Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in an Israeli family

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of hereditary cerebral microangiopathy, and is caused by over 170 different mutations in the NOTCH3 gene at locus 19p13.1-13.26. We report the first study of familial CADASIL in a 39-year-old Jewish woman and her mother who had died previously. The patient's investigations revealed a normal hemogram with no vascular risk factors or chronic disease. Lumbar puncture was normal. Cranial computed tomography scan revealed bilateral diffuse hypodensities in the subcortical white matter. Cranial magnetic resonance imaging showed hyperintense lesions in the cerebral white matter on T2-weighted images. On electron microscopy, a characteristic granular osmiophilic material was seen in the basement membrane surrounding the pericytes and smooth muscle cells in small-sized and medium-sized vessels. Molecular analysis of the NOTCH3 gene was performed with automatic sequencing of exon 3 and 4 (and intron-exon boundaries) showing a nucleotide c.268C > T substitution, leading to a pathogenic amino acid substitution of p.Arg90Cys, confirming a diagnosis of CADASIL. This mutation was also found in the patient's mother. Although the exact prevalence of CADASIL is not known, this disorder has been reported worldwide, and now including Jews, with a genotype and clinical phenotype similar to that in other ethnic groups.