Arg133Cys mutation of Notch3 in two unrelated Japanese families with CADASIL

Objective More than 80 unrelated, but all Caucasian, patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencepha lopathy (CADASIL), originating from various communities around the world, h ave been molecularly identified. To clarify the occurrence of CADASIL in Or ientals, we investigated Japanese families presenting as CADASIL. Methods We performed the PCR-SSCP and sequence analyses using genomic DNA, isolated from venous blood of participants under informed consent. Patients We identified two unrelated Japanese families with CADASIL, includ ing 5 affected members through 2 generations. Results Each of the affected individuals developed recurrent strokes withou t risk factors resulting in progressive dementia, pseudobulbar palsy, and g ait disturbances which started after the fifth decade of life. Although aff ected individuals had no vascular risk factors, they showed various degrees of narrowing of retinal arteries. Their MRI/CTs showed characteristics of the disease; bilateral small infarcts in the thalamus, basal ganglia, brain stem, and deep white matter in addition to the findings of leukoaraiosis. On SPECT imaging, there was severe hypoperfusion in the cortex as well as i n the white matter. Ultrastructural studies revealed an abnormal deposition of granular osmiophilic materials (GOM) within the basal lamina of pericyt es in muscular capillaries, On PCR-SSCP and sequence analyses, a heterozygo us Arg133Cys mutation was present, in the affected individuals, in the exon 4 of Notch3 gene which is the hot spot region for CADASIL mutations in Cau casian families. None of the non-affected members nor the 50 Japanese norma l controls revealed this mutation. Conclusion Thus, our results confirm that CADASIL is a geographically wides pread disorder caused by a Notch3 mutation.