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Introduction: Paediatric uveitis is a rare disease. It can affect any segment and have various etiologies, including infectious, autoimmune, and masquerade diseases. The pupose of this study is to analyse and present the demographic data in paediatric uveitis in a Swiss cohort. Knowledge of local demography may guide targeted work up and treatment., Methods: Single center retrospective study from January 2012 to June 2022. Patients under 18 years of age with uveitis were eligible for inclusion. Demographics (age at first presentation, sex), ocular signs (affected eye segment, laterality, visual acuity; VA, Snellen, decimal, clinical course), and systemic finding were analysed. Frequencies and descriptive statistics were computed, non-parametric tests and odds ratio were applied for sample comparisons. Local ethics committee approved this study., Results: Data from 93 of 133 identified patients were available. 51% were female, mean age at first presentation was 12 years, 60% had bilateral disease. 68% were of non-infectious etiology. Most common identified etiology was toxoplasmosis (20%), followed by JIA (8%) and herpetic (8%). No associated infectious cause or systemic disease was found in 44% of the cases. Most presented with anterior uveitis (50%), followed by posterior (28%), intermediate (20%), and panuveitis (2%). 80% of anterior uveitis were non-infectious; 81% of posterior uveitis were infectious. Bilateral disease was strongly associated with non-infectious uveitis (93%), whereas unilateral disease was more likely to be of an infectious cause (70%); odds ratio = 31. Mean VA of affected eyes at first presentation was 0.79. VA was significantly worse in cases with infectious uveitis compared to non-infectious uveitis (p = 0.007). Nearly a third of affected eyes showed at least one complication. This did not differ between in non-infectious and infectious uveitis cases., Conclusion: Bilateral disease is strongly suggestive of non-infectious uveitis. Unilateral and posterior disease is suggestive of an infectious cause, with toxoplasmosis being the most often diagnosed cause of uveitis in this cohort. Knowledge of demography is important for specialists to target workup and introduce treatment., Competing Interests: Declarations. Ethics approval and consent to participate: Local ethics committee approved this study (Institutional review board of Swiss Ethics/BASEC No. 2023 − 00439). The Tenets of the Declaration of Helsinki were followed. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background/Objectives : Neural retina leucine zipper (NRL) is a transcription factor involved in the differentiation of rod photoreceptors. Pathogenic variants in the gene encoding NRL have been associated with autosomal dominant retinitis pigmentosa and autosomal recessive clumped pigmentary retinal degeneration. Only a dozen unrelated families affected by recessive NRL -related retinal dystrophy have been described. The purpose of this study was to expand the genotypic spectrum of this disease by reporting clinical and genetic findings of two unrelated families. Methods : Index patients affected by retinal dystrophy were genetically tested by whole-exome sequencing (WES) and whole-genome sequencing (WGS). Segregation analysis within the families was performed for candidate variants. A minigene assay was performed to functionally characterize a variant suspected to affect splicing. Results : Variant filtering revealed homozygous NRL variants in both families. The variant in patient A was a small deletion encompassing the donor splice site of exon 1 of transcript NM_006177.3. The minigene assay revealed that this variant led to two aberrant transcripts that used alternative cryptic donor splice sites located in intron 1. In patient B, a stop-gain variant was identified in the last exon of NRL in a homozygous state due to maternal uniparental disomy of chromosome 14. Conclusions : Our study expands the genotypic spectrum of autosomal recessive NRL -related retinal dystrophy. Moreover, it underscores the importance of actively maintaining bioinformatic pipelines for variant detection and the utility of minigene assays in functionally characterizing candidate splicing variants.

Background/Objectives: Stargardt disease (STGD1) is an autosomal recessive disorder caused by pathogenic variants in ABCA4 that affects the retina and is characterised by progressive central vision loss. The onset of disease manifestations varies from childhood to early adulthood. Methods: Whole exome (WES), whole gene, and whole genome sequencing (WGS) were performed for a patient with STGD1. Results: WES revealed a heterozygous pathogenic missense variant in ABCA4 , but no second pathogenic variant was found. ABCA4 whole-gene sequencing, subsequent WGS, and segregation analysis identified a complex deep-intronic allele (NM&#95;000350.2(ABCA4):c.[1555-5882C>A;1555-5784C>G]) in trans to the missense variant. Minigene assays combined with nanopore sequencing were performed to characterise this deep-intronic complex allele in more detail. Surprisingly, the reference minigene revealed the existence of two pseudoexons in intron 11 of the ABCA4 gene that are included in low-abundance (<1%) transcripts. Both pseudoexons could be confirmed in cDNA derived from wildtype retinal organoids. Despite mild splicing predictions, the variant minigene revealed that the complex deep-intronic allele substantially increased the abundance of transcripts that included the pseudoexon overlapping with the variants. Two antisense oligonucleotides (AONs) were designed to rescue the aberrant splicing events. Both AONs increased the proportion of correctly spliced transcripts, and one of them rescued correct splicing to reference levels. Conclusions: Minigene assays combined with nanopore sequencing proved instrumental in identifying low-abundance transcripts including pseudoexons from wildtype ABCA4 intron 11, one of which was substantially increased by the complex allele.

Purpose: People with multiple sclerosis (pwMS) experience autoimmunity-mediated inflammation and neurodegeneration throughout the central nervous system. There remains a need for clinically accessible, reliable functional markers of neurodegeneration in MS. Previous research has described changes to electroretinography (ERG)-derived measures of retinal bipolar cell function in pwMS early in the disease course. We, therefore, investigated ERG as a potential outcome measure in individuals with more advanced disease., Methods: This cross-sectional observational study included pwMS with Expanded Disability Status Scale (EDSS) scores of ≥3.0 and healthy control (HC) participants who underwent ERG, optical coherence tomography, high- and low-contrast visual acuity measurement, and an ophthalmological examination. ERG findings in MS eyes with and without previous optic neuritis (MS +ON; MS -ON) were compared with those in HC eyes. Effects of EDSS, disease duration, ON, and treatment status on selected ERG outcomes were measured. Additional exploratory analyses assessed potential influences of MS phenotype and disease status (clinically active, radiologically active, and disease progression)., Results: Delays to two ERG peak times (dark-adapted 3.0 b-wave; light-adapted flicker) were recorded in MS +ON and MS -ON eyes. No influences of EDSS score, disease duration, previous ON, or treatment status were observed. Exploratory analyses were consistent with no effects of MS phenotype or disease status., Conclusions: ERG findings are abnormal in individuals with moderate-severe disability caused by MS; however, these findings are not distinct from those observed earlier in the disease course. Although bipolar dysfunction appears to be common in pwMS throughout the disease course, ERG is likely not useful in monitoring or prognostication of MS.

Background: Infants born prematurely are at risk of developing retinopathy of prematurity, which is associated with abnormalities in retinal function as measured using electroretinography. The aim of this study was to record non-invasive flicker electroretinograms (ERGs) in preterm infants and compare function of moderate and very or extremely preterm infants., Methods: In this non-randomized, cross-sectional study, 40 moderate preterm (gestational age (GA) 34 0/7 to 36 6/7 weeks, Group A) and 40 very or extremely preterm infants (GA ≤ 31 weeks, Group B) were recruited for flicker ERG recording through closed eyelids using the RETeval® device and skin electrodes. Group A was tested within the first week of life and Group B between 34th and 37th week postmenstrual age. Flicker stimuli were presented at 28.3 Hz with stimulus levels of 3, 6, 12, 30 and 50 cd•s/m 2 . Primary endpoints were peak time (ms) and amplitude (µV)., Results: Flicker ERGs were recordable in most infants with the highest proportion of reproducible ERGs at 30 cd•s/m 2 . Amplitudes increased with stronger flicker stimulation, while peak times did not differ significantly between stimulus levels nor groups. Amplitudes were significantly greater in Group B at the strongest stimulus level (Mann-Whitney-U-Test=198.00, Z = 4.097, p = <0.001)., Conclusions: Feasibility of collecting flicker ERG data in most preterm infants was confirmed. We found no evidence of reduced retinal responses to flicker stimuli associated with extreme prematurity. Higher amplitudes in very and extremely preterm infants could indicate acceleration of retinal development following birth, triggered by visual stimulation., (© 2024. The Author(s).)

Purpose: To investigate the long-term effects of high-dose recombinant human erythropoietin (rhEPO) administered during the perinatal period on retinal and visual function in children born extremely or very preterm., Design: Randomized, double-blind clinical trial follow-up plus cohort study., Methods:  Setting: Department of Ophthalmology, University Hospital Zurich, Zurich, Switzerland., Study Population: Extremely or very preterm-born children aged 7 to 15 years, previously randomized to receive either high-dose rhEPO or placebo in the perinatal period., Inclusion Criteria: participation in an ongoing neuropediatric study (EpoKids), written informed consent., Exclusion Criteria: previous ocular trauma or surgery; retinal or developmental disease unrelated to prematurity. Healthy control (HC) children of comparable age were recruited., Inclusion Criteria: term birth, informed consent., Exclusion Criteria: any ocular/visual abnormality, high refractive error. Intervention status (rhEPO/placebo) was unknown to examiners and subjects at examination, with examiners unblinded only after completion of all analyses., Observation Procedures: The electroretinogram (ERG) was performed with the RETeval device (LKC Technologies, Inc). Ophthalmological and orthoptic examinations excluded comorbidity in the prematurely born cohort and ocular diseases in the HC group., Main Outcome Measures: Scotopic and photopic ERG response amplitudes and peak times (6 amplitudes; 6 peak times). Secondary outcomes were habitual visual acuity and color discrimination performance (for descriptive summary only)., Results: No differences in ERG parameters between EPO (n = 52; 104 eyes) and placebo (n = 35; 70 eyes) subgroups were observed (all corrected P > .05). Two cone system-mediated peak times were slightly slower in the placebo than HC (n = 52; 104 eyes) subgroup (coefficient/95% confidence interval = 0.53/0.21-0.85 and 0.36/0.13-0.60; P = .012 and .022); a predominantly rod system-mediated peak time was slightly faster in the EPO than the HC subgroup (coefficient/95% confidence interval = -4.33/-6.88 to -1.78; P = .011). Secondary outcomes were comparable across subgroups., Conclusions: Administration of high-dose rhEPO to infants born extremely or very preterm during the perinatal period has no measurable effects on retinal function in childhood compared to placebo. Premature birth may cause small, likely clinically insignificant effects on retinal function in childhood, which may be partially mitigated by administration of rhEPO during the perinatal period., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: To study the long-term effects of perinatal high-dose recombinant human erythropoietin (rhEPO) on macular structural and vascular development in preterm children., Design: Randomized, double-blind clinical trial follow-up plus cohort study., Methods: Setting: Department of Ophthalmology, University Hospital Zurich, Zurich, Switzerland., Study Population: extremely or very preterm born children aged 7-15 years from an ongoing neuropediatric study (EpoKids). These had been previously randomized to receive either high-dose rhEPO or placebo perinatally., Inclusion Criteria: participation in the EpoKids Study, written informed consent (IC)., Exclusion Criteria: previous ocular trauma or surgery; retinal or developmental disease unrelated to prematurity. Term-born children of comparable age were enrolled as a healthy control (HC) group., Inclusion Criteria: term birth, IC., Exclusion Criteria: any ocular or visual abnormality, high refractive error. Examiners were blinded regarding intervention status until completion of all analyses. (Participants/guardians remain blinded)., Observation Procedures: Spectral-domain OCT scans (Heidelberg Spectralis system) and OCTA imaging (Zeiss PlexElite 9000) were obtained. Ophthalmological and orthoptic examinations excluded ocular comorbidities., Main Outcome Measures: OCT (central retinal thickness, CRT; total macular volume, TMV), superficial plexus OCTA (foveal avascular zone, FAZ; vessel density, VD; vessel length density, VLD) parameters and foveal hypoplasia grade according to published criteria., Results: Macular vessel density parameters (VD and VLD) were significantly lower (p =0.015, CI-95: 0.01 to 0.06 and p=0.015, CI-95: 0.74 to 3.64) in the EPO group (n= 52) when compared to placebo (n=35). No other significant differences were observed between the EPO and placebo group. When comparing the intervention subgroups to HC we found six significant differences in OCT and OCTA parameters (FAZ, VD, VLD and CRT comparing HC and EPO group; FAZ and CRT when comparing HC and placebo group)., Conclusions: Early high-dose rhEPO in infants born extremely or very preterm affects macular vessel density parameters compared to placebo. Premature birth (regardless of intervention status) affects retinal structure and vascular development. Our findings on macular vascular development do not contraindicate the administration of early high-dose EPO in preterm infants. For further understanding of the role of EPO on macular development and its clinical significance, future studies are needed., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors report no conflicts of interest.

The contribution of splicing variants to molecular diagnostics of inherited diseases is reported to be less than 10%. This figure is likely an underestimation due to several factors including difficulty in predicting the effect of such variants, the need for functional assays, and the inability to detect them (depending on their locations and the sequencing technology used). The aim of this study was to assess the utility of Nanopore sequencing in characterizing and quantifying aberrant splicing events. For this purpose, we selected 19 candidate splicing variants that were identified in patients affected by inherited retinal dystrophies. Several in silico tools were deployed to predict the nature and estimate the magnitude of variant-induced aberrant splicing events. Minigene assay or whole blood-derived cDNA was used to functionally characterize the variants. PCR amplification of minigene-specific cDNA or the target gene in blood cDNA, combined with Nanopore sequencing, was used to identify the resulting transcripts. Thirteen out of nineteen variants caused aberrant splicing events, including cryptic splice site activation, exon skipping, pseudoexon inclusion, or a combination of these. Nanopore sequencing allowed for the identification of full-length transcripts and their precise quantification, which were often in accord with in silico predictions. The method detected reliably low-abundant transcripts, which would not be detected by conventional strategies, such as RT-PCR followed by Sanger sequencing.

The purpose of this study was to assess the added diagnostic value of whole genome sequencing (WGS) for patients with inherited retinal diseases (IRDs) who remained undiagnosed after whole exome sequencing (WES). WGS was performed for index patients in 66 families. The datasets were analyzed according to GATK's guidelines. Additionally, DeepVariant was complemented by GATK's workflow, and a novel structural variant pipeline was developed. Overall, a molecular diagnosis was established in 19/66 (28.8%) index patients. Pathogenic deletions and one deep-intronic variant contributed to the diagnostic yield in 4/19 and 1/19 index patients, respectively. The remaining diagnoses (14/19) were attributed to exonic variants that were missed during WES analysis due to bioinformatic limitations, newly described loci, or unclear pathogenicity. The added diagnostic value of WGS equals 5/66 (9.6%) for our cohort, which is comparable to previous studies. This figure would decrease further to 1/66 (1.5%) with a standardized and reliable copy number variant workflow during WES analysis. Given the higher costs and limited added value, the implementation of WGS as a first-tier assay for inherited eye disorders in a diagnostic laboratory remains untimely. Instead, progress in bioinformatic tools and communication between diagnostic and clinical teams have the potential to ameliorate diagnostic yields.

Competing Interests: The authors declare that they have no conflict of interest.

Background: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) comprises various age-dependent clinical phenotypes and may be monophasic, multiphasic, or chronic. Optic neuritis (ON) is a common manifestation and frequently appears in combination with other MOGAD phenotypes, particularly in young children. Despite permanent structural damage to the retinal nerve fiber layer (RNFL), children often experience complete visual recovery., Aims: To analyze the progression and impact of MOGAD on the visual system of pediatric patients independently of the history of ON., Methods: This retrospective study included children who met specific criteria: myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G (IgG) seropositivity, acute presentation of MOGAD, and written general consent. Main outcome measures were global peripapillary retinal nerve fiber layer (pRNFL) thickness, and near and distance visual acuity, analyzed using descriptive statistics., Results: We identified 10 patients with median age of 7.7 years at first event: 7 patients manifested with acute disseminated encephalomyelitis (ADEM) (with ON 5/7, ADEM only 1/7, with transverse myelitis (TM) 1/7), 2 with isolated ON, and 1 patient with neuromyelitis optica spectrum disorder (NMOSD)-like phenotype with ON. Among ON patients, 5/8 were affected bilaterally, with 3 initially diagnosed with unilateral ON but experiencing subsequent involvement of the fellow eye. None of the patients without previous ON showed a deterioration of visual acuity and, if evaluated, a reduction of the pRNFL., Conclusion: Most pediatric MOGAD-ON patients in our cohort presented with acute vison loss and optic disc edema. All patients achieved complete visual recovery, independent of number of relapses or initial visual loss. The pRNFL thickness decreased for several months and stabilized at reduced levels after 12 months in the absence of further relapses. MOGAD may not have subclinical/'silent' effects on the visual system, as visual acuity and pRNFL were not affected in patients without ON., Competing Interests: Declaration of competing interest There is no conflict of interest in the paper being submitted to the journal., (© 2023 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.)

Congenital cataract (CC), the most prevalent cause of childhood blindness and amblyopia, necessitates prompt and precise genetic diagnosis. The objective of this study is to identify the underlying genetic cause in a Swiss patient with isolated CC. Whole exome sequencing (WES) and copy number variation (CNV) analysis were conducted for variant identification in a patient born with a total binocular CC without a family history of CC. Sanger Sequencing was used to confirm the variant and segregation analysis was used to screen the non-affected parents. The first de novo missense mutation at c.391T>C was identified in exon 3 of CRYGC on chromosome 2 causing the substitution of a highly conserved Tryptophan to an Arginine located at p.Trp131Arg. Previous studies exhibit significant changes in the tertiary structure of the crystallin family in the following variant locus, making CRYGC prone to aggregation aggravated by photodamage resulting in cataract. The variant can be classified as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) criteria (PP3 + PM1 + PM2 + PS2; scoring 10 points). The identification of this novel variant expands the existing knowledge on the range of variants found in the CRYGC gene and contributes to a better comprehension of cataract heterogeneity.

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.

X-linked retinitis pigmentosa (XLRP) caused by mutations in the RPGR gene is one of the most severe forms of RP due to its early onset and intractable progression. Most cases have been associated with genetic variants within the purine-rich exon ORF15 region of this gene. RPGR retinal gene therapy is currently being investigated in several clinical trials. Therefore, it is crucial to report and functionally characterize (all novel) potentially pathogenic DNA sequence variants. Whole-exome sequencing (WES) was performed for the index patient. The splicing effects of a non-canonical splice variant were tested on cDNA from whole blood and a minigene assay. WES revealed a rare, non-canonical splice site variant predicted to disrupt the wildtype splice acceptor and create a novel acceptor site 8 nucleotides upstream of RPGR exon 12. Reverse-transcription PCR analyses confirmed the disruption of the correct splicing pattern, leading to the insertion of eight additional nucleotides in the variant transcript. Transcript analyses with minigene assays and cDNA from peripheral blood are useful tools for the characterization of splicing defects due to variants in the RPGR and may increase the diagnostic yield in RP. The functional analysis of non-canonical splice variants is required to classify those variants as pathogenic according to the ACMG's criteria.

Purpose: To develop and validate a flicker electroretinogram (ERG) protocol in term-born neonates as a potential tool for assessing preterm infants at risk of developing retinopathy of prematurity., Methods: A custom flicker ERG protocol was developed for use with the hand-held RETeval® electrophysiology device. Feasibility of measuring flicker ERG through closed eyelids and without mydriasis was established in a pilot study enabling optimisation of the test protocol. Following this, healthy term-born neonates (gestational age 37-42 weeks) were recruited at the Neonatology clinic of the University Hospital Zurich. Flicker ERG recordings were performed using proprietary disposable skin electrodes during the first four days of life when the infants were sleeping. Flicker stimuli were presented at 28.3 Hz for a stimulus series at 3, 6, 12, 30, and 50 cd·s/m 2 , with two measurements at each stimulus level. Results were analysed offline. Flicker ERG peak times and amplitudes were derived from the averaged measurements per stimulus level for each subject., Results: 28 term-born neonates were included in the analysis. All infants tolerated the testing procedure well. Flicker ERG recording was achieved in all subjects with reproducible flicker ERG waveforms for 30 and 50 cd·s/m 2 stimuli. Reproducible ERGs were recorded in the majority of infants for the weaker stimuli (with detectable ERGs in 20/28, 25/28, and 27/28 at 3, 6, and 12 cd·s/m 2 , respectively). Flicker ERG amplitudes increased with increasing stimulus strength, with peak times concurrently decreasing slightly., Conclusion: Flicker ERG recording is feasible and reliably recorded in sleeping neonates through closed eyelids using skin electrodes and without mydriasis. Flicker ERG amplitude decreases for lower luminance flicker but remains detectable for 3 cd·s/m 2 flicker in the majority of healthy term-born neonates. These data provide a basis to study retinal function in premature infants using this protocol., (© 2022. The Author(s).)

Recessive mutations in the CTNS gene encoding the lysosomal transporter cystinosin cause cystinosis, a lysosomal storage disease leading to kidney failure and multisystem manifestations. A Ctns knockout mouse model recapitulates features of cystinosis, but the delayed onset of kidney manifestations, phenotype variability and strain effects limit its use for mechanistic and drug development studies. To provide a better model for cystinosis, we generated a Ctns knockout rat model using CRISPR/Cas9 technology. The Ctns-/- rats display progressive cystine accumulation and crystal formation in multiple tissues including kidney, liver and thyroid. They show an early onset and progressive loss of urinary solutes, indicating generalized proximal tubule dysfunction, with development of typical swan-neck lesions, tubulointerstitial fibrosis and kidney failure, and decreased survival. The Ctns-/- rats also present crystals in the cornea, and bone and liver defects, as observed in patients. Mechanistically, the loss of cystinosin induces a phenotype switch associating abnormal proliferation and dedifferentiation, loss of apical receptors and transporters, and defective lysosomal activity and autophagy in the cells. Primary cultures of proximal tubule cells derived from the Ctns-/- rat kidneys confirmed the key changes caused by cystine overload, including reduced endocytic uptake, increased proliferation and defective lysosomal dynamics and autophagy. The novel Ctns-/- rat model and derived proximal tubule cell system provide invaluable tools to investigate the pathogenesis of cystinosis and to accelerate drug discovery., (© The Author(s) 2022. Published by Oxford University Press.)

Early infantile epileptic encephalopathy (EIEE) is a severe neurologic and neurodevelopmental disease that manifests in the first year of life. It shows a high degree of genetic heterogeneity, but the genetic origin is only identified in half of the cases. We report the case of a female child initially diagnosed with Leber congenital amaurosis (LCA), an early-onset retinal dystrophy due to photoreceptor cell degeneration in the retina. The first examination at 9 months of age revealed no reaction to light or objects and showed wandering eye movements. Ophthalmological examination did not show any ocular abnormalities. The patient displayed mildly dysmorphic features and a global developmental delay. Brain MRI demonstrated pontine hypo-/dysplasia. The patient developed myoclonic epileptic seizures and epileptic spasms with focal and generalized epileptiform discharges on electroencephalogram (EEG) at the age of 16 months. Genetic screening for a potentially pathogenic DNA sequence variant by whole-exome sequencing (WES) revealed a novel, conserved, homozygous frameshift variant (c.5391delA, p.(Ala1798Leu fs Ter59)) in exon 42 of the DOCK7 gene (NM&#95;001271999.1). Further analysis by SNP array (Karyomapping) showed loss of heterozygosity (LOH) in four segments of chromosome 1. WES data of the parents and the index patient (trio analysis) demonstrated that chromosome 1 was exclusively inherited from the mother. Four LOH segments of chromosome 1 alternately showed isodisomy (UPiD) and heterodisomy (UPhD). In WES data, the father was a noncarrier, and the mother was heterozygous for this DOCK7 variant. The DOCK7 gene is located in 1p31.3, a region situated in one of the four isodisomic segments of chromosome 1, explaining the homozygosity seen in the affected child. Finally, Sanger sequencing confirmed maternal UPiD for the DOCK7 variant. Homozygous or compound heterozygous pathogenic variants in the DOCK7 (dedicator of cytokinesis 7) gene are associated with autosomal recessive, early infantile epileptic encephalopathy 23 (EIEE23; OMIM #615,859), a rare and heterogeneous group of neurodevelopmental disorders diagnosed during early childhood. To our knowledge, this is the first report of segmental uniparental iso- and heterodisomy of chromosome 1, leading to homozygosity of the DOCK7 frameshift variant in the affected patient.

Background: 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"., Patients and Methods: 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)., Results: 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., Conclusion: Despite a low incidence during the history, the psychosocial and psychological component should not be neglected., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

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., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by North American Neuro-Ophthalmology Society.)

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., (© 2021. The Author(s).)

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., (© 2021 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

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.