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目的:探讨 HTRA丝氨酸肽酶1（ HTRA1）基因杂合突变所致脑小血管病（CSVD）的临床表型及遗传学特征。 方法:选取2020年1月至2023年12月中南大学湘雅医院老年医学科、神经内科确诊的9例 HTRA1基因相关显性遗传CSVD患者为研究对象，收集其临床资料，应用全外显子测序法对先证者进行基因检测，并通过Sanger测序对家系进行验证，总结其临床及遗传学特点。 结果:9例 HTRA1基因相关显性遗传CSVD患者的起病年龄为（51.1±9.5）岁，认知障碍、卒中发作和步态障碍是其最常见的临床表现，磁共振成像检查常见弥漫性脑白质病变、多发腔隙性脑梗死、多发脑微出血以及脑萎缩，符合CSVD影像学改变特点。大部分患者脑脊液出现Aβ42水平以及Aβ42/Aβ40比值下降，2/4的患者有磷酸化tau蛋白水平上升。9例患者中发现了7种 HTRA1基因的杂合突变，其中有2个为新突变，分别为c.1160T>C（p.M387T）和c.569G>T（p.A190L）杂合错义突变。 结论:HTRA1基因相关显性遗传CSVD患者的临床表现以认知障碍、卒中发作和步态障碍为主，影像学特征符合CVSD改变。 HTRA1基因c.1160T>C（p.M387T）和c.569G>T（p.A190L）杂合错义突变是新报道的突变，扩展了本病的基因突变谱。

Objective:To investigate the clinical phenotype and genetic characteristics of cerebral small vessel disease (CSVD) caused by heterozygous mutations in high-temperature requirement A serine peptidase 1 ( HTRA1) gene. Methods:Nine patients with HTRA1 gene related autosomal dominant CSVD diagnosed in the Departments of Geriatrics and Neurology,Xiangya Hospital of Central South University between January 2020 and December 2023 were selected. Their clinical data were collected, and the probands received genetic test using whole exome sequencing. The mutations were then verified in the family using Sanger sequencing, and their clinical and genetic characteristics were summarized. Results:Among the 9 patients with HTRA1 gene related autosomal dominant CSVD, the onset age was (51.1±9.5) years. Cognitive impairment, stroke onset, and gait disturbance were the most common clinical manifestations. Magnetic resonance imaging examination usually revealed diffuse white matter lesions, multiple lacunar cerebral infarction, multiple cerebral microbleeds, and brain atrophy, which were consistent with the radiological characteristics of CSVD. Most patients showed a decrease in Aβ42 levels and Aβ42/Aβ40 ratio in cerebrospinal fluid, and 2/4 of patients had an increase in phosphory protein tau levels. Seven heterozygous mutations in the HTRA1 gene were found in 9 patients, including two new heterozygous missense mutations, c.1160T>C(p.M387T) and c.569G>T(p. A190L). Conclusions:The clinical manifestations of HTRA1 gene-related autosomal dominant CSVD patients are mainly cognitive impairment, stroke and gait disturbance, and the imaging features are consistent with CVSD changes. HTRA1 gene c.1160T>C(p.M387T) and c.569G>T(p.A190L) heterozygous missense mutations are newly reported mutations, expanding the genetic mutation spectrum of this disease.