The Developmental Eye Movement Test Does Not Detect Oculomotor Problems: Evidence from Children with Nystagmus.

SIGNIFICANCE: The Developmental Eye Movement (DEM) test, a test purported to assess oculomotor skills, does not detect eye movement disorder in nystagmus syndromes. The test should not be used for the clinical evaluation of oculomotor disorders. PURPOSE: The DEM test ratio compares a horizontal number naming subtest with a vertical one to identify oculomotor problems independent of a child's visual-verbal naming skills. Here, we tested the construct validity of this method by comparing scores of children with and without pathologic nystagmus. Such a nystagmus disturbs normal fixation and saccadic behavior because of the presence of involuntary rhythmic oscillations of the eyes. Therefore, if the ratio is indeed a comprehensive measure of oculomotor problems, children with nystagmus should show an increased ratio score. METHODS: The DEM test performances of normally sighted children (n = 94), children with ocular visual impairments (VI o ; n = 33), and children with cerebral visual impairment (n = 30) were analyzed using linear regression. Part of the children with VI o and cerebral visual impairment had either fusion maldevelopment nystagmus syndrome (n = 8) or infantile nystagmus syndrome (n = 20), whereas the others showed no pathologic nystagmus. RESULTS: The times needed for the horizontal and vertical subtests were significantly different between children with normal vision, VI o , and cerebral visual impairment ( P < .001). However, the presence of nystagmus did not add significantly to the horizontal and vertical times ( P > .20), nor did it have an effect on the ratio ( P > .10). CONCLUSIONS: The DEM test ratio is not sensitive to fixation and saccade abnormalities associated with nystagmus, indicating that it does not have general construct validity to detect true eye movement disorders. Although not suitable for the evaluation of oculomotor disorders, the subtests do have clinical relevance in the diagnosis of cerebral visual impairment.

LONGITUDINAL STUDY OF RPE65-ASSOCIATED INHERITED RETINAL DEGENERATIONS.

PURPOSE: To study the disease course of RPE65-associated inherited retinal degenerations (IRDs) as a function of the genotype, define a critical age for blindness, and identify potential modifiers. METHODS: Forty-five patients with IRD from 33 families with biallelic RPE65 mutations, 28 stemming from a genetic isolate. We collected retrospective data from medical charts. Coexisting variants in 108 IRD-associated genes were identified with Molecular Inversion Probe analysis. RESULTS: Most patients were diagnosed within the first years of life. Daytime visual function ranged from near-normal to blindness in the first four decades and met WHO criteria for blindness for visual acuity and visual field in the fifth decade. p.(Thr368His) was the most common variant (54%). Intrafamilial variability and interfamilial variability in disease severity and progression were observed. Molecular Inversion Probe analysis confirmed all RPE65 variants and identified one additional variant in LRAT and one in EYS in two separate patients. CONCLUSION: All patients with RPE65-associated IRDs developed symptoms within the first year of life. Visual function in childhood and adolescence varied but deteriorated inevitably toward blindness after age 40. In this study, genotype was not predictive of clinical course. The variance in severity of disease could not be explained by double hits in other IRD genes.

Development and validation of a high-speed stereoscopic eyetracker.

Traditional video-based eyetrackers require participants to perform an individual calibration procedure, which involves the fixation of multiple points on a screen. However, certain participants (e.g., people with oculomotor and/or visual problems or infants) are unable to perform this task reliably. Previous work has shown that with two cameras one can estimate the orientation of the eyes' optical axis directly. Consequently, only one calibration point is needed to determine the deviation between an eye's optical and visual axes. We developed a stereo eyetracker with two USB 3.0 cameras and two infrared light sources that can track both eyes at ~ 350 Hz for eccentricities of up to 20°. A user interface allows for online monitoring and threshold adjustments of the pupil and corneal reflections. We validated this tracker by collecting eye movement data from nine healthy participants and compared these data to eye movement records obtained simultaneously with an established eyetracking system (EyeLink 1000 Plus). The results demonstrated that the two-dimensional accuracy of our portable system is better than 1°, allowing for at least ± 5-cm head motion. Its resolution is better than 0.2° (SD), and its sample-to-sample noise is less than 0.05° (RMS). We concluded that our stereo eyetracker is a valid instrument, especially in settings in which individual calibration is challenging.

NR2F1 mutations cause optic atrophy with intellectual disability.

Optic nerve atrophy and hypoplasia can be primary disorders or can result from trans-synaptic degeneration arising from cerebral visual impairment (CVI). Here we report six individuals with CVI and/or optic nerve abnormalities, born after an uneventful pregnancy and delivery, who have either de novo heterozygous missense mutations in NR2F1, also known as COUP-TFI, or deletions encompassing NR2F1. All affected individuals show mild to moderate intellectual impairment. NR2F1 encodes a nuclear receptor protein that regulates transcription. A reporter assay showed that missense mutations in the zinc-finger DNA-binding domain and the putative ligand-binding domain decrease NR2F1 transcriptional activity. These findings indicate that NR2F1 plays an important role in the neurodevelopment of the visual system and that its disruption can lead to optic atrophy with intellectual disability.

CORRIGENDUM: The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype-phenotype correlations.

This corrects the article DOI: 10.1038/gim.2016.18.

A meta-analysis of perceptual and cognitive functions involved in useful-field-of-view test performance.

The useful-field-of-view (UFOV) test measures the amount of information someone can extract from a visual scene in one glance. Its scores show relatively strong relationships with everyday activities. The UFOV test consists of three computer tests, suggested to measure processing speed and central vision, divided attention, and selective attention. However, other functions seem to be involved as well. In order to investigate the contribution of these suggested and other perceptual and cognitive functions, we performed a meta-analysis of 116 Pearson's correlation coefficients between UFOV scores and other test scores reported in 18 peer-reviewed articles. We divided these correlations into nine domains: attention, executive functioning, general cognition, memory, spatial ability, visual closure, contrast sensitivity, visual processing speed, and visual acuity. A multivariate mixed-effects model analysis revealed that each domain correlated significantly with each of the UFOV subtest scores. These correlations were stronger for Subtests 2 and 3 than for Subtest 1. Furthermore, some domains were more strongly correlated to the UFOV than others across subtests. We did not find interaction effects between subtest and domain, indicating that none of the UFOV subtests is more selectively sensitive to a particular domain than the others. Thus, none of the three UFOV subtests seem to measure one clear construct. Instead, a range of visual and cognitive functions is involved. Perhaps this is the reason for the UFOV's high ecological validity, as it involves many functions at once, making it harder to compensate if one of them fails.

The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype-phenotype correlations.

PURPOSE: Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is an autosomal-dominant disorder characterized by optic atrophy and intellectual disability caused by loss-of-function mutations in NR2F1. We report 20 new individuals with BBSOAS, exploring the spectrum of clinical phenotypes and assessing potential genotype-phenotype correlations. METHODS: Clinical features of individuals with pathogenic NR2F1 variants were evaluated by review of medical records. The functional relevance of coding nonsynonymous NR2F1 variants was assessed with a luciferase assay measuring the impact on transcriptional activity. The effects of two start codon variants on protein expression were evaluated by western blot analysis. RESULTS: We recruited 20 individuals with novel pathogenic NR2F1 variants (seven missense variants, five translation initiation variants, two frameshifting insertions/deletions, one nonframeshifting insertion/deletion, and five whole-gene deletions). All the missense variants were found to impair transcriptional activity. In addition to visual and cognitive deficits, individuals with BBSOAS manifested hypotonia (75%), seizures (40%), autism spectrum disorder (35%), oromotor dysfunction (60%), thinning of the corpus callosum (53%), and hearing defects (20%). CONCLUSION: BBSOAS encompasses a broad range of clinical phenotypes. Functional studies help determine the severity of novel NR2F1 variants. Some genotype-phenotype correlations seem to exist, with missense mutations in the DNA-binding domain causing the most severe phenotypes.Genet Med 18 11, 1143-1150.

Assessment of near visual acuity in 0-13 year olds with normal and low vision: a systematic review.

BACKGROUND: The inclusion for rehabilitation of visually impaired children is partly based on the measurement of near vision, but guidelines for near visual acuity assessment are currently lacking. The twofold purpose of this systematic review was to: (i) provide an overview of the impact of the chart design on near visual acuity measured, and (ii) determine the method of choice for near vision assessments in children of different developmental ages. METHODS: A literature search was conducted by using the following electronic databases: PubMed, Cochrane Library, and EMBASE. The last search was run on March 26th 2016. Additional studies were identified by contacting experts and searching for relevant articles in reference lists of included studies. Search terms were: vision test(s), vision assessment(s), visual acuity, chart(s) and near. RESULTS: For children aged 0-3 years the golden standard is still the preferential looking procedure. Norms are available for this procedure for 6-36 month old children. For 4-7 year olds, we recommend using the LEA symbols, because these symbols have been properly validated and can be used in preliterate children. Responses can be verbal or by matching the target symbol. In children aged 8-13 years, the recommended method is the ETDRS letter chart, because letter acuity is more predictive for functional vision and reading than symbol acuity. In 8-13 year olds, letter acuity is 0.1-0.2 logMAR poorer than symbol acuity. CONCLUSIONS: Chart design, viewing distance, and threshold choice have a serious impact on near visual acuity measurements. Near visual acuity measured with symbols is lower than near visual acuity measured with gratings, and near visual acuity measured with letters is lower than near visual acuity measured with symbols. Viewing distance, chart used, and letter spacing should be adapted to the child's development and reported in order to allow comparisons between measurements.

ZNF408 is mutated in familial exudative vitreoretinopathy and is crucial for the development of zebrafish retinal vasculature.

Familial exudative vitreoretinopathy (FEVR) is a genetically heterogeneous disorder characterized by abnormal vascularization of the peripheral retina, which can result in retinal detachment and severe visual impairment. In a large Dutch FEVR family, we performed linkage analysis, exome sequencing, and segregation analysis of DNA variants. We identified putative disease-causing DNA variants in proline-alanine-rich ste20-related kinase (c.791dup; p.Ser265ValfsX64) and zinc finger protein 408 (ZNF408) (c.1363C>T; p.His455Tyr), the latter of which was also present in an additional Dutch FEVR family that subsequently appeared to share a common ancestor with the original family. Sequence analysis of ZNF408 in 132 additional individuals with FEVR revealed another potentially pathogenic missense variant, p.Ser126Asn, in a Japanese family. Immunolocalization studies in COS-1 cells transfected with constructs encoding the WT and mutant ZNF408 proteins, revealed that the WT and the p.Ser126Asn mutant protein show complete nuclear localization, whereas the p.His455Tyr mutant protein was localized almost exclusively in the cytoplasm. Moreover, in a cotransfection assay, the p.His455Tyr mutant protein retains the WT ZNF408 protein in the cytoplasm, suggesting that this mutation acts in a dominant-negative fashion. Finally, morpholino-induced knockdown of znf408 in zebrafish revealed defects in developing retinal and trunk vasculature, that could be rescued by coinjection of RNA encoding human WT ZNF408 but not p.His455Tyr mutant ZNF408. Together, our data strongly suggest that mutant ZNF408 results in abnormal retinal vasculogenesis in humans and is associated with FEVR.

Target-distractor similarity has a larger impact on visual search in school-age children than spacing.

In typically developing children, crowding decreases with increasing age. The influence of target-distractor similarity with respect to orientation and element spacing on visual search performance was investigated in 29 school-age children with normal vision (4- to 6-year-olds [N = 16], 7- to 8-year-olds [N = 13]). Children were instructed to search for a target E among distractor Es (feature search: all flanking Es pointing right; conjunction search: flankers in three orientations). Orientation of the target was manipulated in four directions: right (target absent), left (inversed), up, and down (vertical). Spacing was varied in four steps: 0.04°, 0.5°, 1°, and 2°. During feature search, high target-distractor similarity had a stronger impact on performance than spacing: Orientation affected accuracy until spacing was 1°, and spacing only influenced accuracy for identifying inversed targets. Spatial analyses showed that orientation affected oculomotor strategy: Children made more fixations in the "inversed" target area (4.6) than the vertical target areas (1.8 and 1.9). Furthermore, age groups differed in fixation duration: 4- to 6-year-old children showed longer fixation durations than 7- to 8-year-olds at the two largest element spacings (p = 0.039 and p = 0.027). Conjunction search performance was unaffected by spacing. Four conclusions can be drawn from this study: (a) Target-distractor similarity governs visual search performance in school-age children, (b) children make more fixations in target areas when target-distractor similarity is high, (c) 4- to 6-year-olds show longer fixation durations than 7- to 8-year-olds at 1° and 2° element spacing, and (d) spacing affects feature but not conjunction search-a finding that might indicate top-down control ameliorates crowding in children.

Low vision due to cerebral visual impairment: differentiating between acquired and genetic causes.

BACKGROUND: To gain more insight into genetic causes of cerebral visual impairment (CVI) in children and to compare ophthalmological findings between genetic and acquired forms of CVI. METHODS: The clinical data of 309 individuals (mainly children) with CVI, and a visual acuity ≤ 0.3 were analyzed for etiology and ocular variables. A differentiation was made between acquired and genetic causes. However, in persons with West syndrome or hydrocephalus, it might be impossible to unravel whether CVI is caused by the seizure disorder or increased intracranial pressure or by the underlying disorder (that in itself can be acquired or genetic). In two subgroups, individuals with 'purely' acquired CVI and with 'purely' genetic CVI, the ocular variables (such as strabismus, pale optic disc and visual field defects) were compared. RESULTS: It was possible to identify a putative cause for CVI in 60% (184/309) of the cohort. In the remaining 40% the etiology could not be determined. A 'purely' acquired cause was identified in 80 of the patients (26%). West syndrome and/or hydrocephalus was identified in 21 patients (7%), and in 17 patients (6%) both an acquired cause and West and/or hydrocephalus was present. In 66 patients (21%) a genetic diagnosis was obtained, of which 38 (12%) had other possible risk factor (acquired, preterm birth, West syndrome or hydrocephalus), making differentiation between acquired and genetic not possible. In the remaining 28 patients (9%) a 'purely' genetic cause was identified.CVI was identified for the first time in several genetic syndromes, such as ATR-X, Mowat-Wilson, and Pitt Hopkins syndrome. In the subgroup with 'purely' acquired causes (N = 80) strabismus (88% versus 64%), pale optic discs (65% versus 27%) and visual field defects (72% versus 30%) could be observed more frequent than in the subgroup with 'purely' genetic disorders (N = 28). CONCLUSIONS: We conclude that CVI can be part of a genetic syndrome and that abnormal ocular findings are present more frequently in acquired forms of CVI.

Next-generation sequencing of a 40 Mb linkage interval reveals TSPAN12 mutations in patients with familial exudative vitreoretinopathy.

Familial exudative vitreoretinopathy (FEVR) is a genetically heterogeneous retinal disorder characterized by abnormal vascularisation of the peripheral retina, often accompanied by retinal detachment. To date, mutations in three genes (FZD4, LRP5, and NDP) have been shown to be causative for FEVR. In two large Dutch pedigrees segregating autosomal-dominant FEVR, genome-wide SNP analysis identified an FEVR locus of approximately 40 Mb on chromosome 7. Microsatellite marker analysis suggested similar at risk haplotypes in patients of both families. To identify the causative gene, we applied next-generation sequencing in the proband of one of the families, by analyzing all exons and intron-exon boundaries of 338 genes, in addition to microRNAs, noncoding RNAs, and other highly conserved genomic regions in the 40 Mb linkage interval. After detailed bioinformatic analysis of the sequence data, prioritization of all detected sequence variants led to three candidates to be considered as the causative genetic defect in this family. One of these variants was an alanine-to-proline substitution in the transmembrane 4 superfamily member 12 protein, encoded by TSPAN12. This protein has very recently been implicated in regulating the development of retinal vasculature, together with the proteins encoded by FZD4, LRP5, and NDP. Sequence analysis of TSPAN12 revealed two mutations segregating in five of 11 FEVR families, indicating that mutations in TSPAN12 are a relatively frequent cause of FEVR. Furthermore, we demonstrate the power of targeted next-generation sequencing technology to identify disease genes in linkage intervals.

Crowded task performance in visually impaired children: magnifier versus large print.

BACKGROUND: This study compares the influence of two different types of magnification (magnifier versus large print) on crowded near vision task performance. METHODS: Fifty-eight visually impaired children aged 4-8 years participated. Participants were divided in two groups, matched on age and near visual acuity (NVA): [1] the magnifier group (4-6 year olds [n = 13] and 7-8 year olds [n = 19]), and [2] the large print group (4-6 year olds [n = 12] and 7-8 year olds [n = 14]). At baseline, single and crowded Landolt C acuity were measured at 40 cm without magnification. Crowded near vision was measured again with magnification. A 90 mm diameter dome magnifier was chosen to avoid measuring the confounding effect of navigational skills. The magnifier provided 1.7× magnification and the large print provided 1.8× magnification. Performance measures: [1] NVA without magnification at 40 cm, [2] near vision with magnification, and [3] response time. Working distance was monitored. RESULTS: There was no difference in performance between the two types of magnification for the 4-6 year olds and the 7-8 year olds (p's = .291 and .246, respectively). Average NVA in the 4-6 year old group was 0.95 logMAR without and 0.42 logMAR with magnification (p < .001). Average NVA in the 7-8 year was 0.71 logMAR without and 0.01 logMAR with magnification (p < .001). Stronger crowding effects predicted larger improvements of near vision with magnification (p = .021). CONCLUSIONS: A magnifier is equally effective as large print in improving the performance of young children with a range of visual acuities on a crowded near vision task. Visually impaired children with stronger crowding effects showed larger improvements when working with magnification.

A systematic review on 'Foveal Crowding' in visually impaired children and perceptual learning as a method to reduce Crowding.

BACKGROUND: This systematic review gives an overview of foveal crowding (the inability to recognize objects due to surrounding nearby contours in foveal vision) and possible interventions. Foveal crowding can have a major effect on reading rate and deciphering small pieces of information from busy visual scenes. Three specific groups experience more foveal crowding than adults with normal vision (NV): 1) children with NV, 2) visually impaired (VI) children and adults and 3) children with cerebral visual impairment (CVI). The extent and magnitude of foveal crowding as well as interventions aimed at reducing crowding were investigated in this review. The twofold goal of this review is : [A] to compare foveal crowding in children with NV, VI children and adults and CVI children and [B] to compare interventions to reduce crowding. METHODS: Three electronic databases were used to conduct the literature search: PubMed, PsycINFO (Ovid), and Cochrane. Additional studies were identified by contacting experts. Search terms included visual perception, contour interaction, crowding, crowded, and contour interactions. RESULTS: Children with normal vision show an extent of contour interaction over an area 1.5-3× as large as that seen in adults NV. The magnitude of contour interaction normally ranges between 1-2 lines on an acuity chart and this magnitude is even larger when stimuli are arranged in a circular configuration. Adults with congenital nystagmus (CN) show interaction areas that are 2× larger than those seen adults with NV. The magnitude of the crowding effect is also 2× as large in individuals with CN as in individuals with NV. Finally, children with CVI experience a magnitude of the crowding effect that is 3× the size of that experienced by adults with NV. CONCLUSIONS: The methodological heterogeneity, the diversity in paradigms used to measure crowding, made it impossible to conduct a meta-analysis. This is the first systematic review to compare crowding ratios and it shows that charts with 50% interoptotype spacing were most sensitive to capture crowding effects. The groups that showed the largest crowding effects were individuals with CN, VI adults with central scotomas and children with CVI. Perceptual Learning seems to be a promising technique to reduce excessive foveal crowding effects.

The speed acuity test as a diagnostic aid in cerebral visual impairment.

One of the characteristics of children with cerebral visual impairments (CVI) is that they need more time to process visual information. However, currently, few tests are available that can reliably measure visual processing speed. The speed acuity test, a discrimination reaction-time test in which participants indicate the orientation of Landolt-C symbols as quickly and accurately as possible, was specifically developed to determine the time a child needs to discern visual details. The test measures both the accuracy and the latency of the responses for nine different optotype sizes in order to control for decreased visual acuity. The results show that children with CVI need significantly more time to respond to the largest optotype sizes than age-matched normally sighted children and children with visual impairments due to an ocular disorder (VIo). This effect is independent of the time it takes to make a motor response. However, the reaction-time difference between the children with CVI and VIo is not seen for optotype sizes at the acuity threshold. Together with reaction times on visual and auditory detection tasks as controls, reaction times measured in the speed-acuity test allow for acceptable discrimination (AUC in ROC analysis: 0.81) between CVI and VIo.

Differences between children with Down syndrome and typically developing children in adaptive behaviour, executive functions and visual acuity.

In children with Down syndrome (DS) development of visual, motor and cognitive functions is atypical. It is unknown whether the visual impairments in children with DS aggravate their lag in cognitive development. Visual impairment and developmental lags in adaptive behaviour and executive functions were assessed in 104 children with DS, 2-16 years, by comparing their adaptive behaviour, executive functions and visual acuity (distant and near) scores against published age-matched norm scores of typically developing children. Associations between these lags were explored. Mean (± SEM) differences to age-matched norms indicated reduced performance in DS: Vineland Screener questionnaire, - 63 ± 3.8 months; task-based Minnesota Executive Function Scale (MEFS), - 46.09 ± 2.07 points; BRIEF-P questionnaire, 25.29 ± 4.66 points; BRIEF parents' and teachers' questionnaire, 17.89 ± 3.92 points and 40.10 ± 3.81 points; distant and near visual acuity, 0.51 ± 0.03 LogMAR and 0.63 ± 0.03 LogMAR (near - 0.11 ± 0.04 LogMAR poorer than distant). Adaptive behaviour (Vineland-S) correlated with the severity of visual impairment (r = - 0.396). Children with DS are severely impaired in adaptive behaviour, executive functions and visual acuities (near visual acuity more severely impaired than distant visual acuity). Larger impairment in adaptive behaviour is found in children with larger visual impairment. This supports the idea that visual acuity plays a role in adaptive development.

One-year effects of bifocal and unifocal glasses on executive functions in children with Down syndrome in a randomized controlled trial.

Appropriate glasses can improve visual functioning of children with Down syndrome (DS), but it is unknown if such interventions influence their cognitive impairments. In a randomized controlled trial with 1-year follow-up. Children with DS (2-16 years) were provided either bifocal glasses (add +2.5 Dioptres; n = 50) or unifocal glasses (n = 52). Executive functions were assessed pre- and post-intervention with the task-based Minnesota Executive Function Scale (MEFS) and with questionnaires, BRIEF-P and BRIEF, parents' and teachers' version. Intervention effects and associations between executive functions, (near) vision and ocular alignment were analysed. Intervention improved MEFS-Total-scores in the bifocal group (p = 0.002; Cohen's d = 0.60) but not in the unifocal group (p = 0.191; Cohen's d = 0.24). Post-intervention, there was no intergroup difference (p = 0.120; Cohen's d = 0.34). Post-intervention, higher MEFS-scores were associated with better visual acuities (crowded near p = 0.025; uncrowded near p = 0.019; distant p = 0.045). Pre-post changes in MEFS-scores correlated significantly with improved ocular alignment (p = 0.040). Exploratory analysis of the questionnaires showed improved teacher-rated BRIEF-scores in both groups (bifocals: p = 0.014, Cohen's d = 1.91; unifocals: p = 0.022, Cohen's d = 1.46), with no intergroup difference (p = 0.594; Cohen's d = 0.23). These results demonstrate positive effects of wearing better-correcting glasses on executive functioning in children with DS, suggesting a link between their visual and executive functioning. However, the relative contributions of distant and near vision need further study.

Visual fixations rather than saccades dominate the developmental eye movement test.

When children have visual and/or oculomotor deficits, early diagnosis is critical for rehabilitation. The developmental eye movement (DEM) test is a visual-verbal number naming test that aims to measure oculomotor dysfunction in children by comparing scores on a horizontal and vertical subtest. However, empirical comparison of oculomotor behavior during the two subtests is missing. Here, we measured eye movements of healthy children while they performed a digital version of the DEM. In addition, we measured visual processing speed using the Speed Acuity test. We found that parameters of saccade behavior, such as the number, amplitude, and direction of saccades, correlated with performance on the horizontal, but not the vertical subtest. However, the time spent on making saccades was very short compared to the time spent on number fixations and the total time needed for either subtest. Fixation durations correlated positively with performance on both subtests and co-varied tightly with visual processing speed. Accordingly, horizontal and vertical DEM scores showed a strong positive correlation with visual processing speed. We therefore conclude that the DEM is not suitable to measure saccade behavior, but can be a useful indicator of visual-verbal naming skills, visual processing speed, and other cognitive factors of clinical relevance.

The Developmental Eye Movement Test as a Diagnostic Aid in Cerebral Visual Impairment.

The symptoms that characterize children with cerebral visual impairments (CVI) are diverse, ranging from extensive behavioral or physical disabilities to subtle changes that can easily be missed. A correct diagnosis of CVI is therefore difficult to make, but having a wide variety of tests available can be helpful. This study aims to determine if the developmental eye movement test (DEM) can be one of those tests. In this test, a fixed set of numbers has to be read aloud, first in vertical columns and then in horizontal lines. In order to measure differences between children with CVI compared to normally sighted age-matched controls and children with a visual impairment (VI), we determined DEM times, crowding intensities and the reaction time to a large visual stimulus for all three groups. We found that children with CVI or VI need significantly more time to read the DEM numbers than age-matched controls. Additionally, children with CVI need more time than children with VI to read the horizontal DEM, but not the vertical DEM. We also found a significant difference between the children with CVI and the other two groups in the relationship between horizontal DEM performance and crowding intensity. However, for the relationship between DEM performance and visual detection time, no group-differences were found. We conclude that the DEM can be a useful addition in the diagnosis of CVI, especially in combination with information about crowding.

Overview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP.

Wnt signaling is a crucial component of the cell machinery orchestrating a series of physiological processes such as cell survival, proliferation, and migration. Among the plethora of roles that Wnt signaling plays, its canonical branch regulates eye organogenesis and angiogenesis. Mutations in the genes encoding the low density lipoprotein receptor protein 5 (LRP5) and frizzled 4 (FZD4), acting as coreceptors for Wnt ligands, cause familial exudative vitreoretinopathy (FEVR). Moreover, mutations in the gene encoding NDP, a ligand for these Wnt receptors, cause Norrie disease and FEVR. Both FEVR and Norrie disease share similar phenotypic characteristics, including abnormal vascularization of the peripheral retina and formation of fibrovascular masses in the eye that can lead to blindness. In this mutation update, we report 21 novel variants for FZD4, LRP5, and NDP, and discuss the putative functional consequences of missense mutations. In addition, we provide a comprehensive overview of all previously published variants in the aforementioned genes and summarize the phenotypic characteristics in mouse models carrying mutations in the orthologous genes. The increasing molecular understanding of Wnt signaling, related to ocular development and blood supply, offers more tools for accurate disease diagnosis that may be important in the development of therapeutic interventions.