Department of Neurology, Kangdong Sacred Heart Hospital, College of Medicine, Hallym University, Seoul 05355, Korea.
The Korean Cerebrovascular Research Institute, Seoul 03100, Korea.
Medicina (Kaunas). 2019 Aug 22;55(9):521. doi: 10.3390/medicina55090521.
Previous studies found differences in the characteristics of NOTCH3 mutations in Caucasians and Asians with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Therefore, we sought to investigate the correlations between genetic and clinical/radiological findings in Korean CADASIL patients including some variants of unknown significance (VUS). We screened 198 patients with a suspected diagnosis of CADASIL between 2005 and 2015 via Sanger sequencing. A total of 34 subjects (52.5 ± 9.5 years) were included. The majority of the mutations were in exon 3 and exon 11. R75P mutations (n = 5), followed by Y465C and R544C mutations (n = 4) were the most prevalent. Patients with those mutations exhibited less frequent anterior temporal (AT) or external capsular (EC) hyperintensities compared to patients with other locus mutations. Hemorrhagic stroke (HS) was found to be associated with mutations in exon 3 (R75P), exon 9 (Y465C), exon 11 (R587C), and exon 22 (R1175W variants), which were common locations in our study. Although it is unclear that genetic differences might affect the phenotypes in ethnicities, Asian population shows less migraine or seizure, but more intracerebral hemorrhage. Unlike in westernized countries, typical AT or EC hyperintensities may not be significant MRI markers, at least in Korean CADASIL patients. Furthermore, similar to R75P phenotypes, it is a novel finding that patients with Y465C and R1175W VUS have less frequent AT involvement than Caucasians. The associations between HS and common genetic locations account for the increased development of intracerebral hemorrhage in Koreans rather than Caucasians. We suggest that some CADASIL mutations appear to impart novel region-specific characteristics.
先前的研究发现，具有皮质下梗死和白质脑病的常染色体显性脑动脉病（CADASIL）的高加索人和亚洲人中，NOTCH3 突变的特征存在差异。因此，我们试图研究包括一些意义不明的变异体（VUS）在内的韩国 CADASIL 患者的遗传与临床/影像学发现之间的相关性。我们通过 Sanger 测序在 2005 年至 2015 年间筛查了 198 名疑似 CADASIL 患者。共纳入 34 名受试者（52.5±9.5 岁）。大多数突变位于外显子 3 和外显子 11。最常见的突变是 R75P（n=5），其次是 Y465C 和 R544C（n=4）。与其他突变部位的患者相比，具有这些突变的患者的前颞（AT）或外囊（EC）高信号较少。我们发现，在外显子 3（R75P）、外显子 9（Y465C）、外显子 11（R587C）和外显子 22（R1175W 变体）中发现的突变与出血性中风（HS）有关，这些位置在我们的研究中较为常见。尽管遗传差异可能会影响不同种族的表型尚不清楚，但亚洲人群的偏头痛或癫痫发作较少，但脑出血较多。与西方国家不同，至少在韩国 CADASIL 患者中，典型的 AT 或 EC 高信号可能不是重要的 MRI 标志物。此外，与 R75P 表型相似，我们发现 Y465C 和 R1175W VUS 患者的 AT 受累频率低于高加索人，这是一个新的发现。HS 与常见遗传部位之间的关联导致韩国脑出血的发生率增加，而不是高加索人。我们认为，一些 CADASIL 突变似乎赋予了新的区域特异性特征。
