w/clinical geneticist &/or genetic counselor</td><td headers="hd_h_cadasil.T.recommended_evaluations_follow_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To incl genetic counseling</td></tr><tr><td headers="hd_h_cadasil.T.recommended_evaluations_follow_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Family support/resources</td><td headers="hd_h_cadasil.T.recommended_evaluations_follow_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><p>• Assess use of community or online <a href="#cadasil.Resources">resources</a>.</p>
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<p>• Social work involvement for support</p>
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<p>• Home nursing referral, if needed</p></td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobcadasilTtreatmentofmanifestationsin"><div id="cadasil.T.treatment_of_manifestations_in" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with CADASIL</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1500/table/cadasil.T.treatment_of_manifestations_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cadasil.T.treatment_of_manifestations_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_cadasil.T.treatment_of_manifestations_in_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/<br />Situation</th><th id="hd_h_cadasil.T.treatment_of_manifestations_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_cadasil.T.treatment_of_manifestations_in_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_cadasil.T.treatment_of_manifestations_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Acute stroke/</b>
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<br />
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<b>TIA</b>
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</td><td headers="hd_h_cadasil.T.treatment_of_manifestations_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard supportive treatment following stroke medicine guidelines</td><td headers="hd_h_cadasil.T.treatment_of_manifestations_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Effect of thrombolytic therapy (IV thrombolysis) unknown; no evidence or rationale for thrombolysis in those w/CADASIL, & risk of intracerebral hemorrhage is probably ↑; see <a href="#cadasil.AgentsCircumstances_to_Avoid">Agents/Circumstances to Avoid</a>.</td></tr><tr><td headers="hd_h_cadasil.T.treatment_of_manifestations_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Migraine</b>
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</td><td headers="hd_h_cadasil.T.treatment_of_manifestations_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Symptomatic treatment; may incl triptans & ergot derivatives</td><td headers="hd_h_cadasil.T.treatment_of_manifestations_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NO evidence that triptans or ergot derivatives are contraindicated due to their vasoconstrictive mechanism of action <sup>1</sup></td></tr><tr><td headers="hd_h_cadasil.T.treatment_of_manifestations_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Psychiatric disturbance</b>
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</td><td headers="hd_h_cadasil.T.treatment_of_manifestations_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment <sup>2</sup></td><td headers="hd_h_cadasil.T.treatment_of_manifestations_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Psychometric & psychiatric eval can be used to evaluate whether apathy (if present) is a symptom of depression or of cognitive dysfunction.</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">IV = intravenous; TIA = transient ischemic attack</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="cadasil.TF.5.1"><p class="no_margin">Triptans appear to have the same treatment responses and frequency of serious side effects in individuals with CADASIL as in the general migraine population [<a class="bibr" href="#cadasil.REF.tan.2016.e0157613" rid="cadasil.REF.tan.2016.e0157613">Tan & Markus 2016</a>].</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="cadasil.TF.5.2"><p class="no_margin">No studies have been performed in individuals with CADASIL to determine the effect of the treatment of psychiatric disturbances (e.g. depression) with psychiatric drugs.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobcadasilTpreventionofprimarymanifest"><div id="cadasil.T.prevention_of_primary_manifest" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Prevention of Primary Manifestations in Individuals with CADASIL</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1500/table/cadasil.T.prevention_of_primary_manifest/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cadasil.T.prevention_of_primary_manifest_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_cadasil.T.prevention_of_primary_manifest_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/<br />Situation</th><th id="hd_h_cadasil.T.prevention_of_primary_manifest_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Prevention</th><th id="hd_h_cadasil.T.prevention_of_primary_manifest_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_cadasil.T.prevention_of_primary_manifest_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Stroke/TIA</b>
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</td><td headers="hd_h_cadasil.T.prevention_of_primary_manifest_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider antiplatelet therapy. <sup>1</sup></td><td headers="hd_h_cadasil.T.prevention_of_primary_manifest_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Effect of antiplatelet therapy in persons w/CADASIL unknown; no evidence or rationale for its use in treatment of CADASIL – though also no evidence that it is contraindicated.</td></tr><tr><td headers="hd_h_cadasil.T.prevention_of_primary_manifest_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Control of vascular risk factors</td><td headers="hd_h_cadasil.T.prevention_of_primary_manifest_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Incl hypertension, diabetes, hypercholesterolemia, & smoking</td></tr><tr><td headers="hd_h_cadasil.T.prevention_of_primary_manifest_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Migraine</b>
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</td><td headers="hd_h_cadasil.T.prevention_of_primary_manifest_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider prophylactic therapy.</td><td headers="hd_h_cadasil.T.prevention_of_primary_manifest_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Depending on migraine frequency</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="cadasil.TF.6.1"><p class="no_margin">Such as aspirin and clopidogrel</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobcadasilmolgenTA"><div id="cadasil.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>CADASIL: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1500/table/cadasil.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cadasil.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_cadasil.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_cadasil.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_cadasil.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_cadasil.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_cadasil.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_cadasil.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_cadasil.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="/gene/4854" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
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<i>NOTCH3</i>
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</a>
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</td><td headers="hd_b_cadasil.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=4854" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">19p13<wbr style="display:inline-block"></wbr>​.12</a>
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</td><td headers="hd_b_cadasil.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.uniprot.org/uniprot/Q9UM47" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Neurogenic locus notch homolog protein 3</a>
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</td><td headers="hd_b_cadasil.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.lovd.nl/NOTCH3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Notch homolog 3 (NOTCH3) @ LOVD</a>
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</td><td headers="hd_b_cadasil.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=NOTCH3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NOTCH3</a>
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</td><td headers="hd_b_cadasil.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=NOTCH3[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NOTCH3</a>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="cadasil.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
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<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
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chromosome locus from
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<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
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protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
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For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
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<a href="/books/n/gene/app1/?report=reader">here</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobcadasilmolgenTB"><div id="cadasil.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for CADASIL (<a href="/omim/125310,600276" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1500/table/cadasil.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cadasil.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/125310" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">125310</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 1; CADASIL1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/600276" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">600276</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NOTCH RECEPTOR 3; NOTCH3</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobcadasilTnotablenotch3pathogenicvari"><div id="cadasil.T.notable_notch3_pathogenic_vari" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p>Notable <i>NOTCH3</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1500/table/cadasil.T.notable_notch3_pathogenic_vari/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cadasil.T.notable_notch3_pathogenic_vari_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_cadasil.T.notable_notch3_pathogenic_vari_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_cadasil.T.notable_notch3_pathogenic_vari_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_cadasil.T.notable_notch3_pathogenic_vari_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_cadasil.T.notable_notch3_pathogenic_vari_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_cadasil.T.notable_notch3_pathogenic_vari_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000435.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000435<wbr style="display:inline-block"></wbr>​.2</a>
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<br />
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<a href="https://www.ncbi.nlm.nih.gov/protein/NP_000426.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000426<wbr style="display:inline-block"></wbr>​.2</a>
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</td><td headers="hd_h_cadasil.T.notable_notch3_pathogenic_vari_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.397C>T</td><td headers="hd_h_cadasil.T.notable_notch3_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg133Cys</td><td headers="hd_h_cadasil.T.notable_notch3_pathogenic_vari_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Finnish founder variant [<a class="bibr" href="#cadasil.REF.mykk_nen.2004.813" rid="cadasil.REF.mykk_nen.2004.813">Mykkänen et al 2004</a>]</td></tr><tr><td headers="hd_h_cadasil.T.notable_notch3_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.1630C>T</td><td headers="hd_h_cadasil.T.notable_notch3_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg544Cys</td><td headers="hd_h_cadasil.T.notable_notch3_pathogenic_vari_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Chinese founder variant [<a class="bibr" href="#cadasil.REF.lee.2009.249" rid="cadasil.REF.lee.2009.249">Lee et al 2009</a>]</td></tr><tr><td headers="hd_h_cadasil.T.notable_notch3_pathogenic_vari_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:top;">c.3016C>T</td><td headers="hd_h_cadasil.T.notable_notch3_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">p.Arg1006Cys</td><td headers="hd_h_cadasil.T.notable_notch3_pathogenic_vari_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Marche region of Italy founder variant [<a class="bibr" href="#cadasil.REF.bianchi.2015.134" rid="cadasil.REF.bianchi.2015.134">Bianchi et al 2015</a>]</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the authors. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="http://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>​.hgvs.org</a>). See <a href="/books/n/gene/app3/?report=reader">Quick Reference</a> for an explanation of nomenclature.</p></div></dd></dl></dl></div></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script></div></div>
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