A case of CADASIL caused by NOTCH3 c.512_605delinsA heterozygous mutation

Abstract

Autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic inherited cerebrovascular disease. The disease is caused by the mutations in NOTCH3 on chromosome 19. 1,2 CADASIL usually starts in the middle age, which is different from the traditional cerebrovascular disease, and it usually has no clear high-risk factors for cerebrovascular disease, with recurrent stroke as the main manifestation, which can be accompanied by cognitive impairment, dementia, mental and emotional disorders, and migraine with aura. 3 The presence of granular osmiophilic material (GOM) in close proximity to smooth muscle cells, pericytes, and endothelial cells is critical for the diagnosis of CADASIL. 4,5 Analysis of all the exons of the NOTCH3 gene is crucial to determine the mutation that causes the pathology. 6,7 The NOTCH3 gene, located on chromosome 19p13, encodes a single-pass transmembrane receptor, which is composed of a large extracellular domain (ECD) with 34 tandem epidermal growth factor-like (EGF) repeats encoded by exons 2-24, where NOTCH3 mutations are commonly found, a transmembrane domain, and an intracellular domain (ICD). [8][9][10] In all, 33 exons and 2321 amino acids constitute NOTCH3. 11 CADASIL is caused by the presence of only one mutation in one of the two alleles of NOTCH3 because pathogenic mutations are dominant in this disease. 12

Genetic Mechanisms of Migraine: Insights from Monogenic Migraine Mutations

“…Moreover, despite a common clinical migraine with aura phenotype, there are likely shared yet distinct mechanisms in CADASIL relative to migraine with aura in general. The NOTCH3 gene encodes a transmembrane receptor expressed in smooth muscle cells and pericytes of small vessels in humans [ 120 , 121 ]. In CADASIL, the typical mutation implicates the expansion or duplication of a specific sequence of six amino acids within the EGFr domain [ 122 ].…”