A novel mutation in the Notch3 gene in an Italian family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy - Genetic and magnetic resonance spectroscopic findings

Background: Cerebral autosomal dominant arteriopathy with subcortical infar cts and leukoencephalopathy (CADASIL) is a hereditary syndrome caused by mu tations of the Notch3 gene, usually localized to exons 3 and 4. Objectives: To report a novel pathogenetic mutation occurring in exon 6 of the Notch3 gene, a location not previously recognized in patients with CADA SIL, and to report the results of magnetic resonance spectroscopy in CADASI L. Methods: Mutation analysis of the Notch3 gene was performed in 2 patients b elonging to a large kindred manifesting CADASIL, as well as in 7 clinically unaffected members of the family and 200 control chromosomes. Proton magne tic resonance spectroscopy was used to estimate metabolite resonance intens ities in the 2 affected subjects. Results: Sequence analysis of the Notch3 gene showed a new missense mutatio n CGC --> TGC in codon 332 of exon 6, resulting in the replacement of an ar ginine residue with a cysteine. This mutation was never observed in the 7 u naffected members of the family and the 200 control chromosomes examined. P roton magnetic resonance spectroscopy showed a diffuse decrease in cerebral N-acetylaspartate, indicating the presence of wide-spread axonal damage. Conclusions: Our findings emphasize the role of direct DNA sequence analysi s for the diagnosis of CADASIL. Moreover, the results of proton magnetic re sonance spectroscopy suggest that widespread axonal damage may be an early finding of the disease.