Phenocopy of a heterozygous carrier of X-linked retinitis pigmentosa due to mosaicism for a RHO variant

We describe both phenotype and pathogenesis in two male siblings with typical retinitis pigmentosa (RP) and the potentially X-linked RP (XLRP) carrier phenotype in their mother. Two affected sons, two unaffected daughters, and their mother underwent detailed ophthalmological assessments including Goldmann perimetry, color vision testing, multimodal imaging and ISCEV-standard electroretinography. Genetic testing consisted of targeted next-generation sequencing (NGS) of known XLRP genes and whole exome sequencing (WES) of known inherited retinal disease genes (RetNet-WES). Variant validation and segregation analysis were performed by Sanger sequencing. The mutational load of the RHO variant in the mother was assessed in DNA from leucocytes, buccal cells and hair follicles using targeted NGS. Both affected sons showed signs of classical RP, while the mother displayed patches of hyperautofluorescence on blue light autofluorescence imaging and regional, intraretinal, spicular pigmentation, reminiscent of a carrier phenotype of XLRP. XLRP testing was negative. RetNet-WES testing revealed RHO variant c.404G>C p.(Arg135Pro) in a mosaic state (21% of the reads) in the mother and in a heterozygous state in both sons. Targeted NGQSS of the RHO variant in different maternal tissues showed a mutation load between 25.06% and 41.72%. We report for the first time that somatic mosaicism of RHO variant c.404G>C p.(Arg135Pro) mimics the phenotype of a female carrier of XLRP, in combination with heterozygosity for the variant in the two affected sons

The Natural History of Leber Congenital Amaurosis and Cone-Rod Dystrophy Associated with Variants in the GUCY2D Gene

OBJECTIVE: To describe the spectrum of Leber congenital amaurosis (LCA) and cone-rod dystrophy (CORD) associated with the GUCY2D gene, and to identify potential clinical endpoints and optimal patient selection for future therapeutic trials. DESIGN: International multicenter retrospective cohort study. SUBJECTS: 82 patients with GUCY2D-associated CORD and LCA from 54 molecularly confirmed families. METHODS: Data were gathered by reviewing medical records for medical history, symptoms, best-corrected visual acuity (BCVA), ophthalmoscopy, visual fields, full-field electroretinography and retinal imaging (fundus photography, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence). MAIN OUTCOMES MEASURES: Age of onset, annual decline of visual acuity, estimated visual impairment per age, genotype-phenotype correlations, anatomic characteristics on funduscopy, and multimodal imaging. RESULTS: Fourteen patients with autosomal recessive LCA and 68 with autosomal dominant CORD were included. The median follow-up time was 5.2 years (interquartile range (IQR), 2.6-8.8) for LCA, and 7.2 years (IQR, 2.2-14.2) for CORD. Generally, LCA presented in the first year of life. The BCVA in LCA ranged from no light perception to 1.00 logMAR, and remained relatively stable during follow-up. Imaging for LCA was limited, but showed little to no structural degeneration. In CORD, progressive vision loss started around the second decade of life. The annual decline rate of visual acuity was 0.022 logMAR (P A and the c.2512C>T GUCY2D variant (P = 0.798). At the age of 40 years the probability of being blind or severely visually impaired was 32%. The integrity of the ellipsoid zone (EZ) and external limiting membrane (ELM) on SD-OCT were correlated significantly with BCVA (Spearman's ρ = 0.744, P = 0.001 and ρ = 0.712, P < 0.001, respectively) in CORD. CONCLUSION: LCA due to variants in GUCY2D results in severe congenital visual impairment with relatively intact macular anatomy on funduscopy and available imaging, suggesting a long preservation of photoreceptors. Despite large variability, GUCY2D-associated CORD generally presented during adolescence with a progressive loss of vision and culminated in severe visual impairment during mid to late-adulthood. The integrity of the ELM and EZ may be suitable structural endpoints for therapeutic studies in GUCY2D-associated CORD

Surgical repair of atrioventricular septal defects : incidence and mode of failure of the left atrioventricular valve

OBJECTIVES: Our goal was to investigate the outcome of the left atrioventricular valve (LAVV) after repair of atrioventricular septal defects (AVSDs) by analysing the mechanisms of LAW failure. METHODS: A retrospective investigation of 202 children with AVSD, operated on between 1992 and 2016, was performed. Analysis focused on freedom from reoperation for LAW dysfunction, with specific attention to the modes of failure. RESULTS: The population consisted of 129 (64%) patients with complete AVSD (cAVSD) and 73 (36%) patients with partial AVSD (pAVSD), corrected at a median age of 3.9 (interquartile range 3.4) months and 29.0 (interquartile range 90.4) months, respectively. Within a median follow-up period of 5.9 (interquartile range 12.6) years, 27 (13.4%) patients required reoperation for LAW failure, respectively, in 17 (13.2%) patients with cAVSD and 10 (13.9%) patients with pAVSD. Freedom from reoperation for LAW at 10 years was 87 +/- 4% for cAVSD and 87 +/- 5% for pAVSD (P & nbsp;= 0.789). The failure mode was predominantly technical in cAVSD (71% vs 20% in pAVSD), whereas residual anatomical anomalies entailed more frequently LAVV regurgitation (LAWR) in pAVSD (80% vs 29% in cAVSD) (P = 0.018). Cleft suture dehiscence (n = 8) and incomplete cleft closure (n = 6) were considered technical failures, whereas remnant distortions of the subvalvular apparatus (n = 9), small asymmetric bridging leaflet (n = 2), double orifice (n =1) and additional cleft (n =1) were considered anatomical lesions. The incidence of repair at the 1st reoperation was 92.6%. Eight patients needed a 2nd and 2 patients a 3rd repeat LAW operation. Five patients finally ended with a mechanical prosthesis. CONCLUSIONS: In the long term, patients with AVSD are still subject to LAW failure. Despite systematic cleft closure, patients with cAVSD develop LAW failure mainly because of a recurrent/residual deficit at the cleft, amenable to technical improvement. Patients with pAVSD need increased attention for additional anatomical features of the LAW at the time of primary repair

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Articulated instruments and 3D visualization : a synergy? : evaluation of execution time, errors, and visual fatigue

Objective: The introduction of advanced endoscopic systems, such as the Storz Image1S and the Olympus Endoeye, heralds a new era of 3-dimensional (3D) visualization. The aim of this report is to provide a comprehensive overview of the neurophysiology of 3D view, its relevance in videoscopy, and to quantify the benefit of the new 3D technologies for both rigid and articulated instruments. Method: Sixteen medical students without any laparoscopic experience were trained each for a total of 27 hours. Proficiency scores were determined for rigid and articulated instruments under 2D and 3D visualization conditions. Results: A reduction in execution time of 14%, 28%, and 36% was seen for the rigid instruments, the da Vinci, and Steerable instruments, respectively. A reduction in errors of 84%, 92%, and 87% was seen for the rigid instruments, the da Vinci, and Steerable instruments, respectively. Conclusion: 3D visualization greatly augments endoscopic procedures. The advanced endoscopic systems employed in the recent study caused no visual fatigue or discomfort. The benefit of 3D was most distinct with articulated instruments

The phenotypic spectrum of patients with PHARC syndrome due to variants in ABHD12 : an ophthalmic perspective

This study investigated the phenotypic spectrum of PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and early-onset cataract) syndrome caused by biallelic variants in the ABHD12 gene. A total of 15 patients from 12 different families were included, with a mean age of 36.7 years (standard deviation [SD] ± 11.0; range from 17.5 to 53.9) at the most recent examination. The presence and onset of neurological, audiological and ophthalmic symptoms were variable, with no evident order of symptom appearance. The mean best-corrected visual acuity was 1.1 logMAR (SD ± 0.9; range from 0.1 to 2.8; equivalent to 20/250 Snellen) and showed a trend of progressive decline. Different types of cataract were observed in 13 out of 15 patients (87%), which also included congenital forms of cataract. Fundus examination revealed macular involvement in all patients, ranging from alterations of the retinal pigment epithelium to macular atrophy. Intraretinal spicular hyperpigmentation was observed in 7 out of 15 patients (47%). From an ophthalmic perspective, clinical manifestations in patients with PHARC demonstrate variability with regard to their onset and severity. Given the variable nature of PHARC, an early multidisciplinary assessment is recommended to assess disease severity

Outcome of Cataract Surgery in Patients With Retinitis Pigmentosa

PURPOSE: To assess the visual outcome of cataract surgery in patients with retinitis pigmentosa (RP). DESIGN: Retrospective, noncomparative clinical study. METHODS: Preoperative, intraoperative, and postoperative data of patients with RP who were undergoing cataract surgery were collected from several expertise centers across Europe. RESULTS: In total, 295 eyes of 225 patients were included in the study. The mean age at surgery of the first eye was 56.1 ± 17.9 years. Following surgery, best-corrected visual acuity (BCVA) improved significantly from 1.03 to 0.81 logMAR (ie, 20/214 to 20/129 Snellen) in the first treated eye (−0.22 logMAR; 95% CI = −0.31 to −0.13; P < .001) and from 0.80 to 0.56 logMAR (ie, 20/126 to 20/73 Snellen) in the second treated eye (−0.24 logMAR; 95% CI = −0.32 to −0.15; P < .001). Marked BCVA improvements (postoperative change in BCVA of ≥0.3 logMAR) were observed in 87 of 226 patients (39%). Greater odds for marked visual improvements were observed in patients with moderate visual impairment or worse. The most common complications were zonular dialysis (n = 15; 5%) and (exacerbation of) cystoid macular edema (n = 14; 5%), respectively. Postoperative posterior capsular opacifications were present in 111 of 295 eyes (38%). CONCLUSION: Significant improvements in BCVA are observed in most patients with RP following cataract surgery. Baseline BCVA is a predictor of visual outcome. Preoperative evaluation should include the assessment of potential zonular insufficiency and the presence of CME, as they are relatively common and may increase the risk of complications

Outcome of Cataract Surgery in Patients With Retinitis Pigmentosa

PURPOSE: To assess the visual outcome of cataract surgery in patients with retinitis pigmentosa (RP). DESIGN: Retrospective, noncomparative clinical study. METHODS: Preoperative, intraoperative, and postoperative data of patients with RP who were undergoing cataract surgery were collected from several expertise centers across Europe. RESULTS: In total, 295 eyes of 225 patients were included in the study. The mean age at surgery of the first eye was 56.1 ± 17.9 years. Following surgery, best-corrected visual acuity (BCVA) improved significantly from 1.03 to 0.81 logMAR (ie, 20/214 to 20/129 Snellen) in the first treated eye (−0.22 logMAR; 95% CI = −0.31 to −0.13; P < .001) and from 0.80 to 0.56 logMAR (ie, 20/126 to 20/73 Snellen) in the second treated eye (−0.24 logMAR; 95% CI = −0.32 to −0.15; P < .001). Marked BCVA improvements (postoperative change in BCVA of ≥0.3 logMAR) were observed in 87 of 226 patients (39%). Greater odds for marked visual improvements were observed in patients with moderate visual impairment or worse. The most common complications were zonular dialysis (n = 15; 5%) and (exacerbation of) cystoid macular edema (n = 14; 5%), respectively. Postoperative posterior capsular opacifications were present in 111 of 295 eyes (38%). CONCLUSION: Significant improvements in BCVA are observed in most patients with RP following cataract surgery. Baseline BCVA is a predictor of visual outcome. Preoperative evaluation should include the assessment of potential zonular insufficiency and the presence of CME, as they are relatively common and may increase the risk of complications

Comparative Natural History of Visual Function From Patients With Biallelic Variants in BBS1 and BBS10.

Purpose: The purpose of this study was to compare the natural history of visual function change in cohorts of patients affected with retinal degeneration due to biallelic variants in Bardet-Biedl syndrome genes: BBS1 and BBS10. Methods: Patients were recruited from nine academic centers from six countries (Belgium, Canada, France, New Zealand, Switzerland, and the United States). Inclusion criteria were: (1) female or male patients with a clinical diagnosis of retinal dystrophy, (2) biallelic disease-causing variants in BBS1 or BBS10, and (3) measures of visual function for at least one visit. Retrospective data collected included genotypes, age, onset of symptoms, and best corrected visual acuity (VA). When possible, data on refractive error, fundus images and autofluorescence (FAF), optical coherence tomography (OCT), Goldmann kinetic perimetry (VF), electroretinography (ERG), and the systemic phenotype were collected. Results: Sixty-seven individuals had variants in BBS1 (n = 38; 20 female patients and 18 male patients); or BBS10 (n = 29; 14 female patients and 15 male patients). Missense variants were the most common type of variants for patients with BBS1, whereas frameshift variants were most common for BBS10. When ERGs were recordable, rod-cone dystrophy (RCD) was observed in 82% (23/28) of patients with BBS1 and 73% (8/11) of patients with BBS10; cone-rod dystrophy (CORD) was seen in 18% of patients with BBS1 only, and cone dystrophy (COD) was only seen in 3 patients with BBS10 (27%). ERGs were nondetectable earlier in patients with BBS10 than in patients with BBS1. Similarly, VA and VF declined more rapidly in patients with BBS10 compared to patients with BBS1. Conclusions: Retinal degeneration appears earlier and is more severe in BBS10 cases as compared to those with BBS1 variants. The course of change of visual function appears to relate to genetic subtypes of BBS