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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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Background: Leber congenital amaurosis (LCA) is a monogenic, but genetically heterogenous disease, and at least 27 genes are implicated. This case report is aimed at providing evidence to link the novel variant RPE65 c.393T>A, p.(Asn131Lys), variant of uncertain significance (VUS), to clinical phenotype and to set the ground for objective assignment of pathogenicity confidence. Case Presentation. A case report of a female patient with LCA who manifested with nystagmus, night blindness, profound visual deficiency, and peripheral involvement of the retina consistent with RPE65 dystrophy. A thorough clinical examination, diagnostic evaluation, and genetic testing were performed. The patient was a compound heterozygote in trans form: RPE65 c.304G>T, p.(Glu102∗) pathogenic, and RPE65 c.393T>A, p.(Asn131Lys), VUS. The latter variant is absent in healthy controls and is considered harmful on in silico prediction. Conclusions: We conclude that RPE65 c.393T>A, p.(Asn131Lys) contributed to the pathologic phenotype, demonstrating its significance clearly in the case presented, and should be reclassified according to the criteria of evidence as likely pathogenic. This being the case, patients with this specific variant are likely candidates for genetic treatment.

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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.

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BACKGROUND: The aim of this study was to evaluate the relationship between changes in proton magnetic resonance spectroscopy (1H-MRS) parameters at the start of the index episode recovery phase and at recurrence in patients with recurrent depression who were treated with prolonged maintenance therapy. METHODS: 1H-MRS parameters were analyzed in 48 patients with recurrent depression who required maintenance therapy with antidepressant medication prescribed by a psychiatrist and who continued with the same antidepressant during the maintenance phase, either to recurrence of depression, completion of the 10-year observation period, or the start of the withdrawal phase (tapering-off antidepressant). N-acetylaspartate (NAA), choline-containing metabolites (Cho), creatine (Cr), and glutamine/glutamate were measured at the start of the recovery phase and 6 months later. RESULTS: Recurrent depressive episodes occurred in 20 patients. These individuals had a smaller increase in Cho/Cr after the beginning of the recovery phase compared to the non-recurrent patient group and also exhibited a decreased NAA/Cr ratio. CONCLUSION: Sustainable NAA and increased Cho levels at the onset of the recovery phase of the index episode are early markers of antidepressant effectiveness associated with a lower risk of major depressive disorder recurrence. The NAA and Cho changes in the non-recurrent group may be attributable to increased brain resilience, contrary to the transient temporal effect observed in subjects who experienced a depressive episode.

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The aim of this paper is to show the psychological consequences of participation in the Homeland War and experienced trauma which can indirectly be seen through drawing even after more than 15 years after the war had ended. The research was conducted on a sample of 125 patients of both genders treated in the Daily Hospital program of University Hospital Dubrava, Psychiatry Clinics. All the tested had trauma in their medical history and all of them met the PTSD diagnostic criteria, 75 examinees participated in the Homeland War and they represent the veteran group, and 50 examinees went through a stressful situation during peacetime and they represent the civilian group. All the examinees had to make two individual drawings, and the task was to portray feelings of term "love" (first drawing) and term "hate" (second drawing). They could choose motifs and colors freely. When portraying the term love, choice of motifs between the civilian and the veteran group wasn't considerably different, and only a small number of male veteran population (6.6%) drawings hinted at the connection with the Homeland War. The results between two groups are completely different in portraying the term hate. As much as 76% examinees from the veteran group have unequivocally and directly decided to portray wartime motifs, unlike the civilian group whose use of wartime motifs was just 10%. When choosing color, nearly 90% of the veteran group used neutral and cool colors to portray the term hate.

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