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Purpose: To evaluate the impact of drusen-like deposits (DLD) on retinal layer integrity and retinal function by optical coherence tomography (OCT) and multifocal electroretinography (mfERG) in patients with systemic lupus erythematosus (SLE). Methods: We identified 66 eyes of 33 SLE patients treated with hydroxychloroquine (HCQ) that were categorized into two groups according to whether DLDs were present (34 eyes, Group One) or absent (32 eyes, Group Two). The groups were matched for age, sex, HCQ treatment duration, daily, and cumulative dosage. OCT (retinal layer thicknesses, central retinal thickness, CRT) and mfERG concentric ring analysis were analyzed and compared. Results: CRT was significantly thicker in Group One compared to Group Two (273.21 ± 3.96 vs. 254.5 ± 7.62) (p = 0.023). Group One also demonstrated an overall thicker retinal pigment epithelium compared to Group Two; however, the other outer retinal layers, outer nuclear layer, and photoreceptor layer were found to be significantly thinner in Group One compared to Group Two. We found no differences in mfERG parameters between the two groups. Conclusions: DLDs in SLE patients lead to abnormal central retinal layer thickness, which has no measurable impact on cone-mediated retinal function assessed by mfERG.

Background Researchers have in recent years begun to investigate ophthalmological manifestations of multiple sclerosis (MS) other than optic neuritis (ON), and it is now clear that changes to retinal function (measured using the electroretinogram, ERG) and structure (measured using optical coherence tomography, OCT) are found in MS patients irrespective of prior ON episodes. ERG results are consistent with dysfunctional bipolar cells, as in other autoimmune diseases. To date, studies have presented only cross-sectional data regarding ERG and OCT. We, therefore, studied the longitudinal course of ERG and OCT in patients with MS, as well as the effect of disability changes and non-ON clinical relapses on these functional and structural measures. Methods MS patients (n = 23) participating in an ongoing longitudinal observational study were invited to take part in a 3-year ophthalmological substudy. ERG and OCT were performed, and measures of MS-related disability and relapse history were obtained. Study visits were repeated annually. ERG peak times, rod b-wave amplitude, mixed rod/cone and cone b-/a-wave amplitude ratios, thickness of the peripapillary retinal nerve fibre layer, and volumes of the segmented retinal layers/complexes were analysed. Using generalised estimating equation models adjusted for age, ON, and MS treatment status, we assessed changes to ERG and OCT over the study duration, the effect of changes in disability and recent non-ON MS relapses on ERG and OCT, and the effect of selected OCT parameters on corresponding ERG parameters. Results At the group level, small fluctuations of several ERG peak times were recorded, with OCT values remaining stable. Increased disability between visits was associated with significant prolongation of mixed rod-cone ERG b-wave peak times. No evidence of associations between OCT and ERG parameters was observed. Conclusions Retinal bipolar cell function may be affected by changes in disability in patients with MS; however, recent non-ON MS clinical relapses appear not to affect ERG or OCT results. As ERG changes in MS patients over 3 years are likely to be small and of uncertain clinical relevance, longitudinal studies of retinal function in MS should be planned over an extended period.

Functional visual disorders in children and adolescents are an important but challenging differential diagnosis. What is characteristic is the discrepancy between the symptomatology and the objective findings. The aim of our work was to analyse the data of those patients who were cared for at our clinic with the diagnosis "functional visual disorders".A retrospective data analysis was performed: age 18 years, with diagnosis "functional visual disorder" 2011 to 2020. Historical and clinical data were extracted from the patient's file. In addition, parents or patients were contacted using a questionnaire about current symptoms. The study was approved by the cantonal ethics committee of Zürich (KEK Nr. 2020-01268).A total of 92 patients were identified, and analysis could be performed in 53% (49/92; 32 female, 17 male) with available consent. The age ranged from 3 to 18 years (median 10.5 years) with a follow-up of 1 to 58 months (median 7 months). The most common symptoms were bilateral visual loss (55%) and/or blurred vision (18%) with headache (35%), motility pain (14%), photophobia (4%), dizziness (4%), and malaise (2%). A reduction in distant (22/49 bilateral, 9/49 unilateral) and near (24/49 bilateral, 3/49 unilateral) visual acuity was documented. Subjective visual acuity reduction was no longer detectable in 20% of patients at testing. Psychological distress was documented in 13/49 patients. Moisturising eye drops (18/49), eyeglass prescription (15/49), or no therapy (20/49) was recommended. Subjective and/or objective improvement was documented at follow-up in 49% (24/49). The questionnaire was answered in 86%: no complete remission of visual symptoms (10/42), remission within 1 week (14/41), 1 month (3/41), 2 - 6 months (8/41), 1 year (6/41). There was no correlation between duration of visual symptoms and age at onset or gender. The consultation at our clinic was reported as "supportive and helpful" in 31/42 patients.Despite a low incidence during the history, the psychosocial and psychological component should not be neglected.Funktionelle Sehstörungen stellen bei Kindern und Jugendlichen eine wichtige, aber auch herausfordernde Differenzialdiagnose dar. Charakteristisch ist die Diskrepanz zwischen der Symptomatik und den objektiven Befunden. Ziel unserer Arbeit war die Datenanalyse der Patienten, die aufgrund der Diagnose „funktionelle Sehstörungen“ an unserer Klinik betreut wurden.Es erfolgte eine retrospektive Datenanalyse: Alter 18 Jahre, Diagnose „funktionelle Sehstörung“ 2011 bis 2020. Anamnestische und klinische Daten wurden aus der Patientenakte extrahiert. Zusätzlich wurden die Eltern bzw. die Patienten mittels eines Fragebogens nach den aktuellen Beschwerdebildern kontaktiert. Die Studie wurde von der kantonalen Ethikkommission Zürich (KEK Nr. 2020-01268) bewilligt.Es wurden insgesamt 92 Patienten identifiziert, wobei eine Analyse bei 53% (49/92; 32 weiblich, 17 männlich) bei vorliegendem Consent erfolgen konnte. Das Alter betrug 3 bis 18 Jahre (median 10,5 Jahre) mit einem Follow-up von 1 bis 58 Monaten (median 7 Monate). Die häufigsten Symptome waren bilaterale Visusminderung (55%) und/oder Verschwommensehen (18%) mit Kopfschmerzen (35%), Motilitätsschmerz (14%), Photophobie (4%), Schwindel (4%) und Unwohlsein (2%). Eine Reduktion des Fern- (22/49 bilateral, 9/49 unilateral) und Nahvisus (24/49 bilateral, 3/49 unilateral) wurde dokumentiert. Die subjektive Visusminderung war in 20% der Patienten bei der Testung nicht mehr nachweisbar. Eine psychologische Belastung war in 13/49 Patienten dokumentiert. Befeuchtende Augentropfen (18/49), Brillenordination (15/49) oder keine Therapie (20/49) wurde empfohlen. Eine subjektive und/oder objektive Besserung bestand beim Follow-up in 49% (24/49). Der Fragebogen wurde in 86% beantwortet: keine vollständige Remission der visuellen Symptomatik (10/42), Remission innerhalb 1 Woche (14/41), 1 Monat (3/41), 2 – 6 Monate (8/41), 1 Jahr (6/41). Es lag keine Korrelation zwischen der Dauer der visuellen Symptome und dem Alter bei Beginn oder dem Geschlecht vor. Die Beratung an unserer Klinik wurde als „unterstützend und hilfreich“ in 31/42 Patienten angegeben.Die psychosoziale und psychologische Komponente sollte trotz geringem Vorkommen bei der Anamneseerhebung nicht vernachlässigt werden.

Background Brown syndrome is characterized by a restrictive elevation deficit of the affected eye in adduction. Besides the well-known congenital form, different acquired etiologies including inflammation, trauma, and surgery may prevent the superior oblique (SO) tendon from gliding freely through the trochlea on attempted upgaze. We present MRI findings in pediatric and adult patients with inflammatory acquired Brown syndrome. Methods Retrospective review of clinical and MRI findings of 6 patients (4 children: median age 8.4 years [range 6.1-8.7]; 2 adults: age 46.4 and 51.1 years). Median follow-up was 23 months (range 1-52). Results In all 6 patients, orbital MRI demonstrated inflammatory changes of the SO tendon-trochlea complex. A striking feature was circumferential contrast enhancement of the trochlea with central sparing where the tendon passes, reminiscent of an eyelet. In all cases, the motility restriction improved either spontaneously or with systemic anti-inflammatory treatment. Although both adult patients had a history of known seronegative spondyloarthritis, there was no associated systemic condition in the children in our series. Conclusions Both in children and in adults, MRI can provide evidence of inflammatory changes located at the trochlea-tendon complex in acquired Brown syndrome here referred to as the "eyelet sign," which may be helpful in confirming the clinical diagnosis and guide appropriate treatment.

IMPORTANCE: Identification of geographic population-based differences in genotype and phenotype heterogeneity are important for targeted and patient-specific diagnosis and treatment, counseling, and screening strategies. OBJECTIVE: To report disease-causing variants and their detailed phenotype in patients with bilateral congenital cataract from a single center in Switzerland and thereby draw a genetic map and perform a genotype-phenotype comparison of this cohort. DESIGN, SETTING, AND PARTICIPANTS: This clinical and molecular-genetic cohort study took place through the collaboration of the Department of Ophthalmology at the University Hospital Zurich and the Institute of Medical Molecular Genetics, University of Zurich, Schlieren, Switzerland. Thirty-seven patients from 25 families with different types of bilateral congenital cataract were included. All participating family members received a comprehensive eye examination. Whole exome sequencing was performed in the index patients, followed by a filtering process to detect possible disease-associated variants in genes previously described in association with congenital cataract. Probable disease-causing variants were confirmed by Sanger sequencing in available family members. All data were collected from January 2018 to June 2020, and the molecular-genetic analyses were performed from January 2019 to July 2020. MAIN OUTCOMES AND MEASURES: Identification of the underlying genetic causes of bilateral congenital cataract, including novel disease-causing variants and phenotype correlation. RESULTS: Among the 37 patients (18 [49%] male and 19 [51%] female; mean [SD] age, 17.3 [15.9] years) from 25 families, pathogenic variants were detected in 20 families (80% detection rate), which included 13 novel variants in the following genes: BCOR, COL4A1, CRYBA2, CRYBB2, CRYGC, CRYGS, GJA3, MAF, NHS, and WFS1. Putative disease-causing variants were identified in 14 of 20 families (70%) as isolated cases and in 6 of 20 families (30%) with syndromic cases. A recessive variant in the CRYBB2 gene in a consanguineous family with 2 affected siblings showing a nuclear and sutural cataract was reported in contrast to previously published reports. In addition, the effect on splicing in a minigene assay of a novel splice site variant in the NHS gene (c.[719-2A>G]) supported the pathogenicity of this variant. CONCLUSIONS AND RELEVANCE: This study emphasizes the importance of genetic testing of congenital cataracts. Known dominant genes need to be considered for recessive inheritance patterns. Syndromic types of cataract may be underdiagnosed in patients with mild systemic features.

Acute acquired comitant esotropia (AACE) is an uncommon form of strabismus. The main characteristics of AACE Type 2 in childhood are: acute onset of strabismus around 3 years of age, large and comitant angle of strabismus, absence of accommodative component, hyperopia of not more than 3 dpt, and measurable stereopsis. Strabismus surgery is urgently indicated in AACE Type 2 in order to avoid maldevelopment or loss of stereopsis. Therefore, in order to better describe the characteristics of AACE Type 2, we performed a retrospective analysis of patients previously seen in our clinic.Retrospective analysis of data from patients who underwent strabismus surgery between October 2011 and September 2019 due to suspected AACE Type 2 could be confirmed during postoperative visits by evaluating ocular alignment and stereopsis at our hospital. Analysed data included: age and symptoms at first visit, visual acuity, refractive status, correction by glasses, age at surgery, period of time between first symptoms and surgery, surgical procedure, stereopsis and angle of strabismus (before surgery and 1 day, 3 months, and 12 months after surgery). Ethical approval was obtained from the Cantonal Ethics Committee of Zurich.18 patients (12 male, 6 female) with mean hyperopia of 1.4 ± 0.6 dpt were identified as meeting the inclusion criteria during the defined time period. Amblyopia was present at first assessment in two patients. Strabismus surgery was performed at 2.0 to 11.1 years of age and between 0.4 and 24.6 months after onset of symptoms. Surgery was performed within 6 months after onset of symptoms in 12/18 children. Before surgery, angle of strabismus at near was measured as 38 ± 10 prism diopters (PD) and was reduced after surgery to 3 ± 3 PD at 3 months and 2 ± 2 PD at 12 months. Stereopsis was confirmed in 5/18 patients one day after surgery and in 18/18 patients 12 months after surgery.Our analysis showed that our patients with diagnosis of AACE Type 2 had mild hyperopia and large comitant non-accommodative esotropia; prognosis for recovery of stereopsis is excellent. Preoperative amblyopia does not exclude the diagnosis of AACE Type 2. Therapeutic intervention is advisable within a short period of time after first symptoms and the diagnosis of AACE Type 2.Akutes erworbenes konkomitantes Einwärtsschielen (acute acquired comitant esotropia, AACE) ist eine seltene Schielform. Es besteht Konsens, dass zu den klinischen Merkmalen des AACE Typ 2 im Kindesalter folgende Merkmale gehören: akuter Schielbeginn im etwa 3. Lebensjahr, relativ großer konkomitanter, nicht akkommodativer Schielwinkel, Hyperopie von maximal 3,0 dpt und eine normale Sensorik. Die Diagnose eines AACE Typ 2 stellt eine dringliche Therapieindikation dar, um einen irreversiblen Verlust des bereits erworbenen binokularen Sehens zu vermeiden. Um die klinischen Charakteristika von AACE Typ 2 zu analysieren, wählten wir folgendes Studiendesign.Retrospektive Datenanalyse der Patienten, die zwischen Oktober 2011 und September 2019 eine Strabismusoperation aufgrund der Verdachtsdiagnose eines AACE Typ 2 an unserer Klinik erhielten, welche sich auch postoperativ anhand von Stellung und Binokularitätsgrad bestätigen ließ. Analysierte Daten beinhalteten: Alter und Symptome bei Erstuntersuchung, Visus, Refraktion, Brillenkorrektur, Alter bei Operation, Intervall von Erstsymptomatik bis zur Operation, Operationsverfahren, Schielwinkel und Binokularitätsgrad (präoperativ und postoperativ 1 Tag, postoperativ 3 und 12 Monate). Die Analyse wurde durch die kantonale Ethikkommission Zürich genehmigt.Daten von 18 Patienten (12 männlich, 6 weiblich) konnten in die Studie eingeschlossen werden mit einer Hyperopie von 1,4 ± 0,6 dpt. Eine Amblyopie lag in 2 Fällen vor. Das Alter bei Operation lag zwischen 2,0 und 11,1 Jahren mit einem Intervall zwischen Erstsymptomatik und der Operation von 0,4 bis 24,6 Monaten. Eine Operation wurde innerhalb von 6 Monaten nach Schielbeginn bei 12/18 Kindern durchgeführt. Der präoperativ gemessene Schielwinkel lag in der Nähe bei 38 ± 10 Prismendioptrien (PD) und reduzierte sich nach 3 und 12 Monaten auf 3 ± 3 PD resp. 2 ± 2 PD. Stereosehen erreichten am 1. operativen Tag 5/18 Kinder, nach 12 Monaten dann 18/18 Kinder.Die Evaluation unserer Patientengruppe mit postoperativ gesicherter Diagnose AACE Typ 2 zeigt, dass in allen Fällen eine geringe Hyperopie, eine große konkomitante, nicht akkommodative Esotropie bestand und die Prognose zur Wiederherstellung von normaler Stereopsis ausgezeichnet ist. Das Vorliegen einer präoperativen Amblyopie schließt eine Normosensorik nach erfolgter Strabismuskorrektur nicht aus. Eine zeitnahe therapeutische Intervention sollte bei Vorliegen o. g. Charakteristika angestrebt werden.

Zusammenfassung Hintergrund Akutes erworbenes konkomitantes Einwärtsschielen (acute acquired comitant esotropia, AACE) ist eine seltene Schielform. Es besteht Konsens, dass zu den klinischen Merkmalen des AACE Typ 2 im Kindesalter folgende Merkmale gehören: akuter Schielbeginn im etwa 3. Lebensjahr, relativ großer konkomitanter, nicht akkommodativer Schielwinkel, Hyperopie von maximal 3,0 dpt und eine normale Sensorik. Die Diagnose eines AACE Typ 2 stellt eine dringliche Therapieindikation dar, um einen irreversiblen Verlust des bereits erworbenen binokularen Sehens zu vermeiden. Um die klinischen Charakteristika von AACE Typ 2 zu analysieren, wählten wir folgendes Studiendesign. Patienten und Methoden Retrospektive Datenanalyse der Patienten, die zwischen Oktober 2011 und September 2019 eine Strabismusoperation aufgrund der Verdachtsdiagnose eines AACE Typ 2 an unserer Klinik erhielten, welche sich auch postoperativ anhand von Stellung und Binokularitätsgrad bestätigen ließ. Analysierte Daten beinhalteten: Alter und Symptome bei Erstuntersuchung, Visus, Refraktion, Brillenkorrektur, Alter bei Operation, Intervall von Erstsymptomatik bis zur Operation, Operationsverfahren, Schielwinkel und Binokularitätsgrad (präoperativ und postoperativ 1 Tag, postoperativ 3 und 12 Monate). Die Analyse wurde durch die kantonale Ethikkommission Zürich genehmigt. Ergebnisse Daten von 18 Patienten (12 männlich, 6 weiblich) konnten in die Studie eingeschlossen werden mit einer Hyperopie von 1,4 ± 0,6 dpt. Eine Amblyopie lag in 2 Fällen vor. Das Alter bei Operation lag zwischen 2,0 und 11,1 Jahren mit einem Intervall zwischen Erstsymptomatik und der Operation von 0,4 bis 24,6 Monaten. Eine Operation wurde innerhalb von 6 Monaten nach Schielbeginn bei 12/18 Kindern durchgeführt. Der präoperativ gemessene Schielwinkel lag in der Nähe bei 38 ± 10 Prismendioptrien (PD) und reduzierte sich nach 3 und 12 Monaten auf 3 ± 3 PD resp. 2 ± 2 PD. Stereosehen erreichten am 1. operativen Tag 5/18 Kinder, nach 12 Monaten dann 18/18 Kinder. Schlussfolgerung Die Evaluation unserer Patientengruppe mit postoperativ gesicherter Diagnose AACE Typ 2 zeigt, dass in allen Fällen eine geringe Hyperopie, eine große konkomitante, nicht akkommodative Esotropie bestand und die Prognose zur Wiederherstellung von normaler Stereopsis ausgezeichnet ist. Das Vorliegen einer präoperativen Amblyopie schließt eine Normosensorik nach erfolgter Strabismuskorrektur nicht aus. Eine zeitnahe therapeutische Intervention sollte bei Vorliegen o. g. Charakteristika angestrebt werden.

Ogden syndrome is a rare lethal X‐linked recessive disorder caused by a recurrent missense variant (Ser37Pro) in the NAA10 gene, encoding the catalytic subunit of the N‐terminal acetyltransferase A complex (NatA). So far eight boys of two different families have been described in the literature, all presenting the distinctive and recognizable phenotype, which includes mostly postnatal growth retardation, global severe developmental delay, characteristic craniofacial features, and structural cardiac anomalies and/or arrhythmias. Here, we report the ninth case of Ogden syndrome with an independent recurrence of the Ser37Pro variant. We were able to follow the clinical course of the affected boy and delineate the evolving phenotype from his birth until his unfortunate death at 7 months. We could confirm the associated phenotype as well as the natural history of this severe disease. By describing new presenting features, we are further expanding the clinical spectrum associated with Ogden syndrome and review other phenotypes associated with NAA10 variants.

The purpose of this study was to develop a flexible, cost-efficient, next-generation sequencing (NGS) protocol for genetic testing. Long-range polymerase chain reaction (PCR) amplicons of up to 20 kb in size were designed to amplify entire genomic regions for a panel (n = 35) of inherited retinal disease (IRD)-associated loci. Amplicons were pooled and sequenced by NGS. The analysis was applied to 227 probands diagnosed with IRD: (A) 108 previously molecularly diagnosed, (B) 94 without previous genetic testing, and (C) 25 undiagnosed after whole-exome sequencing (WES). The method was validated with 100% sensitivity on cohort A. Long-range PCR-based sequencing revealed likely causative variant(s) in 51% and 24% of proband from cohorts B and C, respectively. Breakpoints of 3 copy number variants (CNVs) could be characterized. Long-range PCR libraries spike-in extended coverage of WES. Read phasing confirmed compound heterozygosity in 5 probands. The proposed sequencing protocol provided deep coverage of the entire gene, including intronic and promoter regions. Our method can be used (i) as a first-tier assay to reduce genetic testing costs, (ii) to elucidate missing heritability cases, (iii) to characterize breakpoints of CNVs at nucleotide resolution, (iv) to extend WES data to non-coding regions by spiking-in long-range PCR libraries, and (v) to help with phasing of candidate variants., International Journal of Molecular Sciences, 22 (4), ISSN:1422-0067

Coloboma and microphthalmia (C/M) are related congenital eye malformations, which can cause significant visual impairment. Molecular diagnosis is challenging as the genes associated to date with C/M account for only a small percentage of cases. Overall, the genetic cause remains unknown in up to 80% of patients. High throughput DNA sequencing technologies, including whole-exome sequencing (WES), are therefore a useful and efficient tool for genetic screening and identification of new mutations and novel genes in C/M. In this study, we analyzed the DNA of 19 patients with C/M from 15 unrelated families using singleton WES and data analysis for 307 genes of interest. We identified seven novel and one recurrent potentially disease-causing variants in CRIM1, CHD7, FAT1, PTCH1, PUF60, BRPF1, and TGFB2 in 47% of our families, three of which occurred de novo. The detection rate in patients with ocular and extraocular manifestations (67%) was higher than in patients with an isolated ocular phenotype (46%). Our study highlights the significant genetic heterogeneity in C/M cohorts and emphasizes the diagnostic power of WES for the screening of patients and families with C/M. © 2021 by the authors. Li-censee MDPI, Basel, Switzerland., Genes, 12 (1)

BackgroundThe purpose of this study was to develop a flexible, cost-efficient next-generation sequencing (NGS) protocol for genetic testing.MethodsLong-range polymerase chain reaction (LR PCR) amplicons of up to 20 kb in size were designed to amplify entire genomic regions for a panel (n=35) of loci associated with retinal diseases (RDs). Amplicons were pooled and sequenced by NGS. The analysis was applied to 227 probands diagnosed with RD: (A) 108 previously molecularly diagnosed, (B) 94 without previous genetic testing, (C) 25 undiagnosed after exome sequencing (ES).ResultsThe method was validated with 100% sensitivity on cohort A. LR PCR-based sequencing revealed likely causative variant(s) in 51% and 24% of proband from cohorts B and C, respectively. Breakpoints of 3 CNVs could be characterized. LR PCR libraries spike-in extended coverage data of ES. Read phasing confirmed compound heterozygosity in 5 probands.ConclusionThe proposed sequencing protocol provided deep coverage of the entire gene including intronic and promoter regions. Our method can be used (i) as a first-tier assay to reduce genetic testing costs, ii) to elucidate missing heritability cases, iii) to characterize breakpoints of CNVs at the nucleotide level, iv) to extend WES data to non-coding regions by spiking-in LR libraries, and v) to help with phasing of candidate variants.

Purpose To investigate feasibility, reliability and discriminative validity of pseudoisochromatic (PIC) colour vision tests, the Mollon-Reffin minimalist (MRM) test and the Cambridge Colour Test (CCT) among children (3-10 years) with reduced visual acuity. Methods Thirty-three patients with reduced visual acuity and 38 healthy control subjects with age-related normal visual acuity were recruited for this prospective study. Visual acuity in patients was reduced due to amblyopia, binocular maculopathy, or optic neuropathy. Tests were performed in a single 1-hr session. Results All but two children successfully completed the PIC and MRM tests. Success rate for the CCT was lower, 87%, CI [72%, 96%] for control subjects and 79%, CI [61%, 91%] for patients, with a strong positive effect of age on the odds of successful completion (OR 5.63, p = 0.007). Reliability was high in PIC and MRM tests but comparably lower in CCT. The rate of correct answers in PIC tests was between 88% and 100%. One proband was diagnosed with deuteranomaly with an average Ishihara score of 21%. All children (with the exception of one daltonian) scored at least two points in the MRM test. Sensitivity thresholds in CCT decreased with age with a strong effect size in control subjects and weak to moderate effect size in patients. Conclusions Pseudoisochromatic and MRM tests show sufficient feasibility in young children with reduced visual acuity. For CCT feasibility in 3-5-year olds is reduced, most probably due to the longer test duration. Consistent with earlier findings, colour discrimination thresholds decrease with age independent on visual acuity status.

Optic nerve hypoplasia (ONH) is a congenital optic nerve abnormality caused by underdevelopment of retinal ganglion cells (RGCs). Despite being a rare disease, ONH is the most common optic disc anomaly in ophthalmological practice. So far, mutations in several genes have been identified as causative, however many cases of ONH remain without a molecular explanation. The early transcription factor atonal basic-helix-loop-helix (bHLH) transcription factor 7 (ATOH7) is expressed in retinal progenitor cells and has a crucial role in RGC development. Previous studies have identified several mutations in the ATOH7 locus in cases of eye developmental diseases such as nonsyndromic congenital retinal nonattachment and persistent hyperplasia of the primary vitreous. Here we present two siblings with a phenotype predominated by bilateral ONH, with additional features of foveal hypoplasia and distinct vascular abnormalities, where whole-exome sequencing identified two compound heterozygous missense mutations affecting a conserved amino acid residue within the bHLH domain of ATOH7 (NM_145178.3:c.175G>A; p.(Ala59Thr) and c.176C>T; p.(Ala59Val)). ATOH7 expression constructs with patient single nucleotide variants were cloned for functional characterization. Protein analyses revealed decreased protein amounts and significantly enhanced degradation in the presence of E47, a putative bHLH dimerization partner. Protein interaction assays revealed decreased heterodimerization and DNA-binding of ATOH7 variants, resulting in total loss of transcriptional activation of luciferase reporter gene expression. These findings strongly support pathogenicity of the two ATOH7 mutations, one of which is novel. Additionally, this report highlights the possible impact of altered ATOH7 dimerization on protein stability and function.

Purpose: The aim of this study was to investigate the molecular basis of childhood glaucoma in Switzerland to recommend future targeted genetic analysis in the Swiss population. Methods: Whole-exome sequencing and copy number variation (CNV) analysis was performed in a Swiss cohort of 18 patients from 14 unrelated families. Identified variants were validated by Sanger sequencing and multiplex ligation-dependent probe amplification. Breakpoints of structural variants were determined by a microarray. A minigene assay was conducted for functional analysis of a splice site variant. Results: A diagnosis of primary congenital glaucoma was made in 14 patients, of which six (43%) harbored pathogenic variants in CYP1B1, one (7%) a frameshift variant in FOXC1, and seven (50%) remained without a genetic diagnosis. Three patients were diagnosed with glaucoma associated with nonacquired ocular anomalies, of which two patients with mild ocular features of Axenfeld-Rieger syndrome harbored a FOXC1 duplication plus an additional FOXC1 missense variant, and one patient with a Barkan membrane remained without genetic diagnosis. A diagnosis of juvenile open-angle glaucoma was made in one patient, and genetic analysis revealed a FOXC1 duplication. Conclusions: Sequencing of CYP1B1 and FOXC1, as well as analysis of CNVs in FOXC1, should be performed before extended gene panel sequencing. Translational Relevance: The identification of the molecular cause of childhood glaucoma is a prerequisite for genetic counseling and personalized care for patients and families., Translational Vision Science & Technology, 9 (7), ISSN:2164-2591

BACKGROUND: To investigate and quantify the impact of intracranial lesions at different locations within the visual pathway on the ganglion cell layer-inner plexiform layer (GCL-IPL) complex and the retinal nerve fiber layer (RNFL). METHODS: Patients with intracranial lesions affecting the optic chiasm (Group I) or the optic tract and/or lateral geniculate nucleus (Group II) were included. All patients received kinetic visual field assessment and underwent spectral domain optical coherence tomography. Peripapillary and papillomacular bundle (PMB) RNFL and macular GCL-IPL thickness in 4 perifoveal areas were measured and compared with normal values derived from 52 age-matched healthy control subjects. Z-scores for each parameter of every patient were calculated and compared with the normative data. Z-scores less than -2.0 (e.g., -2.5) were considered as being statistically significant. RESULTS: Twenty-two patients (Group I and II: 13 and 9, respectively) were included. Ten of 13 patients in Group I showed significant binasal GCL-IPL thinning, with associated temporal sector thinning in 8 patients. In Group II, all 9 patients showed significant reduction of the GCL-IPL corresponding to the homonymous visual field defect, but only 4 demonstrated RNFL thinning. Contralateral RNFL thinning within the PMB clinically similar to bow-tie atrophy was evident in all patients in Group II. GCL-IPL and RNFL thinning varied in severity from mild (isolated PMB RNFL thickness reduction) to severe (bilateral asymmetrical reduction of PMB RNFL associated with asymmetric, predominantly nasal reduction of GCL-IPL) in Group I. CONCLUSION: Clinical abnormalities in patients with visual pathway lesions are more likely to demonstrate abnormalities of GCL-IPL than global peripapillary RNFL thickness. However, PMB thickness measurement appears to be a valuable tool to detect abnormalities of the anterior visual pathways. If peripapillary RNFL measurements are performed in such patients, PMB thickness should be considered the most useful quantitative parameter.

ZusammenfassungZiliopathien umfassen Erkrankungen und Fehlbildungen einzelner oder mehrerer Organe. Isolierte oder syndromale progressive Netzhautdystrophien stellen die häufigste okuläre Manifestation der Ziliopathien dar. Hierbei ist insbesondere die Struktur der Photorezeptoren mit dem Verbindungscilium (connecting cilium) bedeutend. Durch die dysfunktionalen Zilien besteht eine meist schwere Form der Netzhautdystrophie, der Leberʼschen kongenitalen Amaurose (LCA). Die häufigsten syndromalen Ziliopathien mit okulärer Manifestation sind das Bardet-Biedl-Syndrom (BBS) und das Usher-Syndrom. Die molekulargenetischen Analysen wiesen bisher eine Vielzahl von Genen für ziliäre Proteine nach. Mutationen in diesen Genen sind mit einer klinischen Heterogenität verbunden. Die Diagnose einer LCA oder einer Netzhautdystrophie im Kindesalter sollte immer eine multidisziplinäre Untersuchung und Betreuung einschließen. Eine kausale Therapie der Ziliopathien befindet sich in einem erfolgversprechenden Anfangsstadium, sodass zum jetzigen Zeitpunkt nur unterstützende und rehabilitierende Maßnahmen zur Verfügung stehen.

Zusammenfassung Hintergrund Evaluation und Vergleich des okulären Phänotyps von Patienten, die mit tuberöser Sklerose (TSC) diagnostiziert wurden. Analyse der okulären Komplikationen während der Untersuchungsperiode. Methoden Es wurde eine retrospektive Datenanalyse von Patienten mit TSC, die ophthalmologische Untersuchungen an der Augenklinik des Universitätsspitals Zürich erhalten hatten, durchgeführt. Bestkorrigierter Visus, Refraktion, Gesichtsfeld, Vorderabschnitts- und Fundusbefunde mit Unterscheidung der Hamartomarten wurden aus den Patientenakten extrahiert. Die Studie wurde durch die kantonale Ethikkommission Zürich bewilligt. Resultate Insgesamt wurden Daten von 30 Patienten (19 weiblich, 11 männlich) mit TSC identifiziert. Das Alter bei der Erstuntersuchung variierte von 7 Monaten bis 44 Jahre (median 13,3 Jahre, Standardabweichung [SD] 11,31). Bei 17 von 30 Patienten lagen Daten der Follow-up-Untersuchung zwischen 4 Monaten und 19 Jahren vor (median 4,3 Jahre, SD 5,24). Daten der quantitativen Visusüberprüfung lagen von 26/30 Patienten vor, wobei 22/26 einen beidseitig altersentsprechenden Visus aufwiesen. Die Ursache der Visuseinschränkung bei 4 Patienten waren: Komplikation eines subependymalen Riesenzellastrozytoms mit einer beidseitigen Optikusatrophie; retinale Toxizität bei Vigabatrinmedikation; Vorderabschnittsdysgenesie und einseitige Amblyopie ex Anisometropie. Retinale Hamartome waren in 15/30 Patienten dokumentiert: bei 8 Patienten einseitig, bei 7 beidseitig. Der flache Hamartomtyp wurde häufiger als der multinoduläre Typ (10/15 vs. 6/15) beschrieben. Schlussfolgerungen Der okuläre Phänotyp unserer Patientenkohorte zeigt Übereinstimmungen mit der Literatur. Mit TSC diagnostizierte Patienten erfordern regelmäßige ophthalmologische Kontrollen, um sekundäre Komplikationen wie ein Papillenödem, starken Visusverlust oder Gesichtsfeldeinschränkung frühzeitig zu diagnostizieren.

Evaluation and comparison of the ocular phenotype in patients diagnosed with tuberous sclerosis complex (TSC). Analysis of ocular complications during follow-up.A retrospective chart review was performed of patients with TSC who had received an ocular examination at the eye clinic of the University Hospital Zurich. Data were analysed on visual acuity (VA) assessment, refraction, anterior and posterior eye examination including the distinction of different types of hamartomas and, when available, visual fields. The study was approved by the Cantonal Ethics Committee of Zurich.A total of 30 patients who were diagnosed with TSC (19 female, 11 male) were included in the analysis. The age at first examination varied from 7 months to 44 years (mean 13.3 years, standard deviation 11.31). 17/30 patients received a follow-up examination between 4 months and 19 years (mean 4.3 years, standard deviation 5.24). Data of VA were available in 26/30 patients, of whom 22 had normal vision in both eyes. The causes of reduced VA in the 4 patients were: complications of a subependymal giant cell astrocytoma followed by a bilateral optic nerve atrophy; vigabatrin-associated optic atrophy; anterior segment dysgenesis; unilateral amblyopia. Adequate VA testing was not possible in 4 patients because of intellectual disabilities. Retinal hamartomas were described in 15/30 patients: 8 unilateral, 7 bilateral. The flat hamartoma type was described in 10/15 patients, the multinodular type in 6/15 patients.The ocular phenotype in our patient cohort shows similar TSC involvement to that described in the literature. Patients diagnosed with TSC require regular ophthalmic examinations to diagnose secondary ocular complications, such as papilloedema, severe vision loss or visual field constriction.Evaluation und Vergleich des okulären Phänotyps von Patienten, die mit tuberöser Sklerose (TSC) diagnostiziert wurden. Analyse der okulären Komplikationen während der Untersuchungsperiode.Es wurde eine retrospektive Datenanalyse von Patienten mit TSC, die ophthalmologische Untersuchungen an der Augenklinik des Universitätsspitals Zürich erhalten hatten, durchgeführt. Bestkorrigierter Visus, Refraktion, Gesichtsfeld, Vorderabschnitts- und Fundusbefunde mit Unterscheidung der Hamartomarten wurden aus den Patientenakten extrahiert. Die Studie wurde durch die kantonale Ethikkommission Zürich bewilligt.Insgesamt wurden Daten von 30 Patienten (19 weiblich, 11 männlich) mit TSC identifiziert. Das Alter bei der Erstuntersuchung variierte von 7 Monaten bis 44 Jahre (median 13,3 Jahre, Standardabweichung [SD] 11,31). Bei 17 von 30 Patienten lagen Daten der Follow-up-Untersuchung zwischen 4 Monaten und 19 Jahren vor (median 4,3 Jahre, SD 5,24). Daten der quantitativen Visusüberprüfung lagen von 26/30 Patienten vor, wobei 22/26 einen beidseitig altersentsprechenden Visus aufwiesen. Die Ursache der Visuseinschränkung bei 4 Patienten waren: Komplikation eines subependymalen Riesenzellastrozytoms mit einer beidseitigen Optikusatrophie; retinale Toxizität bei Vigabatrinmedikation; Vorderabschnittsdysgenesie und einseitige Amblyopie ex Anisometropie. Retinale Hamartome waren in 15/30 Patienten dokumentiert: bei 8 Patienten einseitig, bei 7 beidseitig. Der flache Hamartomtyp wurde häufiger als der multinoduläre Typ (10/15 vs. 6/15) beschrieben.Der okuläre Phänotyp unserer Patientenkohorte zeigt Übereinstimmungen mit der Literatur. Mit TSC diagnostizierte Patienten erfordern regelmäßige ophthalmologische Kontrollen, um sekundäre Komplikationen wie ein Papillenödem, starken Visusverlust oder Gesichtsfeldeinschränkung frühzeitig zu diagnostizieren.

Laser pointer devices have become increasingly available in recent years, and their misuse has caused a number of ocular injuries. Online distribution channels permit trade in devices which may not conform to international standards in terms of their output power and spectral content. We present a case study of ocular injury caused by one such device. The patient was examined approximately 9 months following laser exposure using full-field and multifocal electroretinography (ERG and MF-ERG), electrooculography (EOG), and optical coherence tomography (OCT), in addition to a full ophthalmological examination. MF-ERG, OCT, and the ophthalmological examination were repeated 7 months after the first examination. The output of the laser pointer was measured. Despite severe focal damage to the central retina visible fundoscopically and with OCT, all electrophysiological examinations were quantitatively normal; however, qualitatively the central responses of the MF-ERG appeared slightly reduced. When the MF-ERG was repeated 7 months later, all findings were normal. The laser pointer was found to emit both visible and infrared radiation in dangerous amounts. Loss of retinal function following laser pointer injury may not always be detectable using standard electrophysiological tests. Exposure to non-visible radiation should be considered as a possible aggravating factor when assessing cases of alleged laser pointer injury.

Ocular coloboma is a common eye malformation resulting from incomplete fusion of the optic fissure during development. Coloboma is often associated with microphthalmia and/or contralateral anophthalmia. Coloboma shows extensive locus heterogeneity associated with causative mutations identified in genes encoding developmental transcription factors or components of signaling pathways. We report an ultra-rare, heterozygous frameshift mutation in FZD5 (p.Ala219Glufs*49) that was identified independently in two branches of a large family with autosomal dominant non-syndromic coloboma. FZD5 has a single-coding exon and consequently a transcript with this frameshift variant is not a canonical substrate for nonsense-mediated decay. FZD5 encodes a transmembrane receptor with a conserved extracellular cysteine rich domain for ligand binding. The frameshift mutation results in the production of a truncated protein, which retains the Wingless-type MMTV integration site family member-ligand-binding domain, but lacks the transmembrane domain. The truncated protein was secreted from cells, and behaved as a dominant-negative FZD5 receptor, antagonizing both canonical and non-canonical WNT signaling. Expression of the resultant mutant protein caused coloboma and microphthalmia in zebrafish, and disruption of the apical junction of the retinal neural epithelium in mouse, mimicking the phenotype of Fz5/Fz8 compound conditional knockout mutants. Our studies have revealed a conserved role of Wnt–Frizzled (FZD) signaling in ocular development and directly implicate WNT–FZD signaling both in normal closure of the human optic fissure and pathogenesis of coloboma.

Contains fulltext : 168325.pdf (Publisher’s version ) (Open Access) PURPOSE: To identify the genetic cause of autosomal recessive familial foveal retinoschisis (FFR). METHODS: A female sibship with FFR was identified (Family-A; 17 and 16 years, respectively); panel based genetic sequencing (132 genes) and comparative genome hybridization (142 genes) were performed. Whole-exome sequencing (WES) was performed on both siblings using the Illumina-HiSeq-2500 platform. A sporadic male (Family-B; 35 years) with FFR underwent WES using Illumina NextSeq500. All three affected subjects underwent detailed ophthalmologic evaluation including fundus photography, autofluorescence imaging, spectral-domain optical coherence tomography (SD-OCT), and full-field electroretinogram (ERG). RESULTS: Panel-based genetic testing identified two presumed disease causing variants in CRB1 (p.Gly123Cys and p.Cys948Tyr) in Family-A sibship; no deletion or duplication was detected. WES analysis in the sibship identified nine genes with two or more shared nonsynonymous rare coding sequence variants; CRB1 remained a strong candidate gene, and CRB1 variants segregated with the disease. WES in Family-B identified two presumed disease causing variants in CRB1 (p.Ile167_Gly169del and p.Arg764Cys) that segregated with the disease phenotype. Distance visual acuity was 20/40 or better in all three affected except for the left eye of the older subject (Family-B), which showed macular atrophy. Fundus evaluation showed spoke-wheel appearance at the macula in five eyes. The SD-OCT showed macular schitic changes in inner and outer nuclear layers in all cases. The ERG responses were normal in all subjects. CONCLUSIONS: This is the first report to implicate CRB1 as the underlying cause of FFR. This phenotype forms the mildest end of the spectrum of CRB1-related diseases.

Ciliopathies are disorders caused by ciliary dysfunction and can affect an organ system or tissues. Isolated or syndromic retinal dystrophies are the most common ocular manifestation of ciliopathies. The photoreceptor connecting cilium plays a leading role in these ciliopathy-related retinal dystrophies. Dysfunctional photoreceptor cilia cause the most severe type of retinal dystrophy: Leber's congenital amaurosis (LCA). The most common syndromic ciliopathies with an ocular manifestation are Bardet-Biedl syndrome (BBS) and Usher syndrome. Molecular-genetic analysis revealed a large number of cilia genes with a high phenotype heterogeneity. Diagnosis of ciliopathies require a multi-disciplinary approach. Causative treatment of ciliopathies is not yet available; therefore, rehabilitative and supportive treatment is mandatory.Ziliopathien umfassen Erkrankungen und Fehlbildungen einzelner oder mehrerer Organe. Isolierte oder syndromale progressive Netzhautdystrophien stellen die häufigste okuläre Manifestation der Ziliopathien dar. Hierbei ist insbesondere die Struktur der Photorezeptoren mit dem Verbindungscilium (connecting cilium) bedeutend. Durch die dysfunktionalen Zilien besteht eine meist schwere Form der Netzhautdystrophie, der Leberʼschen kongenitalen Amaurose (LCA). Die häufigsten syndromalen Ziliopathien mit okulärer Manifestation sind das Bardet-Biedl-Syndrom (BBS) und das Usher-Syndrom. Die molekulargenetischen Analysen wiesen bisher eine Vielzahl von Genen für ziliäre Proteine nach. Mutationen in diesen Genen sind mit einer klinischen Heterogenität verbunden. Die Diagnose einer LCA oder einer Netzhautdystrophie im Kindesalter sollte immer eine multidisziplinäre Untersuchung und Betreuung einschließen. Eine kausale Therapie der Ziliopathien befindet sich in einem erfolgversprechenden Anfangsstadium, sodass zum jetzigen Zeitpunkt nur unterstützende und rehabilitierende Maßnahmen zur Verfügung stehen.

Purpose: Recent evidence suggests structural changes distal to the inner retina in multiple sclerosis (MS) patients. The functional correlates of these proposed structural abnormalities remain unclear. We investigated outer retinal function and structure in MS patients, and quantified to what extent outer retinal structure influenced function in these patients. Methods: Outer retinal function was assessed using the full-field and multifocal electroretinogram (ERG/MF-ERG), whereas retinal structure was assessed using spectral-domain optical coherence tomography (OCT). Results were compared with preexisting normative data. The relationships between electrophysiology parameters and the OCT values corresponding to the proposed cellular origins of the ERG and MF-ERG were analyzed. Results: Most electrophysiological responses were delayed in MS patients, independently of optic neuritis (ON). Inner retinal thickness and volumes were reduced, and inner nuclear layer volume marginally increased, in eyes with previous ON; all other OCT parameters were normal. OCT results correlated with ERG amplitudes, but not with ERG peak times or any MF-ERG parameters. Conclusions: We recorded outer retinal dysfunction without detectable abnormalities of the corresponding retinal layers in MS patients, not ascribable to retrograde degeneration following ON. The findings complement a growing body of literature reporting primary retinal abnormalities distal to the ganglion cell–inner plexiform layer complex in MS patients, with our data suggesting that this may be a more widespread phenomenon than previously thought. ERG may be of more utility in detecting retinal dysfunction in MS patients than MF-ERG. Analysis of peak times, rather than response amplitudes, is recommended., Investigative Ophthalmology & Visual Science, 59 (1), ISSN:0146-0404

BACKGROUND The incidence of retinopathy of prematurity (ROP) and ROP screening criteria differ between countries. We assessed whether ROP screening could be reduced based on the local ROP incidence. METHODS Observational cohort study of infants born in Switzerland between 2006 and 2015

Background/objectives Infantile hemangiomas (IHs) involving the conjunctiva are only anecdotally reported in the literature and little is known about their clinical course. In a retrospective case series we aimed to better delineate the clinical presentation, complications, and response to treatment of this uncommon subtype of IH. A classification of conjunctival IH is proposed. Methods Medical charts at three academic pediatric dermatology institutions were retrospectively analyzed. Data were collected on the clinical characteristics, ophthalmologic findings, treatments, and outcomes of 22 individuals with conjunctival IH. Results Growth characteristics of conjunctival IH closely mirrored those of their cutaneous counterparts. Ophthalmologic abnormalities were associated with the IH in six individuals (27%); in three, they were considered severe. Seventeen subjects (77%) required treatment, most commonly because of risk of ocular compromise. All treated individuals responded favorably to topical timolol or systemic propranolol. Conclusion Conjunctival IH have clinical characteristics similar to those of cutaneous IH and respond readily to beta-blocker treatment. Ocular complications may occur in a minority of individuals receiving treatment.

Background. Evaluation of anisocoria including pharmacological testing for Horner’s syndrome in the pediatric population is challenging in view of potential serious underlying disease. We describe cocaine test results, outcome of systemic investigation, and long-term follow-up in children with anisocoria.Methods. Retrospective review of medical records and phone interview of consecutive pediatric patients (Results.A total of 35 patients were included with a positive, negative, or inconclusive cocaine test in 12/35, 19/35, and 4/35, respectively. Systemic investigation was performed in 11 of the patients with a positive and in 2 of the patients with an inconclusive cocaine test result. Mediastinal Hodgkin lymphoma was found in one patient with an inconclusive cocaine test result. Two other cases were presumably related to birth trauma and surgical trauma. None of the other children further developed any pathology during the follow-up period of 34.8 months (range 0–106.6).Conclusions.In most children with anisocoria and a positive cocaine test result, systemic investigation did not reveal any underlying etiology. The only malignant disease was diagnosed in a patient with a suspicion of Horner’s syndrome but with an inconclusive cocaine test result in our cohort.

We describe a case of an infant diagnosed with severe combined immune deficiency (Adenosine Deaminase (ADA), SCID) with severe retinopathy and associated low vision in both eyes at first examination. An extensive infectious work up revealed an enterovirus infection, which suggested an early infectious and severe retinopathy. Genetic causes of congenital retinitis pigmentosa/ Leber's congenital amaurosis could be excluded by whole exome sequencing.

Purpose: To define the phenotype of C2orf71 associated retinopathy and to present novel mutations in this gene. Methods: A retrospective multicenter study of patients with retinopathy and identified C2orf71 mutations was performed. Ocular function (visual acuity, visual fields, electroretinogram [ERG] responses); retinal morphology (fundus, optical coherence tomography); and underlying mutations were analyzed. Results: Thirteen patients from 11 families, who were aged 7 to 63 years (mean: 32.1 years) at their first examination with presumed compound heterozygous (6/13 patients) or homozygous (7/13 patients) C2orf71 mutations were identified. Eight of the mutations were novel. Truncation mutations were responsible in all cases. Nyctalopia was observed in less than 50% of patients. Visual acuity ranged from 20/20 to light perception. Severe visual loss was associated with atrophic maculopathy. Full-field ERG responses showed severe progressive cone-rod or rod-cone dysfunction. Typical fundus changes were progressive symmetrical retinopathy with an early mild maculopathy and patchy circular midperipheral RPE atrophy. Normal retinal lamination was preserved despite early disruption of the ellipsoid zone and RPE irregularities. Outer retinal tubulations were associated with better-preserved visual acuity. Conclusions: On the basis of our multicenter analysis, C2orf71 might represent a more frequently mutated gene in autosomal recessive retinitis pigmentosa in some populations. The phenotype analysis over a wide age range showed a variable and progressive retinal degeneration with early onset maculopathy and a better visual potential before the age of 30 years., Investigative Ophthalmology & Visual Science, 58 (10), ISSN:0146-0404

Background We report two novel splice region mutations in OPA1 in two unrelated families presenting with autosomal-dominant optic atrophy type 1 (ADOA1) (ADOA or Kjer type optic atrophy). Mutations in OPA1 encoding a mitochondrial inner membrane protein are a major cause of ADOA. Methods We analyzed two unrelated families including four affected individuals clinically suspicious of ADOA. Standard ocular examinations were performed in affected individuals of both families. All coding exons, as well as exon-intron boundaries of the OPA1 gene were sequenced. In addition, multiplex ligation-dependent probe amplification (MLPA) was performed to uncover copy number variations in OPA1. mRNA processing was monitored using RT-PCR and subsequent cDNA analysis. Results We report two novel splice region mutations in OPA1 in two unrelated individuals and their affected relatives, which were previously not described in the literature. In one family the heterozygous insertion and deletion c.[611-37_611-38insACTGGAGAATGTAAAGGGCTTT;611-6_611-16delCATATTTATCT] was found in all investigated family members leading to the activation of an intronic cryptic splice site. In the second family sequencing of OPA1 disclosed a de novo heterozygous deletion c.2012+4_2012+7delAGTA resulting in exon 18 and 19 skipping, which was not detected in healthy family members. Conclusion We identified two novel intronic mutations in OPA1 affecting the correct OPA1 pre-mRNA splicing, which was confirmed by OPA1 cDNA analysis. This study shows the importance of transcript analysis to determine the consequences of unclear intronic mutations in OPA1 in proximity to the intron-exon boundaries. Electronic supplementary material The online version of this article (doi:10.1186/s12881-017-0383-x) contains supplementary material, which is available to authorized users.

Author(s): Panorgias, Athanasios; Tillman, Megan; Sutter, Erich E; Moshiri, Ala; Gerth-Kahlert, Christina; Werner, John S | Abstract: PurposeTo investigate the topographic changes of the dark-adapted multifocal electroretinogram (mfERG) across adulthood in the central retina and compare the topography between macular versus extramacular, nasal versus temporal, and inferior versus superior retinal areas.MethodsSixty-five subjects (18-88 years) received a comprehensive dilated eye examination to ensure the health of their retina and were tested with a dark-adapted mfERG protocol using a 61-hexagon pattern. The lens absorption of each subject was also estimated using a heterochromatic flicker photometry (HFP) paradigm.ResultsThe response amplitude and latency of the dark-adapted mfERG showed a significant change with age, which was best described with a linear model. All the retinal areas examined demonstrated similar aging effects. The extramacular and temporal retina showed higher response amplitude and faster response latency when compared with the macular and nasal retinae, respectively. No difference was found in response amplitude and latency between the inferior and superior retina. The HFP results also showed a significant correlation with age, consistent with senescent increases in short wavelength absorption by the crystalline lens. However, the change in lens absorption did not exceed the magnitude of the change in response amplitude and latency.DiscussionOur results indicate that there is a decline in dark-adapted retinal activity as measured with the mfERG. These aging processes affect rods and rod-bipolar cells. Their decrease in response can be attributed to both optical and neural factors.

1. Name of the disease (synonyms) Non-syndromic (isolated and complex) microphthalmia; MCOP. 2. OMIM# of the disease 251600; 610093; 611038; 613094; 611040; 613517; 613704; 615113; 300345; 605738; 610092; 251505; 611638; 613703; 614497; 601186; 615145; 616428; 156900; 156850; 600165; 609549; 611897; 615972. 3. Name of the analysed genes or DNA/chromosome segments VSX2; RAX; GDF6; MFRP; PRSS56; GDF3; ALDH1A3; SHH; GDF6; ABCB6; STRA6; TENM3; RBP4; MFRP; TMEM98. 4. OMIM# of the gene(s) 142993; 601881; 601147; 606227; 613858; 606522; 600463; 142993; 600725; 601147; 605452; 610745; 610083; 180250; 606227; 615949. Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in the VSX2, RAX, GDF6, MFRP, PRSS56, GDF3, ALDH1A3, SHH, GDF6, ABCB6, STRA6, TENM3, RBP4, MFRP and TMEM98 genes in ⊠ diagnostic, ⊠ predictive and ⊠ prenatal settings, and for ⊠ risk assessment in relatives.

Purpose To compare phenotype variability in retinitis pigmentosa patients with recessive and dominant mutations in the SNRNP200 gene. Methods In a retrospective study, patients of two unrelated families were identified: family A, five patients aged 36 to 77 years; family B, one patient aged 9 years and his asymptomatic parents and sister. All patients received a comprehensive eye examination with a detailed retinal functional and morphologic assessment. Genetic testing was performed by whole exome sequencing (WES) in the index patient from each family. Genes described to be involved in eye diseases (n > 450) were screened for rare variants and segregation analysis was performed. Results A known heterozygous missense variant (c.3260C>T, p.(Ser1087Leu)) in the SNRNP200 gene was identified in the index patient of family A while a novel homozygous missense mutation (c.1634G>A, p.(Arg545His)) was found in the index patient of family B. Nyctalopia and photophobia were reported by 6/6 and 2/6 patients, respectively. The phenotype associated with the dominant mutation was characterized by variable disease onset (early childhood to the sixth decade of life), disease severity (visual acuity of 20/20-20/200 in the seventh to eighth decade), and advanced rod-cone dysfunction. Characteristics of recessive disease included distinct fundus changes of dot-like hypopigmentation together with retinal atrophy and severe rod-cone dysfunction. Conclusions The phenotype characteristics in autosomal dominant and recessive SNRNP200 mutations show distinct features, with earlier severe disease in the recessive case and a variable disease expression in the dominant inheritance pattern.

Irreversible disability in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) is largely attributed to neuronal and axonal degeneration, which, along with inflammation, is one of the major pathological hallmarks of these diseases. Optical coherence tomography (OCT) is a non-invasive imaging tool that has been used in MS, NMOSD, and other diseases to quantify damage to the retina, including the ganglion cells and their axons. The fact that these are the only unmyelinated axons within the central nervous system (CNS) renders the afferent visual pathway an ideal model for studying axonal and neuronal degeneration in neurodegenerative diseases. Structural magnetic resonance imaging (MRI) can be used to obtain anatomical information about the CNS and to quantify evolving pathology in MS and NMOSD, both globally and in specific regions of the visual pathway including the optic nerve, optic radiations and visual cortex. Therefore, correlations between brain or optic nerve abnormalities on MRI, and retinal pathology using OCT, may shed light on how damage to one part of the CNS can affect others. In addition, these imaging techniques can help identify important differences between MS and NMOSD such as disease-specific damage to the visual pathway, trans-synaptic degeneration, or pathological changes independent of the underlying disease process. This review focuses on the current knowledge of the role of the visual pathway using OCT and MRI in patients with MS and NMOSD. Emphasis is placed on studies that employ both MRI and OCT to investigate damage to the visual system in these diseases.

Aicardi syndrome is a rare X-linked cerebro-retinal disorder characterized by agenesis or dysgenesis of the corpus callosum, seizures, and chorioretinal lacunae; microphthalmia or optic nerve coloboma may also be observed. We report the case of an infant born with severe ocular malformations, including an anterior chamber cyst in one eye, which was surgically removed.

Inherited monogenic diseases of the retina and vitreous affect approximately 1 in 2000 individuals. They are characterized by tremendous genetic heterogeneity and clinical variability involving mutations in approximately 250 genes and more than 20 different clinical phenotypes. Clinical manifestations of retinal dystrophies (RDs) range from mild retinal dysfunctions to severe congenital forms of blindness. A detailed clinical diagnosis and the identification of causative mutations are crucial for genetic counseling of affected patients and their families, for understanding genotype-phenotype correlations and developing therapeutic approaches. Using whole exome sequencing (WES) we have established a reliable and efficient high-throughput analysis pipeline to identify disease-causing mutations. Our data indicate that this approach enables us to genetically diagnose approximately 64% of the patients (n = 58) with variant(s) in known disease-associated genes. We report 20 novel and 26 recurrent variants in genes associated with RDs. We also identified a novel phenotype for mutations in C2orf71 and provide functional evidence for exon skipping due to a splice-site variant identified in FLVCR1. In conclusion, WES can rapidly identify variants in various families affected with different forms of RDs. Our study also expands the clinical and allelic spectrum of genes associated with RDs in the Swiss population., Scientific Reports, 6, ISSN:2045-2322

Sir, Jalili syndrome1 is a rare autosomal-recessive disorder, which is caused by mutations in the CNNM4 gene.2, 3 Two phenotypes are proposed: associated with bull's eye maculopathy and peripheral retinal degeneration (type A), or with minor retinal dystrophy (type B).4 We report two new cases (siblings of 15 and 16 years of age) with different retinal findings, and their relationship with the existing phenotype classification. Fundus examination revealed severe bull's eye maculopathy in one sibling and diffuse retinal dystrophy in the other. ERG showed cone–rod dysfunction. OCT demonstrated thinning of the outer retinal layers, in particular the outer nuclear layer and the outer photoreceptor segments. Both patients showed amelogenesis imperfecta (Figure 1). Phenotype details in comparison with the reported patients with CNNM4 mutations are listed in Table 1. The same homozygous mutation c.1312dup; p.Leu438Profs*9 was found in the affected patients (III:4, III:5). The mother (II:4) was heterozygous for this sequence alteration in CNNM4 (Figure 2). The mutation within the cystathionine beta-synthase domain most likely results in a premature termination codon and nonsense-mediated mRNA decay of the mutant transcript. No mutation in the ABCA4 gene was identified. Figure 1 (a–e) Ocular and dental phenotype: ocular phenotype is illustrated by color fundus images and corresponding autofluoresence images, which show mild (III/4) to severe (III/5) maculopathy and retinopathy. Kinetic visual fields show a central scotoma ... Figure 2 Genetic testing results: Sanger DNA sequencing revealed a homozygous mutation in the two affected siblings (III:4 and III:5) as shown in the forward and reverse sequencing profiles from the DNA of the two patients. The mutation elongates the Oligo-C stretch ... Table 1 Review of published CNNM4 mutations and associated phenotype A similar dental phenotype with the characteristics of AI is described in all publications of patients with CNNM4 mutations. In his phenotype dissection, Jalili described anterior open bite (AOB) in 2/30 and posterior open bite in 1/30 ‘type A' patients, whereas AOB was present in all three patients of the ‘type B' phenotype. No open bite abnormality was seen on examination in our two patients and in one of the two patients reported by Luder et al.5 The intra-familial variability presented here is not consistent with a strict phenotype–genotype correlation, and may also argue against a rigid phenotype differentiation.4 As the patients with ‘type B' phenotype were examined at a younger age than the patient with ‘type A', it is possible that those patients with ‘type B' may have shown minimal macular signs as most of them had a visual impairment and signs of a cone–rod dystrophy. The proposed strict differentiation between type A and B may not be applicable to all affected patients and families.

The combination of progressive cerebellar degeneration, hypogonadotropic hypogonadism and chorioretinal dystrophy defines the rare Boucher-Neuhäuser syndrome (BNS), which has recently been linked to autosomal-recessive mutations in the PNPLA6 gene in four index patients. Here we present two novel unrelated patients with BNS, where we identified four recessive PNPLA6 mutations (3 of them novel) as the genetic cause, using a targeted high-throughput approach. This finding provides the first replication from independent families that BNS is caused by PNPLA6 and, moreover, highlights PNPLA6 as the major gene leading to BNS. Given the fact that the major gene causing BNS has thus now been identified, we summarize the spectrum of clinical presentations and phenotype evolution of BNS based on a systematic in-depth review of the literature of previously published cases (n = 40). Both the two cases presented here and our review of the literature propose that the clinical presentation of BNS can be variable regarding both the age (ranging from 1 to 40 years) and the clinical symptoms at onset (cerebellar ataxia in 38 %; vision loss in 36 %; delayed puberty in 26 %). A substantial fraction of BNS cases may present with relatively selective atrophy of the superior and dorsal parts of the cerebellar vermis along with atrophy of the cerebellar hemispheres on MRI, while brainstem or cortical changes on MRI seem to be present only in small fractions. Also in the literature, no other major genetic causes of BNS other than PNPLA6 mutations were identified.