Atypic Retinitis Pigmentosa Clinical Features Associated with a Peculiar CRX Gene Mutation in Italian Patients.

Purpose: To describe an atypical phenotypic pattern of late-onset retinitis pigmentosa (RP) due to the same specific c.425A>G (p.Tyr142Cys) heterozygous mutation in the cone-rod homeobox gene (CRX gene) in two unrelated Italian patients. Case 1: A 67-year-old woman (P.P.) was incidentally diagnosed with sector RP at the age of 50. The patient was initially asymptomatic and did not have any family history of retinal dystrophy. Fundus examination showed the presence of typical retinal pigmentary deposits with a peculiar pericentral/sector distribution. Genomic sequencing disclosed the missense mutation c.425A>G (p.Tyr142Cys) in the CRX gene. During the follow-up period of 7 years, the patient maintained good visual acuity and complained only of mild symptoms. Case 2: A 76-year-old man (P.E.) presented with nyctalopia and visual field constriction since the age of 50. Fundus examination showed the presence of retinal pigment deposits with a concentric pericentral and perimacular pattern. A full-field electroretinogram (ffERG) showed extinguished scotopic responses and reduced abnormal photopic and flicker cone responses. Genomic sequencing identified the same missense mutation, c.425A>G (p.Tyr142Cys), in the CRX gene. Similarly to the first case, during the whole follow-up of 7 years, the visual acuity remained stable, as did the visual field and the patient's symptoms. Conclusions: We report the first cases of late-onset retinitis pigmentosa related to a specific heterozygous CRX gene mutation in exon 4. We also report two atypical phenotypic RP patterns related to mutations in the CRX gene.

RP1 Dominant p.Ser740* Pathogenic Variant in 20 Knowingly Unrelated Families Affected by Rod-Cone Dystrophy: Potential Founder Effect in Western Sicily.

Background and Objectives. Retinitis pigmentosa (RP) is the most common inherited rod-cone dystrophy (RCD), resulting in nyctalopia, progressive visual field, and visual acuity decay in the late stages. The autosomal dominant form (ADRP) accounts for about 20% of RPs. Among the over 30 genes found to date related to ADRP, RP1 pathogenic variants have been identified in 5-10% of cases. In a cohort of RCD patients from the Palermo province on the island of Sicily, we identified a prevalent nonsense variant in RP1, which was associated with ADRP. The objective of our study was to analyse the clinical and molecular data of this patient cohort and to evaluate the potential presence of a founder effect. Materials and Methods. From 2005 to January 2023, 84 probands originating from Western Sicily (Italy) with a diagnosis of RCD or RP and their relatives underwent deep phenotyping, which was performed in various Italian clinical institutions. Molecular characterisation of patients and familial segregation of pathogenic variants were carried out in different laboratories using Sanger and/or next-generation sequencing (NGS). Results. Among 84 probands with RCD/RP, we found 28 heterozygotes for the RP1 variant c.2219C>G, p.Ser740* ((NM_006269.2)*, which was therefore significantly prevalent in this patient cohort. After a careful interview process, we ascertained that some of these patients shared the same pedigree. Therefore, we were ultimately able to define 20 independent family groups with no traceable consanguinity. Lastly, analysis of clinical data showed, in our patients, that the p.Ser740* nonsense variant was often associated with a late-onset and relatively mild phenotype. Conclusions. The high prevalence of the p.Ser740* variant in ADRP patients from Western Sicily suggests the presence of a founder effect, which has useful implications for the molecular diagnosis of RCD in patients coming from this Italian region. This variant can be primarily searched for in RP-affected subjects displaying compatible modes of transmission and phenotypes, with an advantage in terms of the required costs and time for analysis. Moreover, given its high prevalence, the RP1 p.Ser740* variant could represent a potential candidate for the development of therapeutic strategies based on gene editing or translational read-through therapy for suppression of nonsense variants.

Case report: 3D intracranial vessel wall MRI in Susac syndrome: potential relevance for diagnosis and therapeutic management.

Background: Susac syndrome (SS) is a rare immune-mediated vasculitis affecting retina, inner ear and brain. Assessment of central nervous system (CNS) involvement is currently based on standard brain magnetic resonance imaging (MRI) sequences. Accuracy of three dimensional (3D)-vessel wall imaging (VWI) was compared to standard sequences and contrast-enhanced-3D T2-fluid attenuated inversion recovery (CE-FLAIR) to assess CNS disease activity in two cases of definite SS. Methods: Brain MRI scan and retinal fluorescein angiogram (RFA) were performed at disease onset and at 1, 3, and 6 months after induction therapy start. CE-FLAIR and VWI based on 3D black-blood proton density weighted (PDW) with and without gadolinium were added to standard sequences on a 3 Tesla MRI scanner. Results: Contrast enhanced-VWI (CE-VWI) detected an abnormal diffuse leptomeningeal enhancement (LME) in both cases at onset and during follow-up. Pathological enhancement on CE-VWI persisted at 6-month brain MRI, despite absence of new lesions and disappearance of LME on CE-FLAIR. Follow-up RFA revealed new arterial wall hyperfluorescence in both cases. Conclusions: VWI may represent a useful tool for diagnosing and monitoring CNS disease activity in SS patients, as confirmed by concordance with RFA, leading treatment's choice and timing. Moreover, CE-VWI seemed at least as sensitive as CE-FLAIR in detecting LME, possibly being superior to the latter in posterior fossa. LME remission might be not accurate in predicting suppression of CNS inflammation in SS.

Implantation of a Small Aperture Intraocular Lens in Eyes with Irregular Corneas and Higher Order Aberrations.

Purpose: Corneal irregularities can lead to high order aberrations (HOAs) and may influence the outcomes in terms of intraocular lens (IOL) selection and visual acuity assessment. The aim of this study was to evaluate the visual acuity and satisfaction after IC-8 implants in patients characterized by corneal irregularities and HOAs who could not undergo refractive surgery due to the poor residual thickness of the cornea or other conditions such as astigmatism secondary to previous radial keratotomy. Methods: This descriptive, retrospective cohort study was conducted on nine eyes in six patients affected by corneal irregularities and HOAs who had undergone IC-8 IOL implantation. The primary endpoint was the best-corrected visual acuity (BCVA), the subjective visual function, and the visual field. Results: Nine eyes of six patients (three bilateral implantation) were enrolled. For each patient, BCVA, vision, and lifestyle quality were evaluated. In all patients, we noticed an improvement in all parameters without visual field defects. Conclusion: Our work encourages the use of the IC8 lens to improve visual acuity in patients with irregular corneas and HOAs who cannot be treated with customized refractive surgery. Patients experience a subjective improvement of their quality of vision and also more self-confidence in their daily life. IC-8 lenses do not interfere with the visualization of retinal fundus and there is no impairment of the visual field detected by patients.

Efficacy and safety of Ab interno XEN gel implant after a failed filtering surgery.

Purpose: To evaluate the efficacy and safety of Ab interno XEN gel stent in patients with open angle glaucoma who underwent a previous failed filtering surgery. Methods: A retrospective, observational, multi-centered and descriptive cohort study was conducted from January 2019 to February 2020 on patients with primary open angle glaucoma (POAG) who underwent XEN gel stent implant after a failed filtering surgical procedure. Main parameters evaluated were: changes in IOP measured with Goldmann applanation tonometer, number of anti-glaucomatous eye drops, postoperative complications, and necessity of further surgical procedures. The quantification of quality of life was obtained from the VFQ-25 questionnaire. A descriptive analysis based on pre- post- and intra-operative data was carried out. Results: In all patients included in the study (6 patients for a total of 7 eyes), IOP dropped during the follow up time. We found a mean percentage reduction of -41.5% at 9 months compared to the preoperative data (baseline). IOP lowered from 21.71 ± 4.64 mmHg to 9 ± 3,21 mmHg 1 day after the operation, 11 ± 3.21 at 1 week, 11.42 ± 1.81 mmHg at 1 month, 12.42 ± 3.10 mmHg at 3 months, 13.57 ± 3.45 at 6 months, 12.71 ± 1.79 at 9 months. In 71.4%, the procedure turned out to be complication free and only one case required needling of the bleb in order to achieve optimal intraocular pressure control. A total of 71.4% patients reached a medication free regimen with a percentage of reduction in the mean number of drugs needed of -88.9%. Conclusion: In our experience, XEN gel stent implant performed in Caucasian patients with POAG and a history of failed filtrating surgery, showed to be an effective and safe procedure.