家族性玻璃体淀粉样变性一家系临床特征及基因突变分析

Clinical characteristics and genetic mutation analysis in a family with familial vitreous amyloidosis

目的分析家族性玻璃体淀粉样变性(FVA)一家系的临床特征及转甲状腺素蛋白(TTR)基因突变特点。方法采用家系调查研究方法,分析2005年5月至2019年3月于贵州医科大学附属医院就诊的汉族FVA一家系20名家系成员的临床资料,包括一般情况、眼科常规检查。其中5例9眼患者先后行玻璃体切割术,术中对病变玻璃体采样行刚果红染色,并观察术后1周和6个月最佳矫正视力(BCVA)、眼压、眼前节及眼底表现。抽取该家系20名成员外周静脉血各4 ml并提取DNA,先证者采用二代测序技术进行基因检测,对发现的变异位点进行包括先证者在内的所有受检者的Sanger测序验证。采用ACMG指南对发现的变异位点进行致病性分析。结果5例9眼患者中术前6眼BCVA为0.1~0.2,3眼为数指/50 cm;平均眼压为(15.18±1.32)mmHg(1 mmHg=0.133 kPa);9眼玻璃体絮状混浊;9眼晶状体后囊膜有白色“足盘样”点状颗粒附着。术中玻璃体切割标本经刚果红染色证实为淀粉样变性。术后1周,8眼BCVA为0.8,1眼为0.6;术后6个月6眼BCVA为0.8,2眼为0.6,1眼为光感;术后1周和6个月平均眼压分别为(15.32±2.11)mmHg和(16.13±1.25)mmHg。玻璃体切割术后3~14年,8眼发生继发性青光眼。15例30眼未发病成员中2例4眼检查不配合,其余13例26眼BCVA为0.8~1.0,平均眼压为(15.52±1.15)mmHg,眼前节及眼底检查未见异常。20名家系成员基因检测发现15例受检者TTR基因发生杂合突变(p.Gly103Arg)。根据ACMG指南,该变异评分为PS1+PM2+PP3,为可能致病性变异。结论FVA患者玻璃体切割术后继发性青光眼发病率较高。TTR基因杂合突变(p.Gly103Arg)可能是该FVA家系的变异位点。

Objective To analyze the clinical characteristics and transthyretin(TTR)gene mutation of a family with familial vitreous amyloidosis(FVA).Methods A pedigree investigation was performed.The clinical data of 20 family members of a Han family with FVA treated in the Affiliated Hospital of Guizhou Medical University from May 2005 to March 2019 were collected,including demographic data and ophthalmic examination results.Nine eyes of five patients underwent vitrectomy successively,and vitreous samples collected during operation were sent for pathological examination by Congo red staining.The best corrected visual acuity(BCVA)and intraocular pressure(IOP)were measured,and the anterior segment as well as fundus was observed under the slit lamp microscope at 1 week and 6 months after surgery.Peripheral venous blood(4 ml)was collected from 20 members in this family and DNA was extracted.The next-generation sequencing technology was used for gene detection of proband,and Sanger sequencing was performed in 20 family members including the proband.The pathogenicity of the mutation sites was analyzed according to ACMG guidelines.This study adhered to the Declaration of Helsinki.The study protocol was approved by an Ethics Committee of Affiliated Hospital of Guizhou Medical University(No.2019-296).Written informed consent was obtained from each subject.Results The preoperative BCVA of the nine eyes(5 patients)remained 0.1 to 0.2 in 6 eyes,and counting fingers to 50 cm in 3 eyes,and the mean value of preoperative IOP was(15.18±1.32)mmHg(1 mmHg=0.133 kPa).Cotton-wool like opacity in the vitreous and white pedal disc punctate granule on the posterior lens capsule were seen in the 9 eyes under the slit lamp microscope.Vitreous specimens of patients were Congo red stain positive.The BCVA remained 0.8 in 8 eyes and 0.6 in 1 eye at 1 week after vitrectomy,and remained 0.8 in 6 eyes,0.6 in 2 eyes and light perception in 1 eye at 6 months after surgery.Mean values of postoperative IOP were(15.32±2.11)mmHg and(16.13±1.25)mmHg at 1 week and 6 months after surgery,respectively.Secondary glaucoma occurred in 8 eyes at 3 to 14 years postoperatively.Mean BCVA of the 13 phenotypic normal family members(26 eyes)remained 0.8 to 1.0,and the mean value of IOP was(15.52±1.15)mmHg,and abnormalities were not found in anterior segment or fundus.Additionally,two members(4 eyes)failed to take examinations.Genetic testing revealed heterozygous mutation in p.Gly103Arg of TTR gene in 15 family members.According to ACMG guidelines,the variation score was PS1+PM2+PP3,and it was likely pathogenic.Conclusions The secondary glaucoma is of relatively high incidence in patients with FVA after vitrectomy.The heterozygous mutation of TTR gene(p.Gly103Arg)might be the variation site of the family with vitreous amyloidosis.