ABSTRACT
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.
ABSTRACT
Objective:To investigate the clinical characteristics of two Han families with familial vitreous amyloidosis (FVA) and the gene mutation.Methods:A pedigree investigation was performed.Two Han Chinese families with FVA treated in Xiangya Hospital of Central South University from January 2015 to December 2018 were collected.General examination and ophthalmic examination were performed among 112 members of the two families.Peripheral blood samples were collected from 32 family members (15 patients in MZ001 pedigree, 7 patients in MZ002 pedigree, and 5 persons with normal clinical phenotype from each pedigree) for DNA extraction, polymerase chain reaction (PCR) amplification, transthyretin ( TTR) gene screening and sequencing.Vitreous biopsy following three-channel 23-gauge pars plana vitrectomy was performed on the two probands in the two families.Vitreous specimens were sent for pathological examination.This study adhered to the Declaration of Helsinki.The study protocol was approved by an Ethics Committee of Xiangya Hospital of Central South University (No.201412463), and written informed consent was obtained from all subjects before any medical examination. Results:In MZ001, there were 15 cases of the 63 members presented bilateral vitreous opacity at an average age of (43.6±5.8) years.No lesion was found in nervous system, cardiovascular system, kidney or liver in general inspection.The vitreous of the proband (Ⅲ13) was so sticky that could not be totally removed during vitrectomy.The vitreous specimen showed positive Congo red staining.Ⅲ13 had elevated intraocular pressure after vitrectomy and was diagnosed as open-angle glaucoma.Gene sequencing revealed Gly83Arg mutation in the exon 3 of TTR gene.In MZ002, 7 cases of 49 members had bilateral vitreous opacity at an average age of (50.4±5.5) years, among which, 3 cases appeared symptoms of limb numbness and decreased muscle strength.The vitreous body of the proband (Ⅱ11) in MZ002 pedigree was looser and easier to remove during vitrectomy than that of Ⅲ13 in MZ001 pedigree.Vitreous specimen of Ⅱ11 was positive with Congo red staining.Gene sequencing revealed an Ala36Pro variant in the exon 3 of TTR gene. Conclusions:Gly83Arg or Ala36Pro mutation of TTR gene can cause FVA.Different mutations can lead to different clinical phenotypes such as age of onset, clinical symptoms and complications of other systems.
ABSTRACT
Objective Our purpose was to investigate the pathogenic gene mutation of a Han Chinese family with vitreous amyloidosis.Methods The 9 individuals(proband,1 affected member and 7 unaffected members) of the family were selected and their DNA was extracted from peripheral blood.The 4 exons of transthyretin(TTR) gene were amplified by polymerase chain reaction(PCR) technique.The amplified products of TTR gene were sequencing by Sanger technique.We also selected 100 unrelated healthy individual as the control group.Results By DNA sequencing,a heterozygous mutation was found in 4 of the 9 subjects from the family.The transition of adenine to cytosine(AAG ＞ ACG) was detectable in exon 2 of TTR,which changed the amino acid composition at codon 35 (Lys35Thr).This mutation did not presented in control group.Conclusion The heterozygosis mutation of TTR gene Lys35Thr should be a pathogenic mutation for the family with vitreous amyloidosis.
ABSTRACT
Background Familial vitreous amyloidosis is a rare ocular regional amyloidosis,and it is a kind of autosomal dominant inheritance disease.Familial vitreous amyloidosis demonstrates a variable penetrance due to the mutation in the plasma thyroid hormone-binding protein transtheretin (TTR) gene.Many studies have reported over 100 types of TTR genetic mutation in Switzerland,Portugal and Japan,but rare in China.Objective This survey aimed to investigate the clinical and genetic mutation characteristics in familial vitreous amyloidosis.Methods Physical and eye examinations were performed on 52 family members of this vitreous amyloidosis family.Peripheral blood samples from 52 members were collected for TTR gene test by DNA extract,PCR amplification,clone,bolting and sequencing.Pars plana vitrectomy was firstly performed prior to the pathological examination of vitreous sample on 13 eyes of 8 members.Informed consent was obtained from each individual before any medical procedure.Results Seventeen members suffered from vitreous amyloidosis in this family without nervous system,heart,kidney and liver disease.Vitreous opacity was found in 34 eyes of the 17 members,and retinal vasculopathy was seen in 28 eyes of 15 members.In addition,cataract appeared in 16 eyes of 10 members.None of the members had glaucoma or ocular motility disorders.Congo red test of vitreous specimens showed a positive result in 13 eyes of 8 patients who received vitrectomy.Point mutation was verified on the 83th amine acid location of exon 3 (Gly83Arg) in TTR gene by gene sequencing.Conclusions Clinical characteristics of familial vitreous amyloidosis induced by TTR gene Arg-83 mutation is rate retinal vasculopathy without glaucoma,other ocular regional disease and systemic diseases.