Alström综合征患者眼部临床特征和致病基因分析  

Analysis of the ocular clinical features and pathogenic genes in patients with Alström syndrome

作　　者：刘伟伟[1] 楚莹莹 王惠[1] 王飞[1] 楚瑞雪 孙先桃 卢跃兵 余继锋[2] Liu Weiwei;Chu Yingying;Wang Hui;Wang Fei;Chu Ruixue;Sun Xiantao;Lu Yuebing;Yu Jifeng(Department of Ophthalmology,Children's Hospital Affiliated to Zhengzhou University,Children's Hospital of Henan Province,Zhengzhou Children's Hospital,Zhengzhou 450000,China;Department of Ophthalmology,Beijing Children's Hospital Affiliated to Capital Medical University,National Center for Children's Health,Beijing 100045,China)

机构地区：[1]郑州大学附属儿童医院、河南省儿童医院郑州儿童医院眼科,郑州450000 [2]首都医科大学附属北京儿童医院眼科、国家儿童医学中心,北京100045

出　　处：《中华眼底病杂志》2023年第7期530-537,共8页Chinese Journal of Ocular Fundus Diseases

基　　金：河南省医学科技攻关计划(联合共建)项目(LHGJ20210664);郑州市科技惠民计划项目(2021KJHM0011)。

摘　　要：目的观察并分析Alström综合征(ALMS)患者的眼部临床特征和致病基因。方法回顾性临床研究。2020年10月至2022年7月于河南省儿童医院眼科检查确诊的ALMS患者3例及家系成员5名纳入研究。3例患者来自2个无血缘关系家系。详细询问病史及家族史,并行最佳矫正视力(BCVA)、眼底彩色照相、光相干断层扫描(OCT)、全视野视网膜电图(ERG)以及全身系统性检查。采集受试者外周静脉血3 ml,提取全基因组DNA,应用二代测序技术进行基因测序。对于可疑的致病突变位点,通过Sanger进行验证,并采用生物信息学分析确定基因突变位点的致病性。结果2个家系的3例患者均在婴儿期出现眼球震颤和畏光。家系1先证者BCVA双眼均为无光感;眼底血管衰减,色泽斑驳;OCT检查,视网膜变薄,光感受器细胞层消失,视网膜色素上皮层萎缩;ERG呈熄灭型。先证者弟弟BCVA右眼、左眼分别为0.04、0.02;眼底血管衰减,色素分布大致正常;OCT检查,光感受器细胞层模糊,ERG呈熄灭型。2例患者均有感音神经性耳聋、肥胖、黑棘皮症、胰岛素抵抗/糖尿病、肝功能异常。先证者存在左心增大、高血脂、肾功能异常等。基因检测结果显示,先证者及其弟弟ALMS1基因第8、10号外显子分别存在c.1894C>T/p.Gln632*(M1)、c.9148_9149delCT/p.Leu 3050 Leufs*9(M2)复合杂合突变,均为已知突变。先证者父亲携带M1,母亲携带M2。家系2先证者23月龄时,眼底检查基本正常。ERG暗适应0.01 b波以及3.0 a、b波均轻度降低;明适应3.0 a、b波重度降低。4岁随访时,BCVA右眼、左眼分别为0.01、0.05。眼底血管衰减,黄斑中心凹反光不清;除暗适应3.0 a、b波重度降低外,其余均呈熄灭型。全身暂未出现异常表现。基因检测结果显示,先证者ALMS1基因第11、5号外显子分别存在c.9627delT/p.Pro3210Glnfs*22(M3)、c.1089delT/p.Asp364Ilefs*13(M4)复合杂合突变。均为新发突变,先证者父亲携Objective To observe and analyze the ocular clinical features and pathogenic genes of Alström syndrome(ALMS).Methods A retrospective clinical study.From October 2020 to July 2022,3 patients and 5 normal family members from 2 families affected with ALMS who visited in the Ophthalmology Department of Henan Children's Hospital were enrolled in the study.These 2 families were without blood relationship.The medical history and family history were inquired.Best corrected visual acuity(BCVA),fundus color photography,full-field electroretinogram(ERG),frequency domain optical coherence tomography(OCT)and systemic examination were performed.3 ml peripheral venous blood of patients and their family members were collected,and the whole genomic DNA was extracted.The second generation sequencing analysis was performed on these members.The suspected pathogenic mutation sites were verified by Sanger,and the pathogenicity of the gene mutation sites were determined by bioinformatics analysis.Results Three patients from two families all developed nystagmus and photophobia in infancy.In the family 1,the BCVA of both eyes of the proband was no light perception.The fundus examination revealed vascular attenuation and retinal pigment abnormality.OCT showed retinal thinning,loss of photoreceptor layer and atrophy of the retinal pigment epithelium layer.ERG examination showed extinguished.The BCVA of the proband’s younger brother was 0.04 in the right eye and 0.02 in the left eye.The fundus examination revealed vascular attenuation but the pigment distribution was roughly normal.OCT showed blurred photoreceptor layers in both eyes.ERG examination showed extinguished.Two patients developed sensorineural deafness,obesity,acanthosis nigricans,insulin resistance/diabetes,and abnormal liver function.In addition,the proband also had left heart enlargement,hyperlipidemia and abnormal kidney function.The results of genetic testing showed that the proband and his younger brother had compound heterozygous mutations in exon 8(c.1894C>T/p.Gln632*

关 键 词：Alström综合征 锥杆细胞营养不良 ALMS1基因突变 

分 类 号：R774.1[医药卫生—眼科]