A New Notch3 Mutation for CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) Disease. A Family Reports (P05.075)

Abstract

Objective: A new Notch3 (and other genes) mutations that could cause this genetic disorder. Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare inherited cerebrovascular disease frequently associated with mutations in the Notch3 receptor, localized in chromosome 19. Its main clinical manifestations are subcortical dementia, recurrent subcortical ischemic infarcts, and migraine headaches. We describe three members of a family (cases are brother, sister and cousin) with a clinical-neuroimaging picture of CADASIL who showed a previously undescribed Notch3 mutation. Design/Methods: Three members of the same family with a clinical-neuroimaging picture of CADASIL underwent clinical, radiological, laboratory and genetic characterization studies. The studied subjects were brother, sister and cousin. The associated Notch3 mutation was further evaluated by site-directed mutagenesis. Results: CADASIL was caused by a novel Notch3 missense mutation C.2444t>C (pCys82Arg) in the three members of the studied family. All of them suffered the typical clinical pattern of subcortical dementia, migraine headaches and recurrent subcortical infarcts. The man also suffered from diabetes mellitus and one sister also had dyslipidemia. Cerebral lesions (studied by magnetic resonance imaging) showed both demyelinating and typical CADASIL topography, including para- and periventricular white matter lesions. Conclusions: Although the CADASIL clinical-neuroimaging picture has been well defined, there is increasing evidence for new Notch3 (and other genes) mutations that could cause this genetic disorder. Understanding of these mutations is vital to comprehend the pathophysiology of this disease and the role of Notch3 in vascular tissue. Disclosure: Dr. Bermejo-Velasco has nothing to disclose. Dr. Bermejo-Velasco has nothing to disclose. Dr. Bermejo-Velasco has nothing to disclose.