Genetic Linkage between CAPN5 and TYR Variants in the Context of Albinism and Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy Absence: A Case Report.

We present a case involving a patient whose clinical phenotype aligns with oculocutaneous albinism (OCA), yet exhibits a complex genotype primarily characterized by variants of unknown significance (VUS). An 11-year-old boy manifested iris hypopigmentation and translucency, pronounced photophobia, diminished visual acuity and stereopsis, nystagmus, reduced pigmentation of the retina, and foveal hypoplasia. Genetic testing was performed. A heterozygous missense VUS CAPN5 c.230A>G, p.(Gln77Arg), a heterozygous missense VUS TYR c.1307G>C, p.(Gly436Ala), and a heterozygous missense variant TYR c.1205G>A, p.(Arg402Gln) which was classified as a risk factor, were identified. We hypothesized that the TYR c.1307G>C, p.(Gly436Ala) variant is in genetic disequilibrium with the TYR c.1205G>A, p.(Arg402Gln) variant leading to deficient expression of melanogenic enzymes in retinal cells, resulting in the manifestation of mild OCA. Additionally, this study represents the case where we did not detect chiasmal misrouting in visual evoked potentials, nor did we observe a shift in the distribution of ganglion cell thickness from a temporal to a central position. Moreover, our patient's case supports the probable benign nature of the CAPN5 c.230A>G, p.(Gln77Arg) variant.

Novel Variant IMPDH1 c.134A>G, p.(Tyr45Cys): Phenotype-Genotype Correlation Revealed Likely Benign Clinical Significance.

Pathogenic variants in IMPDH1 are associated with autosomal dominant retinitis pigmentosa 10 (RP10), and Leber congenital amaurosis 11. This case report of a 13-year-old girl with Down's syndrome and keratoglobus is aimed at linking the novel variant IMPDH1 c.134A>G, p.(Tyr45Cys), a variant of uncertain significance, to a clinical phenotype and to provide grounds for the objective assignment of its benign features. RP10 is characterized by the early onset and rapid progression of ocular symptoms, beginning with nyctalopia in childhood, accompanied by typical RP fundus changes. As evidenced via thorough clinical examination and testing, none of the RP10 characteristics were present in our patient. On the contrary, our patient who was heterozygous for IMPDH1 c.134A>G, p.(Tyr45Cys) showed no signs of peripheral retinal dystrophy, and did not manifest any disease characteristics typical of the IMPDH1 gene mutation. Consequently, we conclude that the variant did not contribute to the phenotype. According to standards and guidelines for the interpretation of sequence variants, IMPDH1 c.134A>G, p.(Tyr45Cys) revealed likely benign features.

The First Homozygote Mutation c.499G>T (Asp167Tyr) in the RPE65 Gene Encoding Retinoid Isomerohydrolase Causing Retinal Dystrophy

RPE65, an abundant membrane-associated protein present in the retinal pigment epithelium (RPE), is a vital retinoid isomerase necessary for regenerating 11-cis-retinaldehyde from all-trans retinol in the visual cycle. In patients with inherited retinal dystrophy (IRD), precise genetic diagnosis is an indispensable approach as it is required to establish eligibility for the genetic treatment of RPE65-associated IRDs. This case report aims to report the specific phenotype−genotype correlation of the first patient with a homozygous missense variant RPE65 c.499G>T, p. (Asp167Tyr). We report a case of a 66-year-old male who demonstrated a unique phenotype manifesting less severe functional vision deterioration in childhood and adolescence, and extensive nummular pigment clusters. The underlying causes of the differences in the typical bone spicule and atypical nummular pigment clumping are unknown, but suggest that the variant itself influenced the rate of photoreceptor death. Functional studies are needed to define whether the substitution of aspartate impairs the folding of the tertiary RPE65 structure only and does not lead to the complete abolishment of chromophore production, thus explaining the less severe phenotype in adolescence.

Retinal Ciliopathy in the Patient with Transplanted Kidney: Case Report.

A review of a rare case of a proven mutation in the RP1 gene (RP1c.2029C>T, p. (ARG677*) in a kidney transplant patient was presented herein. According to his medical history, he had tonsillectomy performed at the age of 20 due to erythrocyturia, and at the age of 32 he was treated for malignant hypertension. The patient had been diagnosed with chronic renal failure at age 56 years. During an eye examination in 2016, retinitis pigmentosa was suspected and the patient was advised to run further tests. After an ophthalmological examination and tests, genetic testing was performed and a mutation in the RP1 gene encoding a family of proteins which are components of microtubules in photoreceptor primary cilia was proven. The literature search found that mutations in the RP1 gene have so far been exclusively associated with a non-syndromic form of retinal degeneration. However, the RP1 protein is expressed in the kidneys, and it remains unclear why the mutation of this gene so far was only specifically related to retinal photoreceptor function and not to arterial hypertension and renal disease. Primary cilia are thought to act as potential mechanosensory fluid-flow receptors in the vascular endothelium and kidney and their dysfunction results in atherosclerotic changes, hypertension, and chronic renal failure.

RPE65 c.353G>A, p.(Arg118Lys): A Novel Point Mutation Associated with Retinitis Pigmentosa and Macular Atrophy

Precise genetic diagnosis in RPE65-mediated retinitis pigmentosa (RP) is necessary to establish eligibility for genetic treatment with voretigene neparvovec: a recombinant adeno-associated viral vector providing a functional RPE65 gene. This case report aims to report a novel RP-related point mutation RPE65 c.353G>A, p.(Arg118Lys), a variant of uncertain significance associated with a severe clinical presentation and the striking phenotypic feature of complete macular atrophy. We report the case of a 40-year-old male with inherited retinal dystrophy, all features typical for the RPE65-associated RP, and marked macular atrophy. Genetic testing identified that the patient was a compound heterozygote in trans form with two heterozygous variants: RPE65 c.499G>T, p.(Asp167Tyr) and RPE65 c.353G>A, p.(Arg118Lys). Furthermore, short-wavelength and near-infrared autofluorescence patterns exhibited deficiencies specific to mutations in the visual cycle genes. To the best of our knowledge, RPE65 c.353G>A, p.(Arg118Lys) is the first described point mutation on this locus, among all other reported insertional mutations, currently classified as likely benign and of uncertain significance. We concluded that this variant contributed to the pathological phenotype, demonstrating its significance clearly to be reclassified as likely pathogenic. This being the case, patients with this specific variant in homozygous or compound heterozygous form would be likely candidates for genetic treatment with voretigene neparvovec.

Macular perfusion normative data acquired with optical coherence tomography angiography in healthy four-year-old Caucasian children.

BACKGROUND: The purpose of this cross-sectional study involving healthy emmetropic four-year-old Caucasian children was to provide a macular perfusion normative database acquired with optical coherence tomography angiography (OCTA). One eye of each examinee underwent OCTA imaging. The following parameters were analyzed using AngioTool Image J software: vessels area (VA), vessels density (VD), total number of junctions (TNJ), junctions density (JD), total vessel length (TVL), average vessel length (AVL), total number of endpoints (TNEP), lacunarity (L), vessel diameter index (VDI), tortuosity (T) and foveal avascular zone (FAZ). Average central macular thickness (CMT) and average central macular volume (CMV) were measured. RESULT: Sixty-two eyes of 62 children of average age 50.4 ± 3.8 months were examined. VA, VD, and T increased from the inner towards the outer layers of the retina. The intermediate capillary plexus had the highest JD and TNEP and narrowest FAZ. Retinal sexual differentiation was supported with higher values of the retinal VA, VDI and TNEP, and chorioretinal VA, VDI and L in males. The choriocapillaris presented with the highest VD, AVL, and T and the lowest L and TNEP. CONCLUSION: The study provides the first detailed normative database of the macular vascular network in the youngest uniform cohort of emmetropic four-year-old children.

Macular perfusion analysed by optical coherence tomography angiography after uncomplicated phacoemulsification: benefits beyond restoring vision.

BACKGROUND: The purpose of the study is to investigate the changes of macular perfusion by OCT-angiography (OCT-A) after uncomplicated phacoemulsification. METHODS: OCT-A was performed before cataract surgery, 1 week, 1 month, and 3 months after surgery recording superficial vascular complex (SVC), nerve fiber layer vascular plexus (NFLVP), superficial vascular plexus (SVP), deep vascular complex (DVC), intermediate capillary plexus (ICP) and deep capillary plexus (DCP), as well as large choroidal blood vessels and choriocapillaris (CC). Explant area (EA), vessels area (VA), vessels percentage area (VPA), total number of junctions (TNJ), junctions density (JD), total vessels length (TVL), average vessels length (AVL), total number of end points (TNEP), and mean lacunarity (ML) throughout all layers were analysed. RESULTS: Significant changes of vascular parameters in 55 eyes of 55 patients mostly reached plateau one week after surgery and remained stable up to 3 m after surgery, occurring in all retinal layers but not in choroid and CC. The greatest increase in VPA (22.79%), TVL (16.71%), AVL (166.71%) and JD (29.49%) was in SVC. On the contrary, the greatest change of ML (- 53.41%) appeared in DVC. CONCLUSIONS: This is the first OCT-A study demonstrating perfusion alterations in macula after phacoemulsification due to functional hyperaemia. We presume the effect is evoked by increased light intensity stimulation of retina after cataract removal. Accordingly, phacoemulsification in elderly population could have advantageous feature in addition to restoring visual acuity.

Central retinal artery and vein occlusion as a complication of persistent hyaloid artery - a case report.

BACKGROUND: In this case report, we present for the first time central retinal artery occlusion (CRAO) and central retinal vein occlusion (CRVO) as a complication of persistent hyaloid artery (PHA). CASE PRESENTATION: In August 2019, a six-year-old male patient manifested right eye (RE) excessive tearing, conjunctival injection and pain. On examination, RE demonstrated light perception and intraocular pressure of 36 mmHg. The diagnoses of neovascular glaucoma, CRVO and CRAO were established as affirmed with fluorescein angiography (FA). PHA was not reported. Extensive work-up and family history were unremarkable. The child was born on term after uncomplicated twin pregnancy. In December 2019, he was referred to our Centre. Transillumination revealed fully dilated, non-reactive RE pupil, clear lens and tubular remnant of HA containing blood cells in its lumen freely rotating in the anterior vitreous. CONCLUSIONS: PHA results from failure of apoptosis during gestation. It can easily be observed during the red reflex screening at neonatal wards. We hypothesized that PHA twisting led to torsion of the residual primordial common bulb, branching off to HA and CRA with CRAO occurring first. The consequential CRVO presumably advanced by venous stasis due to decrease in arterial inflow. Liquid vitreous appears as early as 4 years of age enabling PHA to whirl more freely. Thus, in case of PHA, we advocate FA to be performed and if connection with retinal artery is proven, parents should be informed on the possible devastating complications and prompt surgical treatment should be considered.

Cystoid macular lesions are resistant to topical dorzolamide treatment in enhanced S-cone syndrome child.

PURPOSE: To evaluate whether cystoid macular lesions respond to treatment with dorzolamide 2% drops in the enhanced S-cone syndrome (ESCS) child, as several case reports document favorable efficacy in adults. METHODS: Seven-year-old boy with ESCS and cystoid macular lesions was treated with dorzolamide 2% in both eyes three times a day for a period of 7 months. The efficacy of treatment was analyzed by visual acuity assessment (ETDRS), multifocal electroretinography and SD-OCT central foveal thickness (CFT) measurement. RESULTS: Baseline RE CFT was 540 and 453 µm in the LE, with amplitude of P1-wave density 39.8 and 50.4 nV/deg(2), respectively. Best corrected visual acuity (BCVA) was 0.3 logMAR RE and 0.3 logMAR LE at distance. At 7-month follow-up examination, CFT showed no reduction in thickness (RE 599 µm, LE 521 µm). P1-wave density increased (RE 49.1 nV/deg(2), LE 84.9 nV/deg(2)), with BCVA 0.3 logMAR RE and 0.2 logMAR LE. CONCLUSIONS: To the best of our knowledge, this is the youngest ESCS patient treated with dorzolamide drops and the first report recording that cystoid macular lesions are resistant to topical dorzolamide treatment. Furthermore, these data are in favor of the hypothesis that microcystoid changes in ESCS appear due to defects in cell-to-cell adhesion rather than the disintegration of the retinal barrier. The marked differences in treatment response to carbonic anhydrase inhibitors between the adults and the child here presented suggest that the breakdown of the blood-retinal barrier may play a more important role later in life.

Zagreb Amblyopia Preschool Screening Study: near and distance visual acuity testing increase the diagnostic accuracy of screening for amblyopia.

AIM: To present and evaluate a new screening protocol for amblyopia in preschool children. METHODS: Zagreb Amblyopia Preschool Screening (ZAPS) study protocol performed screening for amblyopia by near and distance visual acuity (VA) testing of 15 648 children aged 48-54 months attending kindergartens in the City of Zagreb County between September 2011 and June 2014 using Lea Symbols in lines test. If VA in either eye was >0.1 logMAR, the child was re-tested, if failed at re-test, the child was referred to comprehensive eye examination at the Eye Clinic. RESULTS: 78.04% of children passed the screening test. Estimated prevalence of amblyopia was 8.08%. Testability, sensitivity, and specificity of the ZAPS study protocol were 99.19%, 100.00%, and 96.68% respectively. CONCLUSION: The ZAPS study used the most discriminative VA test with optotypes in line as they do not underestimate amblyopia. The estimated prevalence of amblyopia was considerably higher than reported elsewhere. To the best of our knowledge, the ZAPS study protocol reached the highest sensitivity and specificity when evaluating diagnostic accuracy of VA tests for screening. The pass level defined at ≤0.1 logMAR for 4-year-old children, using Lea Symbols in lines missed no amblyopia cases, advocating that both near and distance VA testing should be performed when screening for amblyopia.

Unveiling Visual Acuity in 58,712 Four-Year-Olds: Standardized Assessment Defined Normative Visual Acuity Threshold.

The purpose was to define the threshold of normal visual acuity (VA), mean monocular and binocular VA, and interocular difference in the uniform cohort of healthy four-year-old children. All the children were recruited from the Croatian National Registry of Early Amblyopia Detection database. LEA Symbols® inline optotypes were used for VA testing at near and distance, binocularly and monocularly. The pass cut-off level was set to ≤0.1 logMAR. The final sample consisted of 58,712 four-year-old children. In total, 83.78% of the children had unremarkable results, and 16.22% of the children were referred to examination. Of those, 92% of the children were referred due to binocular, and 8% of the children due to monocular causes. The children referred due to binocular causes demonstrated a VA of 0.3 ± 0.24, while the children referred due to monocular causes 0.6 ± 0.21. The ROC curve analysis defined the uniform cut-off value for a normative VA of 0.78. We analyzed the largest uniform cohort of 58,712 children, and have determined normative data for binocular and monocular VA tested with gold standard logMAR chart in four-year-old children. The results presented here established no reasoning to further utilize historical protocols in testing VA in preschool children aged ≥ 4 years.

Genotype-Phenotype Correlation Model for the Spectrum of TYR-Associated Albinism.

We present two children aged 3 and 5 years who share identical TYR genotype, yet exhibit contrasting phenotypic manifestations in terms of eye, skin, and hair coloration. The patients are heterozygous for TYR c.1A>G, p. (Met1?), which is pathogenic, and homozygous for TYR c.1205G>A, p. (Arg402Gln), which is classified as a risk factor. The children manifested diminished visual acuity, nystagmus, and foveal hypoplasia. The first patient presented with hypopigmentation of the skin, hair, and ocular tissues, while the second patient presented with hypopigmentation of the skin, hair, retinal pigment epithelium, and choroid with dark brown irises. Furthermore, the brown-eyed subject presented astigmatic refractive error and both global and local stereopsis capabilities, contrasting with the presentation of hypermetropia, strabismus, and the absence of stereopsis in the blue-eyed individual. Herein, we propose a genotype-phenotype correlation model to elucidate the diverse clinical presentations stemming from biallelic and triallelic pathogenic variants in TYR, establishing a link between the residual tyrosinase activity and resultant phenotypes. According to our proposed model, the severity of TYR variants correlates with distinct albino phenotypes. Our findings propose the potential association between reduced pigmentation levels in ocular tissues and binocular functions, suggesting pigmentation as a possible independent variable influencing the onset of strabismus-an association unreported until now in the existing literature.

Corneal Fourier and Belin-Ambrósio Enhanced Ectasia Analysis in Healthy 4-Year-Old White Children.

PURPOSE: The aim of this study was to provide normative databases of Fourier analysis (FA) and Belin-Ambrósio enhanced ectasia display (BAD) in healthy White 4-year-old emmetropic children. METHODS: FA parameters analyzed were spherical component (SRmin), spherical eccentricity (SEcc), maximal decentration (MD), regular astigmatism at the center (Astigm. C) and periphery (Astigm. P), and irregularity (I). The parameters obtained by BAD included summary indicator BAD D, anterior corneal curvature (K1 and K2, D), maximal keratometry (Kmax, D), maximal Ambrósio relational thinnest (ART max), and pachymetric and BAD indices. RESULTS: Eighty-nine eyes of eighty-nine 4-year-old children were included. The mean values of FA parameters were the following: SRmin 7.77, SEcc 0.600, MD 0.160, Astigm. C 0.070, Astigm. P 0.050, and I 0.019. The mean K1 and K2 in our study group were 42.92 ± 1.29 D and 43.75 ± 1.41 D, with the mean BAD D value 0.42 ± 0.67. The mean PPI min 0.629 ± 0.117, PPI max 1.059 ± 0.155, PPI avg 0.847 ± 0.103, Kmax 44.10 ± 1.39, and median of ART max 515.0 were recorded. No statistically significant differences between male and female sex in any of FA or BAD parameters were found. CONCLUSIONS: This is the first study providing large normative data on FA and BAD in 4-year-old White emmetropic children. We proposed a cutoff D value for early ectasia and clinical keratoconus in 4-year-old children.

Intra- and interobserver reliability of ocular surface analyzer LacryDiag®.

AIM: To invastigate intra- and interobserver reliability of interferometry, tear meniscus height (TMH) measurement and meibography (MBG) of an ocular surface analyzer, LacryDiag (Quantel Medical, France). METHODS: Five consecutive measurements and subsequent analysis of interferometry, TMH, and MBG were recorded by two examiners using the LacryDiag. To assess intra- and interobserver reliability, we used Cohen's kappa for categorical variables (interferometry), or intraclass correlation coefficient for continuous variables (TMH, MBG). RESULTS: Thirty eyes of 30 examinees were included. For both observers, there was excellent intraobserver reliability for MBG (0.955 and 0.970 for observer 1 and 2, respectively). Intraobserver reliability for observer 1 was substantial for interferometry (0.799), and excellent for TMH (0.863). Reliability for observer 2 was moderate for interferometry (0.535) and fair to good for TMH (0.431). Interobserver reliability was poor for interferometry (0.074) and fair to good for TMH (0.680) and MBG (0.414). CONCLUSION: LacryDiag ocular surface analyzer in our study proves to be a reliable noninvasive tool for the evaluation of TMH and MBG. As for interferometry, poor interobserver reliability, fair to good intraobserver reliability for observer 1, and moderate for observer 2, leave room for improvement.

Pathogenicity reclassification of the RPE65 c.1580A>G (p.His527Arg) - a case report.

BACKGROUND: It is of utmost importance to define the molecular diagnosis of patients with retinitis pigmentosa (RP) due to existing targeted therapeutic option: voretigene neparvovec.We provide clinical evidence for pathogenicity reclassification of variants of uncertain significance (VUSs) RPE65 c.1580A>G (p.His527Arg). MATERIALS AND METHODS: A case report of a 10-year-old boy with progressive vision loss. The patient manifested disease highly suggestive of RPE65 retinal dystrophy: nyctalopia, fairly good central vision, severely depressed full-field electroretinography responses and complete loss of peripheral fundus aut ofluorescence. RESULTS: Invitae Inherited Retinal Disorders Panel identified likely pathogenic mutation RPE65 c.499G>T (p.Asp167Tyr) and RPE65 c.1580A>G (p.His527Arg), variant of uncertain significance. Segregation analysis confirmed that these variants are in trans. CONCLUSIONS: We conclude that the variant RPE65 c.1580A>G (p.His527Arg) has contributed to the pathologic phenotype, demonstrating its significance clearly in the case presented, and should be reclassified according to the criteria of evidence as pathogenic. Therefore, patients with this specific variant in homozygous or compound heterozygous form would likely benefit from genetic treatment based on recombinant adeno-associated virus vector, providing a working RPE65 gene to act in place of a mutated RPE65 gene.

Thyroid peroxidase antibodies may induce demyelination and oculomotor neuromyotonia in the absence of thyroid eye disease.

INTRODUCTION: The first report of oculomotor neuromyotonia (ONM) in a child induced by thyroid peroxidase antibodies (anti-TPO) in the absence of thyroid eye disease (TED). CASE: 14-year-old girl complained of left eye (LE) paroxysmal upper lid fluttering and ptosis precipitated by hyperventilation or sustained left gaze. On sustained left gaze, right eye (RE) upper lid retraction and LE upper lid fluttering with ptosis ensued. RESULTS: Diagnostic work-up revealed markedly elevated anti-TPO (> 600 IU/ml) and no TED. Brain MRI was normal with no signs of tortuous vessels presenting focal demyelination. We hypothesized that anti-TPO directly induced demyelination and set the ground for right ONM with ephaptic transmission between neurons supplying right medial rectus and levator muscle. CONCLUSIONS: Plethora of theories try to decode the ONM. TED associated ONM is not reported in children but is the second most common cause of ONM in adults, advocated to be of compressive origin. Conversely, this case holds true for cross talk hypothesis. All extraocular muscles must be tested to determine the triggering one. ONM should not be overlooked due to its positive response to carbamazepine.

The New Face of the Switch Flap in the Reconstruction of a Large Upper Eyelid Defect.

Reconstruction of a large defect after the removal of a massive malignant upper lid tumor is still a challenge in oculoplastic surgery. Our method of choice is Mustardé switch flap. Due to the lack of Mohs micrographic surgery and frozen section technique as well as waiting time of two weeks for histopathological results, we made modifications enabling us to reexcise in case of positive margins: the width of the pedicle of the flap was 7 mm allowing the length of the flap to be increased if needed, the lids were closed with temporary lateral tarsorrhaphy to protect the eye, and the lower lid is finally reconstructed in the second stage of the procedure. In three patients with malignant upper lid tumors, this method of reconstruction proved to be safe and effective with favorable long-term results.

Long-Term Functional Hyperemia after Uncomplicated Phacoemulsification: Benefits beyond Restoring Vision.

The purpose of the study was to investigate the long-term effects of uncomplicated phacoemulsification on macular perfusion using optical coherence tomography angiography (OCTA) in healthy aging subjects. OCTA was performed before phacoemulsification and 1 week, 1 month, 3 months, and 6 months after. Superficial vascular complex (formed of nerve fiber layer vascular plexus and superficial vascular plexus), deep vascular complex (formed of intermediate capillary plexus and deep capillary plexus), as well as choriocapillaris (CC) and large choroidal blood vessels were recorded. Significant changes of vascular parameters in 95 eyes of 95 patients reached plateau 1 week after surgery and remained stable up to 6 months, occurring in all retinal layers but not in choroid and CC. Statistically significant increases in retinal vessels area, vessels percentage area, total number of junctions, junctions density, and total and average vessels length were found, followed by the total number of end points and mean lacunarity decline, proving an increase in blood supply. The study confirmed that uncomplicated phacoemulsification leads to a long-term increase in macular retinal perfusion. The results might ease the decision regarding timing for cataract surgery as long-term perfusion benefits can be achieved. Furthermore, study results provide a normative database of retinal and choroidal vasculature in healthy aging patients.