CADASIL has been reported notably in Europe, has recently been found to occur in Japan and, with the increase in the number of reported cases, has been attracting attention. Currently, the diagnosis of CADASIL is established clinically if the patient: (1) develops the condition at a relatively young age (40-50 years), (2) is not at risk for stroke, (3) has repeated attacks of lacunar infarction with gradual progression to pseudobulbar paralysis and dementia, and (4) has other family members with similar symptoms. The diagnosis is also established by imaging and laboratory studies if: (1) MRI reveals leukoaraiosis and multiple small infarcts in the deep white matter, basal ganglia, thalamus, and pons, with hyperintensities of the temporal pole and external capsule bilaterally; (2) electron microscopy demonstrates granular osmiophilic material (GOM) around vascular smooth muscles in the brain, skeletal muscle, and skin; and (3) DNA analysis shows notch3 mutations.
The mechanism of development of CADASIL due to notch3 mutations is still unknown. However, a recent study revealed that Notch3 ectodomain is a major component of GOM. On binding to the ligand, Notch3 normally undergoes proteolytic cleavage, with the resulting clearance of the extracellular domain. However, in CADASIL, it accumulates as GOM and potentially inhibits normal metabolism in smooth muscle cells. It is necessary to suppress the production of GOM for fundamental therapy of CADASIL.