No abstract

The Notch3 gene has been recently identified as a causative gene for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). To investigate the genetic contribution of Notch mutations in familial cases with vascular leukoencephalopathy, we screened 13 patients from 11 unrelated families, which were selected on the basis of magnetic resonance imaging findings and positive family history. We identified three different missense mutations in 5 patients from 4 families. Two (Arg90Cys and Arg133Cys) are the same as previously reported in Caucasian patients, the other (Cys174Phe) is a novel mutation causing a loss of a cysteine in epidermal-growth-factor-like repeats of Notch3. These data indicate that the CADASIL Notch3 mutations were found in approximately 35% of familial cases with leukoencephalopathy, suggesting genetic heterogeneity of the disease.

No abstract

Objective More than 80 unrelated, but all Caucasian, patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), originating from various communities around the world, have been molecularly identified. To clarify the occurrence of CADASILin Orientals, we investigated Japanese families presenting as CADASIL. Methods Weperformed the PCR-SSCPand sequence analyses using genomic DNA,isolated from venous blood of participants under informed consent. Patients Weidentified two unrelated Japanese families with CADASIL,including 5 affected members through 2 generations.Results Each of the affected individuals developed recurrent strokes without risk factors resulting in progressive dementia, pseudobulbar palsy, and gait disturbances which started after the fifth decade of life. Although affected 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 SPECTimaging, there was severe hypoperfusion in the cortex as well as in the white matter. Ultrastructural studies revealed an abnormal deposition of granular osmiophilic materials (GOM)within the basal lamina of pericytes in muscular capillaries. On PCR-SSCPand sequence analyses, a heterozygous Argl33Cys mutation was present, in the affected individuals, in the exon 4 of Notch3 gene which is the hot spot region for CADASILmutations in Caucasian families. None of the non-affected membersnor the 50 Japanese normal controls revealed this mutation. Conclusion Thus, our results confirm that CADASIL is a geographically widespread disorder caused by a Notch3 mutation. (Internal Medicine 39: 732-737, 2000)

No abstract