The packet lists NOTCH3, on chromosome 19, as the single known gene, with autosomal dominant inheritance. No ClinGen validity classification is supplied. GeneReviews states that most individuals diagnosed with CADASIL have an affected parent, although a negative family history is occasionally reported, and that de novo pathogenic variants have been described.

On variant location, GeneReviews reports that individuals with cysteine-altering pathogenic variants in epidermal growth-factor like repeat (EGFr) domains 1-6 of NOTCH3 have an onset of stroke about 12 years earlier, lower survival and greater white matter hyperintensity volume than those with variants in EGFr domains 7-34. Variants in domains 1-6 appear fully penetrant, whereas variants in domains 7-34 have a much higher population frequency (about 1 in 300) and are described as likely predisposing to a milder small-vessel disease that may even be non-penetrant. Specific genotype-phenotype associations for individual variants are described as not firmly established, and biallelic NOTCH3 pathogenic variants have been described within the CADASIL spectrum.

The packet supplies no diagnostic methods list or newborn screening information. GeneReviews states that there are no generally accepted diagnostic criteria for CADASIL. It describes the condition as suspected in individuals with unexplained white matter hyperintensities and a family history of stroke or vascular dementia, while noting that lack of an apparent family history does not preclude the diagnosis. Listed clinical signs are transient ischemic attacks and ischemic stroke, cognitive impairment beginning with executive dysfunction, migraine with aura with a mean onset of 30 years, and psychiatric disturbances. Brain imaging findings include symmetric and progressive white matter hyperintensities, often involving the anterior temporal lobes and external capsules, lacunes, recent subcortical infarcts, dilated perivascular spaces, brain atrophy and cerebral microbleeds.

GeneReviews states that the diagnosis is established in a proband by identification of a heterozygous pathogenic or likely pathogenic variant in NOTCH3 on molecular genetic testing or, if molecular testing is not definitive, by characteristic findings on electron microscopy and immunohistochemistry of a tissue sample. A heterozygous NOTCH3 variant of uncertain significance is described as neither establishing nor ruling out the diagnosis.

The packet contains no approved treatment records, so FDA-approved options specific to CADASIL are not documented in this packet. The packet lists one orphan drug record for a different indication, which is not related to CADASIL and is not an approval.

GeneReviews describes management by manifestation. For acute stroke or transient ischemic attack, it lists standard supportive treatment following stroke medicine guidelines, and states that the effect of intravenous thrombolysis in CADASIL is unknown, with no evidence or rationale for it and a probable increased risk of intracerebral hemorrhage. For migraine, symptomatic treatment is described, and GeneReviews states there is no evidence that triptans or ergot derivatives are contraindicated despite their vasoconstrictive mechanism. For psychiatric disturbance, standard treatment is listed, although no studies have examined the effect of psychiatric drugs specifically in CADASIL. GeneReviews notes that oral anticoagulants could increase the risk of intracerebral hemorrhage because of microbleeds, and that smoking increases the risk of stroke in CADASIL.

GeneReviews states that acetazolamide has been associated with beneficial effects on migraine and cerebral perfusion in case reports and small observational studies, but is not given on a routine basis because large studies have not been performed. GeneReviews states that no standard international surveillance guidelines exist.

The packet supplies no certified survival estimate. GeneReviews states that ischemic episodes are often recurrent and lead to severe disability in many individuals, that cognitive decline is in most cases slowly progressive with stepwise deterioration, and that decline becomes more apparent with aging. It reports a mean survival time of 68.5 years for those with cysteine-altering variants in EGFr domains 1-6 and 76.9 years for those with variants in domains 7-34.

The packet reports 17 clinical trial records, all counted as active. NCT05072483 is a natural history study of CADASIL sponsored by the National Heart, Lung, and Blood Institute (recruiting; start 2022-04-18, listed completion 2041-06-01). NCT07692399 is a Phase 2 study of edaravone dexborneol sublingual tablets for blood-brain barrier dysfunction in CADASIL, sponsored by Huashan Hospital (not yet recruiting; start 2026-07-01, listed completion 2027-12-01). NCT06938100, sponsored by Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, examines genotype, clinical features and imaging abnormalities in CADASIL (recruiting; start 2023-11-21). NCT07497867, sponsored by Jeju National University Hospital, is a long-term prospective study of Korean patients with CADASIL (recruiting; start 2023-07-10). NCT04753970, sponsored by Mayo Clinic, studies the retina as a marker for cerebrovascular health in a Phase 1 design (recruiting; start 2021-02-09).

The trial summary lists drug therapy, procedural interventions, medical devices and other interventions, with no gene therapy trials flagged. GeneReviews describes pre-clinical work in cells and mouse models on immunotherapy, antisense-mediated NOTCH3 exon skipping, and stem cell factor with granulocyte colony-stimulating factor.