Visual evoked cortical potential can be used to differentiate between uncorrected refractive error and macular disorders

The visual evoked cortical potential (VECP) is widely used to verify complaints of reduced visual performance and to identify the site of the disorder. In this study, we investigated the correlation between reduced visual acuity and VECP in volunteers with normal corrected visual acuity and in patients suffering from inherited macular degeneration or from age related macular degeneration (ARMD). Flash evoked VECP was not affected by the visual acuity in the cases of refractive error and in ARMD patients but was reduced in amplitude and delayed in implicit time in the patients suffering from inherited macular degeneration. The VECP elicited by pattern reversal checkerboard (PVECP) was not affected by the quality of the visual image in volunteers with uncorrected refractive error when checks of 60′ or larger were used but were considerably reduced in size and prolonged in implicit time for checks smaller than 15′. In both groups of patients suffering from macular dysfunction, pattern reversal VECP was very subnormal and was characterized by prolonged implicit time compared to values expected from their visual acuity. These findings indicate that the PVECP does not directly correlate with visual acuity but rather with foveal function. Therefore, we suggest that recordings of PVECP can be used to differentiate between refractive error and macular disorders as causing reduction in visual acuity when other clinical signs are missing or not available.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42621/1/10633_2004_Article_336241.pd

Elastic Deformation of Optical Coherence Tomography Images of Diabetic Macular Edema for Deep-Learning Models Training: How Far to Go?

&#x2013; Objective: To explore the clinical validity of elastic deformation of optical coherence tomography (OCT) images for data augmentation in the development of deep-learning model for detection of diabetic macular edema (DME). Methods: Prospective evaluation of OCT images of DME (n &#x003D; 320) subject to elastic transformation, with the deformation intensity represented by ( $\sigma$ ). Three sets of images, each comprising 100 pairs of scans (100 original &#x0026; 100 modified), were grouped according to the range of ( $\sigma$ ), including low-, medium- and high-degree of augmentation; ( $\sigma$ &#x003D; 1-6), ( $\sigma$ &#x003D; 7-12), and ( $\sigma$ &#x003D; 13-18), respectively. Three retina specialists evaluated all datasets in a blinded manner and designated each image as &#x2019;original&#x2018; versus &#x2019;modified&#x2018;. The rate of assignment of &#x2019;original&#x2018; value to modified images (false-negative) was determined for each grader in each dataset. Results: The false-negative rates ranged between 71-77&#x0025; for the low-, 63-76&#x0025; for the medium-, and 50-75&#x0025; for the high-augmentation categories. The corresponding rates of correct identification of original images ranged between 75-85&#x0025; ( \text{p}> 0.05) in the low-, 73-85&#x0025; ( \text{p}> 0.05 for graders 1 &#x0026; 2, p &#x003D; 0.01 for grader 3) in the medium-, and 81-91&#x0025; ( \text{p} < 0.005 ) in the high-augmentation categories. In the subcategory ( $\sigma$ &#x003D; 7-9) the false-negative rates were 93-83&#x0025;, whereas the rates of correctly identifying original images ranged between 89-99&#x0025; ( \text{p}> 0.05 for all graders). Conclusions: Deformation of low-medium intensity ( $\sigma$ &#x003D; 1-9) may be applied without compromising OCT image representativeness in DME. Clinical and Translational Impact Statement&#x2014;Elastic deformation may efficiently augment the size, robustness, and diversity of training datasets without altering their clinical value, enhancing the development of high-accuracy algorithms for automated interpretation of OCT images

Reduced Electroretinogram Responses in Morphologically Normal Retina in Patients with Primary Hyperoxaluria Type 1

Purpose: To describe ocular findings in individuals with primary hyperoxaluria type 1 (PH1), focusing on the correlations between retinal anatomy and retinal function. To characterize the retinal alterations that occur at different disease stages by evaluating individuals with diverse degrees of renal impairment associated with PH1. Design: A cross-sectional study. Participants: Patients diagnosed with PH1 based on clinical criteria and genetic testing, treated in the Pediatric Nephrology Unit of the Ruth Children’s Hospital, Rambam Health Care Campus, Haifa, Israel between 2013 and 2021. Methods: The ophthalmological assessment included a slit-lamp biomicroscopy of the anterior and posterior segment or indirect ophthalmoscopy. Electroretinography was employed for assessment of the retinal function, and retinal imaging included spectral-domain OCT and fundus autofluorescence. A systematic evaluation of the disease stage was based on clinical criteria including physical examination, purposeful imaging (X-ray, echocardiography, and US abdomen), and laboratory tests as needed. Main Outcome Measures: Anatomical and functional assessment of the retina in patients with PH1, and the relationship between retinal dysfunction and kidney impairment. Results: A total of 16 eyes were examined in the study of 8 children ranging in age from 4 to 19 years. Four eyes (25%) showed normal structural and functional retinal findings, 8 eyes (50%) presented functional impairment in the absence of pathological structural findings, and 4 eyes (25%) had advanced retinal damage that manifested as significant morphological and functional impairment. There was no direct relationship between the severity of the renal disease and the severity of the retinal phenotype. Conclusions: Subjects with PH1 present varying severity levels of the retinal phenotype, with possible discrepancy between the clinical retinal morphology and the retinal function noted on electroretinography. These findings raise questions about the molecular basis of the retinal manifestations in PH1. The presence of functional impairment in the absence of evident crystal deposition in the retina suggests that, in addition to oxalate crystal accumulation, other biomolecular processes may play a role in the development of retinopathy. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article

A novel intronic mutation of PDE6B is a major cause of autosomal recessive retinitis pigmentosa among Caucasus Jews

Purpose: To identify the genetic basis for retinitis pigmentosa (RP) in a cohort of Jewish patients from Caucasia. Methods: Patients underwent a detailed ophthalmic evaluation, including funduscopic examination, visual field testing, optical coherence tomography (OCT), and electrophysiological tests, electroretinography (ERG) and visual evoked potentials (VEP). Genetic analysis was performed with a combination of whole exome sequencing (WES) and Sanger sequencing. Bioinformatic analysis of the WES results was performed via a customized pipeline. Pathogenicity of the identified intronic variant was evaluated in silico using the web tool Human Splicing Finder, and in vitro, using a minigene-based splicing assay. Linkage disequilibrium (LD) analysis was used to demonstrate a founder effect, and the decay of LD over generations around the mutation in Caucasus Jewish chromosomes was modeled to estimate the age of the most recent common ancestor. Results: In eight patients with RP from six unrelated families, all of Caucasus Jewish ancestry, we identified a novel homozygous intronic variant, located at position −9 of PDE6B intron 15. The c.1921–9C>G variant was predicted to generate a novel acceptor splice site, nine bases upstream of the original splice site of intron 15. In vitro splicing assay demonstrated that this novel acceptor splice site is used instead of the wild-type site, leading to an 8-bp insertion into exon 16, which is predicted to cause a frameshift. The presence of a common ancestral haplotype in mutation-bearing chromosomes was compatible with a founder effect. Conclusions: The PDE6B c.1921–9C>G intronic mutation is a founder mutation that accounts for at least 40% (6/15 families) of autosomal recessive RP among Caucasus Jews. This result is highly important for molecular diagnosis, carrier screening, and genetic counseling in this population

Phenotypic Diversity and Mutation Spectrum in Hypotrichosis with Juvenile Macular Dystrophy

Hypotrichosis with juvenile macular dystrophy is a rare autosomal recessive disorder characterized by abnormal growth of scalp hair during infancy, and by the later occurrence of macular degeneration leading to blindness during the first to third decade of life. Hypotrichosis with juvenile macular dystrophy was recently shown to result from mutations in CDH3 encoding P-cadherin. In this study, we assessed 27 individuals, including nine patients, belonging to five families in an attempt to characterize further the CDH3 mutation spectrum and delineate possible phenotype–genotype correlations. Deleterious biallelic mutations, predicted to lead to the translation of a dysfunctional protein, were found in all affected individuals. Four of these mutations are novel. Affected individuals of two large separate apparently unrelated families of Arab Israeli origin were found to carry the same homozygous mis-sense mutation (R503H) in exon 11 of the CDH3 gene. This mutation, which alters a Ca2+-binding site in the fourth extracellular domain of P-cadherin, was previously described in a third unrelated Arab Israeli family. Using haplotype analysis for a series of polymorphic markers encompassing the CDH3 gene, we obtained evidence suggesting a founder effect for R503H in the Arab Israeli population. We also compared the dermatologic and ophthalmologic features of 22 hypotrichosis with juvenile macular dystrophy patients with known recessive mutations in CDH3. Whereas hair paucity and macular degeneration were found in all patients, we noticed significant interfamilial and intrafamilial differences in hair morphology, associated skin findings as well as severity and age of onset of visual disability. Altogether, our results obtained in a series of families of various ethnic origins firmly establish mutations in CDH3 as the proximal cause of hypotrichosis with juvenile macular dystrophy and demonstrate genetic homogeneity as well as phenotypic heterogeneity in this disorder

Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity

Cell adhesion molecules are membrane-bound proteins predominantly expressed in the central nervous system along principal axonal pathways with key roles in nervous system development, neural cell differentiation and migration, axonal growth and guidance, myelination, and synapse formation. Here, we describe ten affected individuals with bi-allelic variants in the neuronal cell adhesion molecule NRCAM that lead to a neurodevelopmental syndrome of varying severity; the individuals are from eight families. This syndrome is characterized by developmental delay/intellectual disability, hypotonia, peripheral neuropathy, and/or spasticity. Computational analyses of NRCAM variants, many of which cluster in the third fibronectin type III (Fn-III) domain, strongly suggest a deleterious effect on NRCAM structure and function, including possible disruption of its interactions with other proteins. These findings are corroborated by previous in vitro studies of murine Nrcam-deficient cells, revealing abnormal neurite outgrowth, synaptogenesis, and formation of nodes of Ranvier on myelinated axons. Our studies on zebrafish nrcama(Delta) mutants lacking the third Fn-III domain revealed that mutant larvae displayed significantly altered swimming behavior compared to wild-type larvae (p < 0.03). Moreover, nrcama(Delta) mutants displayed a trend toward increased amounts of alpha-tubulin fibers in the dorsal telencephalon, demonstrating an alteration in white matter tracts and projections. Taken together, our study provides evidence that NRCAM disruption causes a variable form of a neurodevelopmental disorder and broadens the knowledge on the growing role of the cell adhesion molecule family in the nervous system

Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity

Cell adhesion molecules are membrane-bound proteins predominantly expressed in the central nervous system along principal axonal pathways with key roles in nervous system development, neural cell differentiation and migration, axonal growth and guidance, myelination, and synapse formation. Here, we describe ten affected individuals with bi-allelic variants in the neuronal cell adhesion molecule NRCAM that lead to a neurodevelopmental syndrome of varying severity; the individuals are from eight families. This syndrome is characterized by developmental delay/intellectual disability, hypotonia, peripheral neuropathy, and/or spasticity. Computational analyses of NRCAM variants, many of which cluster in the third fibronectin type III (Fn-III) domain, strongly suggest a deleterious effect on NRCAM structure and function, including possible disruption of its interactions with other proteins. These findings are corroborated by previous in vitro studies of murine Nrcam-deficient cells, revealing abnormal neurite outgrowth, synaptogenesis, and formation of nodes of Ranvier on myelinated axons. Our studies on zebrafish nrcama(Delta) mutants lacking the third Fn-III domain revealed that mutant larvae displayed significantly altered swimming behavior compared to wild-type larvae (p < 0.03). Moreover, nrcama(Delta) mutants displayed a trend toward increased amounts of alpha-tubulin fibers in the dorsal telencephalon, demonstrating an alteration in white matter tracts and projections. Taken together, our study provides evidence that NRCAM disruption causes a variable form of a neurodevelopmental disorder and broadens the knowledge on the growing role of the cell adhesion molecule family in the nervous system