CADASIL is caused by heterozygous pathogenic variants in NOTCH3, which encodes notch receptor 3, a transmembrane signaling protein. The condition follows autosomal dominant inheritance. Pathogenic variants alter epidermal growth factor-like repeat (EGFr) domains of the NOTCH3 protein, with disease severity and penetrance influenced by variant location within NOTCH3. Variants in EGFr domains 1–6 are associated with a classic CADASIL presentation, earlier stroke onset (by approximately 12 years compared to EGFr domains 7–34 variants), greater white matter hyperintensity volume, and lower overall survival; mean survival has been reported at approximately 68.5 years for this group. Variants in EGFr domains 7–34 occur at a higher population frequency and are associated with a milder small-vessel disease presentation or possibly even non-penetrance; mean survival in this group has been reported at approximately 76.9 years.

The diagnosis of CADASIL is established by identification of a heterozygous pathogenic variant in NOTCH3 through molecular genetic testing, or — when molecular testing is not definitive — by characteristic findings on electron microscopy and immunohistochemistry of a skin or arterial wall biopsy. Molecular testing approaches include single-gene NOTCH3 sequence analysis (covering at minimum exons 2–24), multigene panels for inherited cerebrovascular conditions, or comprehensive genomic testing. No universally accepted clinical diagnostic criteria currently exist for CADASIL; proposed diagnostic screening tools incorporate clinical and neuroimaging features. Characteristic MRI findings — particularly white matter hyperintensities in the anterior temporal lobes and external capsules — in the context of relevant clinical history support suspicion for the diagnosis. A negative family history does not preclude the diagnosis, as de novo pathogenic variants and variable expressivity within families have been described.

No treatment has been established as effective in preventing stroke, vascular dementia, or CADASIL disease progression. Acute stroke and transient ischemic attack events are managed with standard supportive care consistent with stroke medicine guidelines. The effect of intravenous thrombolytic therapy in CADASIL is not established; the clinical literature notes that increasing cerebral microbleed burden and white matter hyperintensity lesion load are associated with elevated intracerebral hemorrhage risk following thrombolysis in non-CADASIL populations, and this context is reflected in CADASIL clinical management discussions. Migraine is addressed with symptomatic pharmacological treatment; no evidence indicates that triptans or ergot derivatives are contraindicated in CADASIL due to vasoconstrictive mechanism. Psychiatric manifestations are addressed with standard psychiatric approaches. No FDA-approved medications are listed in the certified packet as specifically indicated for CADASIL.

CADASIL is a progressive neurological condition with a variable clinical course. Mean survival has been reported at approximately 68.5 years for individuals with pathogenic variants in EGFr domains 1–6 and approximately 76.9 years for those with variants in domains 7–34, based on genotype-phenotype data in the GeneReviews chapter. Cognitive deterioration accumulates over time, with eventual impairment across all cognitive domains in most individuals. Up to 75% of affected individuals develop dementia, often with prominent apathy. Recurrent subcortical ischemic events contribute to progressive disability, including gait disturbance, urinary incontinence, and pseudobulbar palsy. Disease severity and rate of progression vary both between and within affected families. Biallelic NOTCH3 pathogenic variants have been described and fall within the CADASIL clinical spectrum.

Active clinical investigations include prospective cohort studies and longitudinal registries enrolling individuals with CADASIL across multiple countries, including Korea, Italy, Australia, China, and the United States. Biorepository projects are collecting biological samples and genomic data linked to clinical and neuroimaging phenotypes. A Phase 2 investigation of edaravone dexborneol sublingual tablets for blood-brain barrier dysfunction in CADASIL is underway in China. A Phase 2 study of cerebrolysin in individuals with CADASIL has been conducted in Europe. Pre-clinical research approaches described in the literature include antisense-mediated NOTCH3 exon skipping, immunotherapy directed at NOTCH3 aggregates, and stem cell-based strategies, though these have not yet advanced to approved clinical use.