Disease relevance of CADASIL

• To our knowledge, this is the first study showing that NOTCH3 mutation carriers may be at increased risk of early acute myocardial infarction, expanding CADASIL disease expression beyond the central nervous system to include the heart [1].
• The new acronym "cerebral autosomal dominant arteriopathy with subcortical infarcts, leukoencephalopathy, and migraine" (CADASILM) is proposed to better describe this particular subvariety of CADASIL [2].
• A novel mitochondrial DNA mutation and a mutation in the Notch3 gene in a patient with myopathy and CADASIL [3].
• The clinical and radiological overlap between multiple sclerosis and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; MIM 125310) raises the possibility of diagnostic confusion and suggests that pleiotropic effects of the Notch3 gene might include influencing susceptibility to multiple sclerosis [4].
• Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a systemic vascular disease caused by Notch 3 gene mutations [5].

Psychiatry related information on CADASIL

• Mutations in the EGF repeats of the human Notch 3 receptor lead to the vascular dementia disease Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) [6].
• Moreover, the human cerebral autosomal dominant artriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) syndrome of premature stroke and dementia is a heritable arteriopathy with alterations in vascular smooth muscle cells (VSMCs) resulting from mutations within Notch3 [7].
• Recently, Notch receptors have been hypothesized to play a role in neurodegeneration and in particular in Alzheimer's disease (Notch1) and CADASIL (Notch3) [8].

High impact information on CADASIL

• Clinical spectrum of CADASIL: a study of 7 families. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [9].
• In this study, we investigated the effect of CADASIL mutations on Notch3 activity [10].
• To address this issue, we have generated and analyzed stable cell lines expressing either wild-type murine Notch 3 (mNotch 3) or the mutant mNotch 3(R142C), which corresponds to the prevalent CADASIL form of Notch 3, Notch 3(R141C) in humans [6].
• The vast majority of CADASIL mutations are missense mutations removing or inserting cysteine residues in the EGF repeats, but it is not yet clear whether these mutations primarily affect receptor trafficking, maturation, andor signaling [6].
• We investigated whether O-fucosylation or Fringe-mediated elongation of O-fucose on Notch3 is impaired by CADASIL mutations [11].

Chemical compound and disease context of CADASIL

• Cerebral hemodynamics in CADASIL before and after acetazolamide challenge assessed with MRI bolus tracking [12].
• RESULTS: 1H-MRSI-Patients with CADASIL showed significantly reduced NAA, Cho, Cr, and total metabolite content (Met(tot)) in WMH and NAWM [13].
• No significant change in absolute CBF and CBV values was observed in the cortex of patients with CADASIL [12].
• CONCLUSION: This study showed that cortical glucose metabolism is significantly lower in CADASIL patients than in healthy volunteers [14].
• 1. In 18 out of the 21 Finnish CADASIL families so far identified, the causative mutation is an arginine to cysteine substitution in position 133 (R133C) [15].

Biological context of CADASIL

• BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary syndrome caused by mutations of the Notch3 gene, usually localized to exons 3 and 4 [16].
• The diagnosis of CADASIL was confirmed by molecular analysis (heterozygotes for the C406T mutation on exon 3 of the Notch3 gene) [17].
• Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is caused by point mutations in the Notch3 gene [18].
• Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a condition caused by mutations of Notch3 gene on chromosome 19 [19].
• Our findings emphasize the importance of genetic analysis of NOTCH3 for Asians with a phenotype typical of CADASIL [20].

Anatomical context of CADASIL

• Based upon clinical evidence that CADASIL arteriopathy results in degeneration and loss of vascular smooth muscle cells (VSMC) from the arterial wall, we postulated that Notch3 signaling is a critical determinant of VSMC survival [21].
• RESULTS: Cerebral microbleeds were present in 31% of symptomatic CADASIL mutation carriers, predominantly in the thalamus [22].
• We have investigated cerebrospinal fluid (CSF) from three CADASIL cases with known mutations in Notch-3 using two-dimensional gel electrophoresis [23].
• Relatively specific magnetic resonance imaging (MPI) markers of CADASIL include involvement of the anterior temporal lobes and external capsules and, as illustrated in this report, these MRI findings may aid in the differentiation of the two conditions [24].
• Here, we report two more Japanese CADASIL families carrying a missense mutation in the Notch3 gene (R141C) with a unique lesion in the corpus callosum [25].

Gene context of CADASIL

• Mutations in the Notch3 receptor result in the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephelopathy (CADASIL) syndrome, a heritable arteriopathy predisposing to early onset stroke [21].
• NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL [26].
• It is as yet unclear which disturbance in the Notch signaling pathway leads to the characteristic vascular pathology of CADASIL [27].
• CADASIL is caused by mutations in the Notch3 gene [28].
• OBJECTIVES: To understand the functional consequences of a recurrent CADASIL mutation on furin processing, cell surface expression, ligand binding, and activation of a downstream effector CBF1 by the Notch3 receptor [29].

Analytical, diagnostic and therapeutic context of CADASIL

• Notch3 sequence analysis of CADASIL patients in a diagnostic laboratory is a feasible procedure to confirm the clinical diagnosis in individual patients [30].
• It is also of interest to know that Notch3 mutant CADASIL exists in other Asian countries.We next examined the localization of Notch3 protein in the tissue by immunohistochemistry [31].

References