The ophthalmological course of Usher syndrome type III

Usher syndrome is a recessive hereditary disease group with clinical and genetical heterogeneity leading to handicapped hearing and visual loss until middle age. It is the most common cause for deaf-blindness. Three distinct phenotypes and five distinct genotypes are already known. In Finland the distribution of known Usher types is different than elsewhere. Usher syndrome type III (USH3) is common in Finland and it is thought to include 40% of patients. Progressive hearing loss is characteristic of USH3. Elsewhere USH3 has been regarded as a rarity covering only several percent of the whole Usher population. The aim of this paper is to describe, for the first time, the course of visual handicap and typical refractive errors in USH3 and compare it with other USH types. From a total patient sample consisting of 229 Finnish USH patients, 200 patients' visual findings were analyzed in a multicenter retrospective follow-up study. The average progress rate during a 10-year follow-up period in different USH types was similar. The essential progress occurred below the age of 40 and was continuous up to that age. Visual acuity dropped below 0.05 (severely impaired) at the age of 37 and the visual fields were of tubular shape without any peripheric islands at the average age of 30. Clinically significant hypermetropia with astigmatism seems to be a pathognomonic clinical sign of USH3.     

Tractional retinal detachment in Usher syndrome type II

Retinal detachment is a rare complication in patients with retinitis pigmentosa. A case is reported of tractional retinal detachment in a patient with retinitis pigmentosa and sensorineural hearing loss, which was diagnosed as Usher syndrome type II. Because of the poor visual prognosis, the patient refused surgery in that eye. Tractional retinal detachment should be added to the differential diagnoses of visual loss in patients with retinitis pigmentosa.     

Molecular Epidemiology in 591 Italian Probands With Nonsyndromic Retinitis Pigmentosa and Usher Syndrome

PurposeTo describe the molecular epidemiology of nonsyndromic retinitis pigmentosa (RP) and Usher syndrome (US) in Italian patients.MethodsA total of 591 probands (315 with family history and 276 sporadics) were analyzed. For 155 of them, we performed a family segregation study, considering a total of 382 relatives. Probands were analyzed by a customized multigene panel approach. Sanger sequencing was used to validate all genetic variants and to perform family segregation studies. Copy number variants of selected genes were analyzed by multiplex ligation-dependent probe amplification. Four patients who tested negative to targeted next-generation sequencing analysis underwent clinical exome sequencing.ResultsThe mean diagnostic yield of molecular testing among patients with a family history of retinal disorders was 55.2% while the diagnostic yield including sporadic cases was 37.4%. We found 468 potentially pathogenic variants, 147 of which were unpublished, in 308 probands and 66 relatives. Mean ages of onset of the different classes of RP were autosomal dominant RP, 19.3 ± 12.6 years; autosomal recessive RP, 23.2 ± 16.6 years; X-linked RP, 13.9 ± 9.9 years; and Usher syndrome, 18.9 ± 9.5 years. We reported potential new genotype-phenotype correlations in three probands, two revealed by TruSight One testing. All three probands showed isolated RP caused by biallelic variants in genes usually associated with syndromes such as PERCHING and Senior-Loken or with retinal dystrophy, iris coloboma, and comedogenic acne syndrome.ConclusionsThis is the largest molecular study of Italian patients with RP in the literature, thus reflecting the epidemiology of the disease in Italy with reasonable accuracy.     

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%).     

A novel splice-site variant in CDH23 in a patient with Usher syndrome type 1

ABSTRACT

Background: Gene editing has shown huge potential in correcting aberrant splicing and Cas13 has been identified as being particularly suitable for targeting RNA. It has therefore become increasingly important to highlight new splice site mutations that may be correctable, particularly in genes that are too large to be encoded by AAV vectors. About 20% of Usher Type 1 cases are caused by mutations in CDH23.

Purpose: To report a novel splice site mutation of CDH23 associated with Usher Type 1D.

Materials and Methods: Case report.

Results: A 35-year-old Caucasian female who is congenitally deaf with vestibular dysfunction presented with visual acuity of 6/12 in both eyes. Fundus examination revealed findings typical of retinitis pigmentosa with foveal preservation of photoreceptor layer. Next generation sequencing analysis revealed a novel homozygous variant, c.9319 + 1G>T in CDH23 consistent with the diagnosis of Usher Syndrome Type 1D. The c.9319 + 1G>T variant is predicted to affect splicing at the exon 65/intron 65 boundary, which highly likely leads to complete skipping of exon 65.

Conclusions: We describe a case of a typical Usher Syndrome Type 1D caused by a novel splice site variant in CDH23. Currently there are no treatments for CDH23 related retinal degeneration, partly because the cDNA size of 10kb is too large for AAV vector gene augmentation therapy. Alternative strategies include CRISPR-Cas9 adenine base editors and RNA editing with CRISPR-Cas13. Single-nucleotide editing represents a promising approach for targeting this variant in CDH23 to restore the wildtype splice donor site at this position.     

Retinitis pigmentosa in Usher syndrome in India: Electronic medical records driven big data analytics: Report III

Purpose:To describe the clinical presentation and demographic distribution of retinitis pigmentosa (RP) in patients with Usher syndrome (USH).Methods: This is a cross-sectional observational hospital-based study including patients presenting between March 2012 and October 2020. In total, 401 patients with a clinical diagnosis of USH and RP in at least one eye were included as cases. The data were retrieved from the electronic medical record database. For better analysis, all 401 patients were reclassified into three subtypes (type 1, type 2, and type 3) based on the USH criteria.Results: In total, there were 401 patients with USH and RP, with a hospital-based prevalence rate of 0.02% or 2/10,000 population. Further, 353/401 patients were subclassified, with 121 patients in type 1, 146 patients in type 2, and 86 patients in the type 3 USH group. The median age at presentation was 27 years (IQR: 17.5–38) years. There were 246 (61.35%) males and 155 (38.65%) females. Males were more commonly affected in all three subtypes. Defective night vision was the predominant presenting feature in all types of USH (type 1: 43 (35.54%), type 2: 68 (46.58%), and type 3: 40 (46.51%) followed by defective peripheral vision. Patients with type 2 USH had more eyes with severe visual impairment.Conclusion: RP in USH is commonly bilateral and predominantly affects males in all subtypes. Patients with USH and RP will have more affection of peripheral vision than central vision. The key message of our study is early visual and hearing rehabilitation in USH patients with prompt referral to otolaryngologists from ophthalmologists and vice versa.     

Retinitis pigmentosa in association with acromegaly: a case report

Retinal abnormalities, unrelated to visual pathway compression, in acromegalic patients were originally described by Smail in 1972 (Smail JM. Primary pigmentary degeneration of the retina and acromegaly in a case of pituitary adenoma. Br J Ophthalmol 1972; 56: 25–31). He illustrated a case of primary pigmentary degeneration of the retina occurring in a patient with a chromophobe adenoma of the pituitary gland. To the best of our knowledge this remains the sole, published case of this association. We report on two male patients, with an acromegalic appearance, one caused by a pituitary adenoma, the other associated with a Rathke's cleft cyst, presenting to our department of ophthalmology with the clinical picture of pigmentary degeneration of the retina. This revised version was published online in July 2006 with corrections to the Cover Date.     

中国人与欧美人USH2A基因突变谱不同

Usher综合征是一种常见的综合征性视网膜色素变性（RP）,为常染色体隐性遗传性疾病,具有临床和遗传高度异质性。迄今已将Usher综合征的致病基因定位了12个染色体位点,确定了其中的9个致病基因。很多研究证实USH2A基因是Usher综合征的主要致病基因,USH2A基因突变还可引起单纯性RP,但国内的一些研究结果发现,中国人USH2A基因突变谱与欧美人不同。中国人RP致病的热点基因谱尚有待进一步研究。     

Putative digenic inheritance of heterozygous RP1L1 and C2orf71 null mutations in syndromic retinal dystrophy

Background: Retinitis pigmentosa (RP) is the most common cause of inherited retinal degeneration and can occur in non-syndromic and syndromic forms. Syndromic RP is accompanied by other symptoms such as intellectual disability, hearing loss, or congenital abnormalities. Both forms are known to exhibit complex genetic interactions that can modulate the penetrance and expressivity of the phenotype.

Materials and methods: In an individual with atypical RP, hearing loss, ataxia and cerebellar atrophy, whole exome sequencing was performed. The candidate pathogenic variants were tested by developing an in vivo zebrafish model and assaying for retinal and cerebellar integrity.

Results: Exome sequencing revealed a complex heterozygous protein-truncating mutation in RP1L1, p.[(Lys111Glnfs*27; Gln2373*)], and a heterozygous nonsense mutation in C2orf71, p.(Ser512*). Mutations in both genes have previously been implicated in autosomal recessive non-syndromic RP, raising the possibility of a digenic model in this family. Functional testing in a zebrafish model for two key phenotypes of the affected person showed that the combinatorial suppression of rp1l1 and c2orf71l induced discrete pathology in terms of reduction of eye size with concomitant loss of rhodopsin in the photoreceptors, and disorganization of the cerebellum.

Conclusions: We propose that the combination of heterozygous loss-of-function mutations in these genes drives syndromic retinal dystrophy, likely through the genetic interaction of at least two loci. Haploinsufficiency at each of these loci is insufficient to induce overt pathology.     

Survey in to the Prevalence of Hearing Loss in Patients Diagnosed with Retinitis Pigmentosa

Sensorineural hearing loss is the most common disease associated with systemic retinitis pigmentosa (RP). We have conducted an epidemiological study to assess the correlation of age at onset of visual symptoms and hearing loss associated with RP. Epidemiological data was derived from a questionnaire-based study of patients who are registered members of the Japanese Retinitis Pigmentosa Society (n = 3200). The questionnaire was mailed to these patients in 2002, and information was requested regarding age at onset of visual disturbance, awareness of hearing loss and the presence of progressive hearing loss, age at onset of hearing loss, awareness of tinnitus, and history of audiometric examination and hearing aid usage. 26.1% of the questionnaires were returned, and data for 828 patients with RP diagnosed by an ophthalmologist were evaluated. Cochlear symptoms were reported by 356 patients (43.0% of the total population), with hearing loss in 29.5%, tinnitus in 31.5% and hearing loss and tinnitus in 39.3% of the 356 patients. Of these 356 patients, progressive hearing loss was reported by 44.9% and was independent of age at onset of cochlear symptoms. The mean age at onset of visual symptoms was higher for patients with progressive hearing loss, and a significant correlation was found between the age at onset of visual symptoms and hearing loss for patients who were older at onset of the symptoms (>30 years of age). Onset of hearing loss occurs later and hearing loss is also more progressive for patients with late onset of RP. This suggests that particular care regarding hearing loss is necessary for this patient population, and that cooperation between opthalmologists and otologists is required for diagnosis of RP-hearing impairment-associated syndromes in this group of patients.     

Extended mutation spectrum of Usher syndrome in Finland

Purpose: The Finnish distribution of clinical Usher syndrome (USH) types is 40% USH3, 34% USH1 and 12% USH2. All patients with USH3 carry the founder mutation in clarin 1 (CLRN1), whereas we recently reported three novel myosin VIIA (MYO7A) mutations in two unrelated patients with USH1. This study was carried out to further investigate the USH mutation spectrum in Finnish patients. Methods: We analysed samples from nine unrelated USH patients/families without known mutations and two USH3 families with atypically severe phenotype. The Asper Ophthalmics USH mutation chip was used to screen for known mutations and to evaluate the chip in molecular diagnostics of Finnish patients. Results: The chip revealed a heterozygous usherin (USH2A) mutation, p.N346H, in one patient. Sequencing of MYO7A and/or USH2A in three index patients revealed two novel heterozygous mutations, p.R873W in MYO7A and c.14343+2T>C in USH2A. We did not identify definite pathogenic second mutations in the patients, but identified several probably nonpathogenic variations that may modify the disease phenotype. Possible digenism could not be excluded in two families segregating genomic variations in both MYO7A and USH2A, and two families with CLRN1 and USH2A. Conclusion: We conclude that there is considerable genetic heterogeneity of USH1 and USH2 in Finland, making molecular diagnostics and genetic counselling of patients and families challenging.     

骨髓间充质干细胞(MSCs)对N-甲基-N-亚硝脲(MNU)诱导的C57BL小鼠视网膜变性的治疗作用

目的 观察骨髓间充质干细胞(mesenchymal stem cells,MSCs)对N-甲基-N-亚硝脲(N-methyl-N-nitrosourea,MNU)诱导的C57BL小鼠视网膜色素变性(retinitis pigmentosa,RP)的治疗作用.方法 应用不同剂量(30 mg·kg-1、45 mg·kg-1、60 mg·kg-1、75 mg·kg-1、90 mg·kg-1)的MNU腹腔注射给予C57BL小鼠和MNU作用不同时间(1d、3d、7d)后,通过视网膜电图(electroretinogram,ERG)和HE染色检测小鼠视网膜的电生理功能和组织形态变化,优化建立稳定的RP动物模型的最佳条件;在此动物模型的基础上,经玻璃体内注射和尾静脉注射给予MSCs移植,并应用ERG和HE染色评估MSCs对MNU诱导的RP的治疗作用.结果 与对照组相比,30 mg·kg-、45mg·kg-1剂量的MNU可引起视网膜形态和功能的轻微损伤,而60 mg·kg-1及其以上剂量的MNU可使视网膜ERG波幅明显降低(均为P ＜0.001),视网膜外核层(outer nuclear layer,ONL)厚度明显变薄(P ＜0.001),损伤严重;与对照组相比,60 mg·kg-的MNU作用后1d和3d,视网膜ERG波形开始降低,形态结构开始出现ONL厚度变薄的损伤,作用7d时,ERG波形呈现熄灭型(均为P＜0.001),ONL厚度明显变薄(P ＜0.001),内外核层融合,损伤严重.与MNU单独作用组相比,60 mg·kg-1 MNU作用1d后给予MSCs移植,7d后MSCs组内ONL厚度增加(P ＜0.001),视网膜ERG波形趋于恢复(均为P＜0.001).结论 MSCs移植对MNU诱导的视网膜退行性变有一定的治疗作用.     

Nongranulomatous anterior uveitis in a patient with Usher syndrome

A 34-year-old female with Usher syndrome, but no family history of similar illness, presented with complaints of vision reduction, redness, and photophobia. Biomicroscopic examination showed mildly injected conjunctivae bilateral, small, round keratic precipitates; bilateral +2 cells with no flare reaction in the anterior chamber; and bilateral posterior subcapsular cataracts. No associated posterior synechiae, angle neovascularization, or iris changes were detected; normal intraocular pressures were obtained. Fundus examination demonstrated waxy pallor of both optic nerves, marked vasoconstriction in retinal vessels, and retinal bone spicule pigment formation, with a normal macula. Electroretinography confirmed the diagnosis of retinitis pigmentosa, optical coherent tomography was normal and otolaryngology consultation was conducted.To our knowledge, an association between Usher syndrome and bilateral nongranulomatous anterior uveitis has not been previously reported, and our purpose is to report this association.     

Histopathological Changes of Inner Retina,Optic Disc,and Optic Nerve in Rabbit with Advanced Retinitis Pigmentosa

We observed the histopathological changes of retinal ganglion cells (RGCs), optic disc, and optic nerve in rabbit with advanced retinitis pigmentosa (RP). Wild-type (WT) and rhodopsin transgenic (Tg) of RP rabbits were used at age 24 months. Light and electron microscopy were used to observe the retina, optic disc, and optic nerve. RGCs were also confirmed by immunofluorescent staining with a TUJ-1 monoclonal antibody. In addition to the rod and cone degeneration, we observed the astrocyte infiltration of the optic disc due to the damage of small RGCs and nerve fibres and atrophy of small optic nerve fibres. They subsequently lead to the optic disc excavation and atrophy of the optic nerve. Consequently, our histopathological study clarified that not only the outer retina but also the inner retina, the optic disc, and the optic nerve were also affected in the late stages of RP rabbit.     

Identification of a novel mutation in the paired domain of PAX3 in an Iranian family with Waardenburg syndrome Type I

Background: Intravenous etoposide is widely used in multiagent chemotherapy regimens for intraocular retinoblastoma despite the lack of phase II data documenting its efficacy. Because oral etoposide has been found to be highly effective in patients with relapsed medulloblastoma and neuroblastoma who had previously received intravenous etoposide, we investigated its use for intraocular retinoblastoma. Procedure: A pilot trial of oral etoposide (50mg/m 2 /day for 21 days) in five children (6 eyes) with relapsed refractory intraocular retinoblastoma was performed. All had previously received chemotherapy, including intravenous etoposide in four patients, and all had received radiation therapy. Three patients (3 eyes) had vitreous seeds. Response was evaluated after one cycle. Results: No serious acute toxicity was encountered, and no responses were noted. Four patients (5 eyes) had progressive disease. Stable disease was noted in one eye without vitreous disease. One patient developed secondary acute myeloid leukemia 30 months after exposure to oral etoposide. Conclusions: Oral etoposide was not an effective agent in this population. The role of etoposide in the treatment of higher risk intraocular retinoblastoma deserves further study.     

The RUSH2A Study: Dark-Adapted Visual Fields in Patients With Retinal Degeneration Associated With Biallelic Variants in the USH2A Gene

PurposeTo measure visual fields using two-color dark-adapted chromatic perimetry in a subset of participants in the Rate of Progression of USH2A-related Retinal Degeneration (RUSH2A), a study of USH2A-mediated syndromic (USH2) and autosomal recessive nonsyndromic retinitis pigmentosa, determine percentage retaining rod function, and explore relationships between dark-adapted visual fields (DAVF) and rod function from ERG and full-field stimulus thresholds (FST).MethodsFull-field rod mean sensitivity, number of rod loci, maximum sensitivity, DAVF full-field hill of vision (DAVF V_TOT), and 30° hill of vision (DAVF V₃₀) were measured in one eye for DAVF ancillary study participants (n = 49). Loci where cyan relative to red sensitivity was more than 5 dB on dark-adapted chromatic perimetry were considered rod mediated. Correlation coefficients between the DAVF measures and standard clinical measures were estimated, as were kappa statistics (κ) for agreement between DAVF and other measures of rod function.ResultsOf 49 participants tested with DAVF, 38 (78%) had evidence of rod function, whereas 15 (31%) had measurable rod ERGs. DAVF maximum sensitivity was highly correlated with FST white thresholds (r = −0.80; P < .001). Although not statistically significant, the number of rod loci and DAVF V_TOT were lower in eyes with longer disease duration by 0.82 (95% confidence interval, −1.76, 0.12) loci/year and 0.59 (95% confidence interval, −1.82, 0.64) dB-steradians/year, respectively.ConclusionsRod-mediated function on FST and DAVF is present in many patients with symptomatic USH2A-related retinal degeneration, including some without measurable rod ERGs. RUSH2A longitudinal data will determine how these measures change with disease progression and whether they are useful for longitudinal studies in inherited retinal degenerations.     

Variable expressivity in patients with autosomal recessive retinitis pigmentosa associated with the gene CNGB1

ABSTRACT

Purpose

In a cohort of eight families (11 patients) with autosomal recessive retinitis pigmentosa (arRP), we clinically characterized disease associated with mutations in CNGB1.     

视网膜色素变性一家系与IMPDH1基因突变相关

目的检测一个常染色体显性遗传性视网膜色素变性家系的IMPDHl基因的突变特征以及与临床表型的关系，探讨其病因和发病机制，利用分子遗传学的方法，确定家系内遗传连锁关系。方法严格按照有关伦理学要求进行家系收集，所有现存家系成员行详细的眼科检查（包括视力检查、裂隙灯和眼底镜检查、视野、暗适应阈值以及ERG检查）。提取该家系lO例患者、lO例未患病成员外周血基因组DNA：应用聚合酶链反应扩增IMPDHl第7外显子基因片段，利用扩增产物直接测序方法对样本进行IMPDHl基因突变检测。结果该家系中lO例患者的IMPDHl基因发生了Asp-226-Asn（GAC→AAC）的错义突变，lO例家系未患病成员则没有此突变。结论IMPDHl基因的一种已知突变Asp-226-Asn与该家系所发生的视网膜色素变性存在紧密连锁关系。