Vitreous hyper-reflective dots and the macular thickness after cataract surgery.

PURPOSE: To assess the association between vitreous hyper-reflective dots (VHD) and the macular thickness changes following uneventful phacoemulsification. METHODS: In this prospective cohort study optical coherence tomography (OCT) examinations were performed preoperatively and 1 week, 1 month and 3 months postoperatively in patients undergoing cataract surgery. OCT images were analyzed for retinal central subfield thickness (CST) and preretinal VHDs. Surgeries were recorded for the assessment of lens fragments in the space of Berger. RESULTS: 111 eyes of 97 patient were enrolled of whom 69 (62.2%) were female. VHDs were seen in 25 eyes (22.5%) at week 1; in 21 eyes (18.9%) at month 1 and in 3 eyes (2.7%) at month 3. In all eyes with VHDs retro-capsular lens fragments were visible immediately after phacoemulsification. The number of VHDs significantly decreased over the postoperative period. There was a moderate correlation between the number of VHDs and CST at 1 month (r = 0.426, p<0.001). In eyes with VHD the CST averaged 238.8±17.6 µm (214-266) at 1 week; 276.1±63.5 µm (231-481) at 1 month and 285.1±122.3 µm (227-785) at 3 months. In eyes with no detectable VHDs CST averaged 235.9±23.3 µm (192-311) at 1 week; 240.1±21.6 µm (200-288) at 1 month and 242.2±21.3 µm (205-289) at 3 months. Although the differences among the assessment points were relatively low, there was a significant difference in general (p<0.001, Friedman test). CONCLUSION: In conclusion, VHDs seem to cause macular thickening throughout the postoperative course. The origin of VHDs is still unknown; however, they presumably represent lens fragments that provoke subclinical inflammation.

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.

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.

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.

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.

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.

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.

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.

RPE65 c.393T>A, p.(Asn131Lys): Novel Sequence Variant Detected.

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.