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.
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
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.
To describe the natural course, phenotype, and genotype of patients with X-linked retinoschisis (XLRS).
Retrospective cohort study.
Three hundred forty patients with XLRS from 178 presumably ...unrelated families.
This multicenter, retrospective cohort study reviewed medical records of patients with XLRS for medical history, symptoms, visual acuity (VA), ophthalmoscopy, full-field electroretinography, and retinal imaging (fundus photography, spectral-domain SD OCT, fundus autofluorescence).
Age at onset, age at diagnosis, severity of visual impairment, annual visual decline, and electroretinography and imaging findings.
Three hundred forty patients were included with a mean follow-up time of 13.2 years (range, 0.1-50.1 years). The median ages to reach mild visual impairment and low vision were 12 and 25 years, respectively. Severe visual impairment and blindness were observed predominantly in patients older than 40 years, with a predicted prevalence of 35% and 25%, respectively, at 60 years of age. The VA increased slightly during the first 2 decades of life and subsequently transitioned into an average annual decline of 0.44% (P < 0.001). No significant difference was found in decline of VA between variants that were predicted to be severe and mild (P = 0.239). The integrity of the ellipsoid zone (EZ) as well as the photoreceptor outer segment (PROS) length in the fovea on SD OCT correlated significantly with VA (Spearman's ρ = -0.759 P < 0.001 and -0.592 P = 0.012, respectively). Fifty-three different RS1 variants were found. The most common variants were the founder variant c.214G→A (p.(Glu72Lys)) (101 patients 38.7%) and a deletion of exon 3 (38 patients 14.6%).
Large variabilities in phenotype and natural course of XLRS were seen in this study. In most patients, XLRS showed a slow deterioration starting in the second decade of life, suggesting an optimal window of opportunity for treatment within the first 3 decades of life. The integrity of EZ as well as the PROS length on SD OCT may be important in choosing optimal candidates for treatment and as potential structural end points in future therapeutic studies. No clear genotype-phenotype correlation was found.
To assess the visual outcome of cataract surgery in patients with retinitis pigmentosa (RP).
Retrospective, noncomparative clinical study.
Preoperative, intraoperative, and postoperative data of ...patients with RP who were undergoing cataract surgery were collected from several expertise centers across Europe.
In total, 295 eyes of 226 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%).
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.
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.
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.
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.
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.
X-Linked Retinoschisis Hahn, Leo C.; van Schooneveld, Mary J.; Wesseling, Nieneke L. ...
Ophthalmology (Rochester, Minn.),
February 2022, Volume:
129, Issue:
2
Journal Article
Peer reviewed
Open access
To describe the natural course, phenotype, and genotype of patients with X-linked retinoschisis (XLRS).
Retrospective cohort study.
Three hundred forty patients with XLRS from 178 presumably ...unrelated families.
This multicenter, retrospective cohort study reviewed medical records of patients with XLRS for medical history, symptoms, visual acuity (VA), ophthalmoscopy, full-field electroretinography, and retinal imaging (fundus photography, spectral-domain SD OCT, fundus autofluorescence).
Age at onset, age at diagnosis, severity of visual impairment, annual visual decline, and electroretinography and imaging findings.
Three hundred forty patients were included with a mean follow-up time of 13.2 years (range, 0.1–50.1 years). The median ages to reach mild visual impairment and low vision were 12 and 25 years, respectively. Severe visual impairment and blindness were observed predominantly in patients older than 40 years, with a predicted prevalence of 35% and 25%, respectively, at 60 years of age. The VA increased slightly during the first 2 decades of life and subsequently transitioned into an average annual decline of 0.44% (P < 0.001). No significant difference was found in decline of VA between variants that were predicted to be severe and mild (P = 0.239). The integrity of the ellipsoid zone (EZ) as well as the photoreceptor outer segment (PROS) length in the fovea on SD OCT correlated significantly with VA (Spearman’s ρ = –0.759 P < 0.001 and –0.592 P = 0.012, respectively). Fifty-three different RS1 variants were found. The most common variants were the founder variant c.214G→A (p.(Glu72Lys)) (101 patients 38.7%) and a deletion of exon 3 (38 patients 14.6%).
Large variabilities in phenotype and natural course of XLRS were seen in this study. In most patients, XLRS showed a slow deterioration starting in the second decade of life, suggesting an optimal window of opportunity for treatment within the first 3 decades of life. The integrity of EZ as well as the PROS length on SD OCT may be important in choosing optimal candidates for treatment and as potential structural end points in future therapeutic studies. No clear genotype–phenotype correlation was found.
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 LAVV failure.
A retrospective ...investigation of 202 children with AVSD, operated on between 1992 and 2016, was performed. Analysis focused on freedom from reoperation for LAVV dysfunction, with specific attention to the modes of failure.
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 LAVV failure, respectively, in 17 (13.2%) patients with cAVSD and 10 (13.9%) patients with pAVSD. Freedom from reoperation for LAVV at 10 years was 87 ± 4% for cAVSD and 87 ± 5% for pAVSD (P = 0.789). The failure mode was predominantly technical in cAVSD (71% vs 20% in pAVSD), whereas residual anatomical anomalies entailed more frequently LAVV regurgitation (LAVVR) 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 LAVV operation. Five patients finally ended with a mechanical prosthesis.
In the long term, patients with AVSD are still subject to LAVV failure. Despite systematic cleft closure, patients with cAVSD develop LAVV 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 LAVV at the time of primary repair.
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.
To date, there is no standard treatment regimen for carbonic anhydrase inhibitors (CAIs) in X-linked retinoschisis (XLRS) patients. This retrospective study aims to evaluate the efficacy of CAIs on ...visual acuity and cystoid fluid collections (CFC) in XRLS patients in Dutch and Belgian tertiary referral centers.
Retrospective cohort study.
Forty-two patients with XLRS.
In total, 42 patients were enrolled. To be included, patients had to have previous treatment with an oral CAI (acetazolamide), a topical CAI (brinzolamide/dorzolamide), or a combination of an oral and a topical CAI for at least 4 consecutive weeks. We evaluated the effect of the CAI on best-corrected visual acuity (BCVA) and central foveal thickness (CFT) on OCT.
Central foveal thickness and BCVA.
The median age at the baseline visit of the patients in this cohort study was 14.7 (range, 43.6) years, with a median (interquartile range IQR) follow-up period of 4.0 (2.2–5.2) years. During the follow-up period, 25 patients were treated once with an oral CAI (60%), 24 patients were treated once with a topical CAI (57%), and 11 patients were treated once with a combination of both topical and oral CAI (26%). We observed a significant reduction of CFT for oral CAI by 14.37 μm per 100 mg per day (P < 0.001; 95% confidence interval CI, −19.62 to −9.10 μm) and for topical CAI by 7.52 μm per drop per day (P = 0.017; 95% CI, −13.67 to −1.32 μm). The visual acuity changed significantly while on treatment with oral CAI by −0.0059 logMAR per 100 mg (P = 0.008; 95% CI, −0.010 to −0.0013 logMAR). Seven patients (17%) had side effects leading to treatment discontinuation.
Our data indicate that treatment with (oral) CAI may be beneficial for short-term management of CFC in patients with XLRS. Despite a significant reduction in CFT, the change in visual acuity was modest and not of clinical significance. Nonetheless, the anatomic improvement of the central retina in these patients may be of value to create an optimal retinal condition for future potential treatment options such as gene therapy.
The authors have no proprietary or commercial interest in any materials discussed in this article.
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