Prevalence of 2314delG mutation in Spanish patients with Usher syndrome type II (USH2)

The Usher syndrome (USH) is a group of autosomal recessive diseases characterized by congenital sensorineural hearing loss and retinitis pigmentosa. Three clinically distinct forms of Usher syndrome have so far been recognized and can be distinguished from one another by assessing auditory and vestibular function. Usher syndrome type II (USH2) patients have congenital moderate-to-severe nonprogressive hearing loss, retinitis pigmentosa, and normal vestibular function. Genetic linkage studies have revealed genetic heterogeneity among the three types of USH, with the majority of USH2 families showing linkage to the USH2A locus in 1q41. The USH2A gene (MIM 276901) has been identified: three mutations, 2314delG, 2913delG, and 4353-54delC, were initially reported in USH2A patients, the most frequent of which is the 2314delG mutation. It has been reported that this mutation can give rise to typical and atypical USH2 phenotypes. USH2 cases represent 62% of all USH cases in the Spanish population, and 95% of these cases have provided evidence of linkage to the USH2A locus. In the present study, the three reported mutations were analyzed in 59 Spanish families with a diagnosis of USH type II. The 2314delG was the only mutation identified in our population: it was detected in 25% of families and 16% of USH2 chromosomes analyzed. This study attempts to estimate the prevalence of this common mutation in a homogeneous Spanish population.     

Spectrum of mutations in USH2A in British patients with Usher syndrome type II

Usher syndrome (USH) is a combination of a progressive pigmentary retinopathy, indistinguishable from retinitis pigmentosa, and some degree of sensorineural hearing loss. USH can be subdivided in Usher type I (USHI), type II (USHII) and type III (USHIII), all of which are inherited as autosomal recessive traits. The three subtypes are genetically heterogeneous, with six loci so far identified for USHI, three for USHII and only one for USHIII. Mutations in a novel gene, USH2A, encoding the protein usherin, have recently been shown to be associated with USHII. The gene encodes a protein with partial sequence homology to both laminin epidermal growth factor and fibronectin motifs. We analysed 35 British and one Pakistani Usher type II families with at least one affected member, for sequence changes in the 20 translated exons of the USH2A gene, using heteroduplex analysis and sequencing. Probable disease-causing mutations in USH2A were identified in 15 of 36 (41.7%) Usher II families. The most frequently encountered mutation (11/15 families or 11/18 mutated alleles) was del2299G in exon 13, resulting in a frameshift and premature stop codon. Other mutations include insertions and point mutations, of which two are previously unreported. Five different polymorphisms were also detected. Our results indicate that mutations in this gene are responsible for disease in a large proportion of British Usher type II patients. Moreover, if screening for mutations in USH2A is considered, it is sensible to screen for the del2299G mutation first.     

Disease expression in Usher syndrome caused by VLGR1 gene mutation (USH2C) and comparison with USH2A phenotype

PURPOSE: To investigate the retinal disease expression in USH2C, the subtype of Usher syndrome type 2 recently shown to be caused by mutation in the VLGR1 gene, and compare results with those from USH2A, a more common cause of Usher syndrome. METHODS: Three siblings with USH2C and 14 patients with USH2A were studied. Visual function was measured by kinetic perimetry, static chromatic perimetry, and electroretinography (ERG). Central retinal microstructure was studied with optical coherence tomography (OCT). RESULTS: The siblings with VLGR1 mutation showed abnormal photoreceptor-mediated function in all retinal regions, and there was greater rod than cone dysfunction. USH2A had a wider spectrum of disease expression and included patients with normal function in some retinal regions. When abnormalities were detected, there was more rod than cone dysfunction. Retinal microstructure in both USH2C and USH2A shared the abnormality of loss of outer nuclear layer thickness. Central retinal structure in both genotypes was complicated by cystic macular lesions. A coincidental finding in an USH2C patient was that oral intake of antihistamines was associated with temporary resolution of the macular cystic change. CONCLUSIONS: USH2C and USH2A manifest photoreceptor disease with rod- and cone-mediated visual losses and thinning of the outer nuclear layer. An orderly progression through disease stages was estimated from cross-sectional and limited longitudinal data. Intrafamilial and interfamilial variation in retinal severity in USH2A, however, suggests that genetic or nongenetic modifiers may be involved in the disease expression.     

2型Usher综合征和视网膜色素变性家系USH2A基因突变及临床表型分析

目的观察2型Usher综合征(USH2)和视网膜色素变性(RP)患者的基因突变型及其临床表型。方法2018年8月至2019年1月于河南省立眼科医院就诊的USH2和RP 3个家系的4例患者和11名正常家系成员纳入研究。详细询问病史并行视力、眼底彩色照相、OCT、视野、全视野ERG检查。3个家系中,家系1为USH2;家系2、3为RP。采集患者及其家系成员外周静脉血,提取全基因组DNA,应用基于靶向捕获的二代测序技术进行基因测序,对可疑致病突变位点通过Sanger进行验证,并在家系成员中进行共分离。结果家系1先证者除眼底有RP表现外,同时合并神经性耳聋。基因检测结果显示,先证者USH2A基因第64、5号外显子分别存在c.13877-13880 del AGAC(p.Q4626P)(M1)、c.798 del T(p.F266L)(M2)2个杂合性移码突变。家系2、3先证者仅有眼底典型RP表现。基因检测结果显示,家系2先证者USH2A基因第70、37、29号外显子分别存在c.15178T>c(p.S5060P)(M3)、c.6986C>A(p.P2329H)(M4)2个杂合性错义突变和c.5836C>T(p.R1946X)(M5)终止突变。家系3先证者USH2A基因第67、57号外显子分别存在c.14951C>T(p.P4984L)(M6)、c.11156G>A(p.R3719H)(M7)2个杂合性错义突变。保守性分析结果显示,USH2A p.Q4626P、p.F266L、p.S5060P、p.P2329H、p.P4984L所对应的氨基酸位点在多个物种中均高度保守。检测出的7个致病突变中,M1~M4、M6为新发现突变位点。结论USH2A基因突变是导致USH2和非综合征性RP的主要原因;不同突变位点影响蛋白质翻译和合成,导致不同临床表型。     

Comprehensive screening of the USH2A gene in Usher syndrome type II and non-syndromic recessive retinitis pigmentosa

A screen of the entire coding region of the USH2A gene in 129 unrelated patients with Usher syndrome type II (USH2) and in 146 unrelated patients with non-syndromic autosomal recessive retinitis pigmentosa (ARRP) uncovered 54 different sequence variations, including 18 likely pathogenic mutations (13 frameshift, three nonsense, and two missense), 12 changes of uncertain pathogenicity (11 missense changes and one in-frame deletion), and 24 non-pathogenic rare variants or polymorphisms. Of the 18 likely pathogenic mutations, nine were novel. Among the USH2 patients, 50 (39%) had one or two likely pathogenic mutations. The most common mutant allele in USH2 patients was E767fs, which was found in 29 patients, including one homozygote. Among the ARRP patients, we found 17 (12%) with one or two likely pathogenic mutations. The most common mutant allele in ARRP patients was C759F and it was found in 10 patients. The C759F allele was also found in two USH2 patients; in neither of them was a change in the other allele found. The second most common mutant allele in both patient groups was L1447fs (found in 6/50 USH2 patients and 6/17 ARRP patients). Of the 50+17=67 patients with identified USH2A mutations, only one mutation in one allele was found in 41+12=53 (79%); the reason for the high proportion of patients with only one identified mutation is obscure. Our results indicate that USH2A mutations are found in about 7% of all cases of RP in North America, a frequency similar to the RPGR gene (8%) and the rhodopsin gene (10%).     

Management of cataract surgery in Lowe syndrome

AIM: To evaluate the ophthalmic and anesthesiologic management of cataract surgery in children with Lowe syndrome receiving lens removal, the development and management of secondary glaucoma. METHODS: This retrospective case series included 12 eyes of 6 children with genetically verified Lowe syndrome receiving cataract removal. Information regarding the type and duration of surgery and total anesthesia time were recorded. Additionally, intra- and postoperative complications were noted as well as clinical examinations such as visual acuity and funduscopy. RESULTS: All children received simultaneous bilateral cataract surgery at the mean age of 8.98±3.58wk. Lensectomy combined with posterior capsulotomy and anterior vitrectomy was performed in all children. The mean time for cataract surgery per eye was 35.83±8.86min, whereas the total time of surgery was 153.33±22.11min. The mean extubation time and duration at recovery room was 42.33±22.60min and 130.00±64.37min, respectively. During surgery, a decrease of oxygen saturation below 93% was found in only one child. During the postoperative follow-up, nystagmus (6 children) and strabismus (5 children) was commonly found in contrast to no case of visual axis opacification. Secondary glaucoma developed in five eyes of three children, which was treated with topical eye drops in only one child. A trabeculectomy was performed in both eyes of one child, whereas removal of syechia and an iridectomy in one eye of one child. CONCLUSION: Bilateral simultaneous cataract surgery under general anesthesia is a safe surgical procedure in Lowe syndrome children. The glaucoma screening with intraocular pressure measurements is crucial in the postoperative management of Lowe syndrome patients to avoid additional visual impairment.     

双眼粉尘状白内障单眼人工晶状体植入术

目的　评估双眼先天中央粉尘状白内障单眼人工晶状体植入术后的生活质量。方法　 3 0例先天中央粉尘状白内障患者随机分为两组 ,试验组 (单眼手术组 )与对照组 (双眼手术组 )。采用晶状体超声乳化吸出后房人工晶状体植入术。用问卷的方式 ,对试验组术前及术后进行调查计分。对照组仅对其术后进行调查计分。对视觉和生活质量方面的问题进行全面的调查。采用加权Kappa值计算法对计分员的一致性进行评估。结果　试验组术前总分值为 3 2 7分 ,术后为 5 41分 ,生活质量明显提高 (P <0 0 2 )。对照组总分值为 462分 ,低于试验组 (P <0 0 1)。结论　对于双眼先天性粉尘状白内障患者采用单眼人工晶状体植入术 ,是一种较好的选择 ,可以全面提高患者的生活质量。     

Phenotype associated with an R120X nonsense mutation in the RP2 gene in a Japanese family with X-linked retinitis pigmentosa

We examined a Japanese family with X-linked retinitis pigmentosa (RP) associated with a nonsense mutation, R120X, in the RP2 gene. The 26-year-old proband presented at the age of seven years with a two-year history of night blindness. Visual disability worsened with increasing age. At age 24, visual acuity was 0.08 in both eyes. Testing for refractive error indicated mild myopia. Visual fields showed bilateral-constriction to 10 degrees. He had central macular areolar sclerosis in both eyes. Two maternal uncles had vision of light perception to hand movement in their early forties together with dense bilateral cataracts. The ocular phenotype of this family with R120X was considered severe; reported phenotypes associated with this mutation have not been uniform.     

GJA3基因在先天性白内障患者中的突变筛查

目的研究缝隙连接蛋白基因GJA3与先天性白内障的关系。方法收集2个先天性白内障家系及30例散发先天性白内障患者,制备外周血白细胞基因组DNA,PCR扩增GJA3基因的外显子及其邻近的内含子,应用SSCP法检测并发现变异条带,将相应的扩增产物回收并纯化后进行GJA3基因测序。测序结果与GenBank公布的GJA3基因正常序列比对找出突变。结果在68例先天性白内障患者中,仅发现1例患者其GJA3基因外显子D段扩增产物SSCP电泳有3条DNA单链带,而其他患者为2条带。将该段序列进行PCR扩增并测序,于编码区未见任何突变,仅在非编码区域发现碱基CA的缺失。结论GJA3基因与本组先天性白内障无关。先天性白内障临床表型与基因型之间的确切关系有待进一步的研究。     

Screening of the USH1G gene among Spanish patients with Usher syndrome. Lack of mutations and evidence of a minor role in the pathogenesis of the syndrome

The Usher syndrome (USH) is an autosomal recessive hereditary disorder characterized by the association of sensorineural hearing loss, retinitis pigmentosa (RP) and, in some cases, vestibular dysfunction. The USH1G gene, encoding SANS, has been found to cause both Usher syndrome type I and atypical Usher syndrome. 109 Spanish unrelated patients suffering from Usher syndrome type I, type II, type III and unclassified Usher syndrome were screened for mutations in this gene, but only eight different changes without a clear pathogenic effect have been detected. Based on these results as well as previous studies in other populations where mutational analysis of this gene has been carried out, one can conclude that USH1G has a minor involvement in Usher syndrome pathogenesis.     

Novel mutation in OCRL leading to a severe form of Lowe syndrome

AIM: To investigate the phenotype and genotype of a family with X-linked recessive Lowe syndrome. METHODS: All the members in the Chinese pedigree underwent comprehensive ophthalmologic and systemic examinations. Genomic DNA was isolated from peripheral blood of the pedigree members and 100 unrelated healthy Chinese subjects. Direct sequencing was performed to screen the exons and intron boundaries of OCRL. RESULTS: The ophthalmological and systemic examinations suggested that the affected individual had Lowe syndrome. The phenotype in the pedigree is severe and consistent among all the affected individuals except for an individual who additionally suffered from congenital heart disease and laryngeal cartilage dysplasia. Directional Sanger sequencing identified a complex mutation c.(2368_2368delG; c.2370A>C) in the Rho-GTPase activating protein domain. This complex mutation causes termination of protein synthesis at amino acid 824 and result in a new peptide with 823 amino acids (p.Ala790ProfsX34). This mutation was not detected in 100 unrelated healthy Chinese subjects. CONCLUSION: Our findings expand the phenotypic and genotypic spectrum of Lowe syndrome.     

Visual field behavior after intra-ocular surgery in glaucoma patients with advanced defects

Fifty advanced glaucoma patients with central visual field islands were evaluated before and after intra-ocular surgery with respect to visual acuity and visual field behavior. Thirteen patients underwent a cataract extraction, and 37 a filtering procedure. Visual acuity generally improved to a certain extent after lens extraction, and deteriorated after filtering surgery. For both groups the visual field island became somewhat larger with respect to the surface area, but the foveal value was usually lower after the operation. There was no clear relationship between visual acuity and foveal values or the surface area of the central island. One patient suffered unexplained loss of central vision.     

Population-based study of cataract surgery among patients with type 2 diabetes in Kinmen, Taiwan

BACKGROUND: The purpose of this study was to assess the prevalence and associated factors of cataract surgery among patients with type 2 diabetes in Kinmen, Taiwan. METHODS: A community-based population survey between 1991 and 1993 identified 971 patients over the age of 30 years with type 2 diabetes. In 1999, a total of 578 patients (59.5%) with type 2 diabetes from the population were examined in an ophthalmic screening study. Two senior ophthalmologists employed slit-lamp biomicroscopy, indirect ophthalmoscopy, and retinal photographs with pupil dilatation to examine the patients' lenticular and retinal status. RESULTS: The prevalence of cataract surgery in one eye, both eyes, and any cataract surgery among patients with type 2 diabetes was 4.5%, 5.4%, and 9.9%, respectively. The prevalence of cataract surgery in women (11.3%) was not significantly higher than in men (7.7%), but there was a statistical increase with age (p = 0.001, chi2 trend test). Multiple logistic regression showed that age (OR 1.13, 95% CI 1.07-1.19) and diabetic retinopathy (OR 4.68, 95% CI 1.94-11.33) were independent factors associated with cataract surgery. INTERPRETATION: Age and diabetic retinopathy were associated with prevalence of cataract surgery among persons with type 2 diabetes.     

Prevalence of macular abnormalities assessed by optical coherence tomography in patients with Usher syndrome

Background: To investigate the prevalence of macular abnormalities in patients affected by Usher syndrome (USH), by comparing the clinical findings between two types (i.e., USH1 and USH2).

Material and methods: A retrospective study was performed by reviewing optical coherence tomography (OCT) in 134 USH patients to determine the presence of macular abnormalities, including cystoid macular edema (CME), epiretinal membrane (ERM), vitreo-macular traction syndrome (VMT), and macular hole (MH).

Results: Macular abnormalities were observed in 126/268 (47.0%) examined eyes. The most frequent abnormality was ERM observed in 51 eyes (19%), followed by CME observed in 42 eyes (15.7%). Moreover, CME was significantly (p < 0.05) associated with younger age (CME: 30.1 ± 11.1 years; without CME: 36.9 ± 14.9 years), whereas VMT and full thickness MH were associated with older age (p < 0.05). Moreover, a significantly (p < 0.05) decreased best-corrected visual acuity was associated with MH compared to eyes without MH. Finally, CME was more frequent in USH1 compared to USH2.

Conclusion: Our study, for the first time in the literature, showed the distribution of all macular abnormalities assessed by SD-OCT in a large USH cohort, comparing USH1 and USH2 patients. We observed that ocular abnormalities are highly prevalent in USH patients compared to general population, with ERM and CME being the most common alterations. Based on these findings, OCT screening in USH patients is recommended for early detection of macular changes and early treatment.     

0.5%聚维酮碘眼周皮肤消毒预防白内障术后感染的疗效研究

目的探讨使用0.5%的聚维酮碘消毒眼周皮肤对于预防白内障术后感染的效果。方法选择自2011年1月～2012年7月于云南省第二人民医院眼科接受白内障手术的8872例患者,术后使用0.5%的聚维酮消毒液在睑缘、内外眦及眼周5cm范围的眼睑皮肤进行消毒,与对照组进行比较,分析感染发生率。结果 8872例白内障手术患者未发生术后感染,2010年1月～2011年7月的6023例白内障术后未使用聚维酮碘消毒眼周的患者中有14例患者发生术后感染,二者进行统计学分析,差异有统计学意义(P<0.05)。结论白内障术后用0.5%的聚维酮碘消毒眼周皮肤可有效预防术后感染,减少术后并发症的发生。     

多焦点人工晶状体在近视合并白内障患者中的远期疗效评价

目的评价近视合并白内障患者在白内障超声乳化联合多焦点人工晶状体（multifocal intraocular lens，MIOL）植入术后的视觉质量。方法近视眼白内障患者行小切口超声乳化术，植入MIOL（Array SA-40N，AMO）14眼，单焦点人工晶状体（monofocal or single-focal intraocular lens，SIOL）（SA60AT，Alcon）20眼。手术后6个月，观察两组的术后视力、对比敏感度及视觉不良症状．使用Hartmann-Shack波前像差仪测定患者术后高阶像差，Pentacam检测两组人工晶状体（intraocular lens，IOL）的居中性（偏心值和倾斜度）。结果MIOL组术后裸眼近视力≥4．7的患者占64．29％，矫正远视度数下的近视力≥4．7的患者占85．71％，MIOL组裸眼近视力及矫正远视力下的近视力明显好于SIOL组（P〈0．05）。MIOL组在低、中、高频段对比敏感度及眩光对比敏感度与SIOL组差异均无统计学意义（P〉0．05）。分析孔径为5mm时，SIOL组球差显著高于MIOL组（P〈0．05），两组总高阶像差、余各阶像差的差异均无统计学意义（P〉0．05）。两组IOL居中性（偏心值和倾斜度）差异无统计学意义（P〉0．05）。结论MIOL植入治疗近视白内障，可为患者提供较好的全程视力和良好的视觉质量，显著减少了术后对于框架眼镜的依赖。其远期的对比敏感度及眩光对比敏感度均在正常范围,球差低于SIOL。