Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease whose key features are recurrent transient ischemic attacks (TIA), strokes, migraine with aura, vascular dementia, and diffuse white matter abnormalities detectable through neuroimaging. The disease results from mutations in the NOTCH3 gene, encoding a transmembrane receptor involved in cellular signaling and fate during embryonic development. Genetic testing is the gold standard for diagnosing this condition, but the syndrome can be suspected clinically based on family history and characteristic findings of white matter changes. Nevertheless, different individual symptom types, onset, and disease severity, even among individuals in the same family, have been increasingly recognized. The molecular mechanisms by which NOTCH3 mutations lead to vascular degeneration remain unclear. Most CADASIL-associated mutations result in either a gain or loss of cysteine residue in one of the 34 EGF-like repeats in the extracellular domain of the Notch3 protein, thus sparing the number of cysteine residues. More than 200 different mutations in the NOTCH3 gene have been reported in CADASIL patients, of which 95% are missense point mutations. Although it has been suggested that some mutations may be associated with a milder or more severe phenotype, so far no clear genotype-phenotype correlation has been found. To date, no disease-modifying treatment is available for this condition.
Part of the book: Rare Diseases