Phenotypes Associated with NOTCH3 Cysteine-Sparing Mutations in Patients with Clinical Suspicion of CADASIL: A Systematic Review

• Published in: International journal of molecular sciences 2024-08, Vol.25 (16), p.8796
• Main Authors: Cao, Yuan, Zhang, Ding-Ding, Han, Fei, Jiang, Nan, Yao, Ming, Zhu, Yi-Cheng
• Format: Article
• Language: English
• Subjects: Asian people; CADASIL; CADASIL - diagnostic imaging; CADASIL - genetics; CADASIL - pathology; clinical phenotype; Cognitive ability; Cognitive Dysfunction - genetics; Convulsions & seizures; Cysteine - genetics; cysteine-sparing; Gait; Humans; Ischemia; Migraine; Mutation; NOTCH3; Phenotype; radiological cerebral phenotype; Receptor, Notch3 - genetics; Review; Smooth muscle; Stroke; systematic review
• ISSN: 1661-6596; 1422-0067; 1422-0067
• DOI: 10.3390/ijms25168796

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is caused by mutations affecting the number of cysteines. The pathogenic role of cysteine-sparing mutations with typical clinical CADASIL syndrome is still debated. This review aimed to characterize cysteine-sparing mutations in patients with clinical suspicion of CADASIL. Articles on cysteine-sparing mutations with clinical suspicion of CADASIL were reviewed. Clinical and radiological cerebral phenotypes data were extracted and characterized across regions and compared with phenotypes of typical CADASIL patients. We screened 298 cysteine-sparing mutation individuals from 20 publications, and mutations in exon 3 were the most frequently reported (21.46%). Gait impairment (76.47%), cognitive impairment (67.47%), and stroke (62.37%) were the three most common clinical phenotypes; the most frequent radiological cerebral phenotypes were lacunes (74.29%) and cerebral microbleeds (72.73%). Compared with CADASIL patients, cognitive impairment and cerebral microbleed frequencies were significantly higher in patients with NOTCH3 cysteine-sparing mutations, while the white matter hyperintensities in anterior temporal polar and external capsule were rarely observed. Compared with Western patients, radiological phenotypes were more common than clinical phenotypes in cysteine-sparing Asian patients. More than half of cysteine-sparing patients had positive granular osmiophilic material deposits. cysteine-sparing mutations in patients with clinical suspicion of CADASIL mainly manifested with gait and cognitive impairment but rare white matter hyperintensities in anterior temporal pole and external capsule. Further studies are warranted to pay attention to atypical variants, which could guide specific diagnosis and help unravel underlying mechanisms.