Analysis of clinical and imaging features of cysteine-sparing NOTCH3 gene missense mutations in five cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy patients

Objective: To summarize the clinical and imaging features of five patients of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with cysteine-sparing NOTCH3 gene missense mutations and explore potential pathogenicity of gene mutations. Methods: The clinical data from five patients who were admitted to the People’s Hospital of Zhengzhou University from March 2017 to November 2018 were collected. The patients were found to carry cysteine-sparing NOTCH3 gene mutations through genetic testing and diagnosed pathologically. They were probands confirmed from five unrelated family and all five patients were performed full exon detection and skin biopsy. Results: Genetic testing identified five patients with cysteine-sparing NOTCH3 gene missense mutations, a total of five different mutations, including p.R75Q, p.D80G, p.V237M, p.S1418L and p.R1761H. The first three mutations were found in the epidermal growth factor-like repeats (EGFr), the latter two mutations near the transmembrane domain. Granular osmiophilic material was identified in all cases examined with skin biopsy. The age at initial symptom onset of these five cases was ranged from 22 to 58 years and three cases presented cardiovascular risk factors. The primary clinical manifestations included migraine in one case, ischemic stroke in three cases, psychiatric disturbances in four cases, cognitive dysfunction in five cases, while gait disturbance, pseudobulbar palsy, and seizures accounted for only one case each. Magnetic resonance imaging of five patients all showed white matter hyperintensities (WMLs) and lacunar infarcts, and WMLs involved the anterior temporal pole and external capsules in three cases separately. According to the criteria proposed by Muiño et al for evaluating the pathogenicity of cysteine-sparing NOTCH3 mutations, all five mutations are potentially pathogenic. Conclusions: Most characteristics of CADASIL patients with cysteine-sparing NOTCH3 gene mutations are similar to those of CADASIL patients with cysteine NOTCH3 gene mutations. Mutations not involving the EGFr may also have potential pathogenicity, and the specific mechanism still needs further study.