Rita Teixeira-Martins

Introduction: Retinitis pigmentosa (RP) is a genetically and phenotypically heterogeneous inherited type of retinal dystrophy in which the RHO gene is frequently implicated. The missense variant NM_000539.3:c.545G>A, p.(Gly182Asp), has been reported in genetic databases as pathogenic, and a recent large cohort identified a single patient carrying this variant with sector RP. However, no detailed intrafamilial phenotypic characterization has been described. This study provides the first such characterization in a Portuguese family. Case Presentation: Four individuals across three generations underwent multimodal ophthalmologic evaluations, including visual acuity, fundus imaging (OCT, FAF), visual field testing, and electrophysiology. Three patients underwent genetic testing, and all carried the heterozygous RHO p.(Gly182Asp) variant. The clinical manifestations ranged from typical RP in three members to sector RP in one, with preferential inferior and nasal retinal involvement. Structural and functional severity increased with age, and all presented with nyctalopia. The oldest patient exhibited advanced degeneration with minimal central vision. This intrafamily phenotypic variability underscores the differential expression of the same genotype. Conclusion: This is the first report linking the RHO p.(Gly182Asp) variant with both typical and sector RP, highlighting intrafamilial heterogeneity. Detailed phenotyping is crucial for genetic counseling and potential inclusion in future gene-based therapies.

Background: ROSAH syndrome (Retinal dystrophy, Optic nerve edema, Splenomegaly, Anhidrosis, and Headache) is a rare autosomal dominant disorder caused by heterozygous missense pathogenic variants in ALPK1 . This gene encodes alpha-kinase 1, a key regulator of the inflammatory NF-κB pathway. Pathogenic variants in ALPK1 are associated with increased NF-κB activation and chronic inflammation. Clinically, ROSAH syndrome presents with early-onset retinal dystrophy and optic nerve edema, alongside systemic inflammatory and non-inflammatory features. Case presentation: We present a 16-year-old female diagnosed with ROSAH syndrome, genetically confirmed. Her clinical course began with subtle abnormalities in her hands by 18 months of age, and by the age of 2 years-old (YO) it was suspected of acquired arthrogryposis and advanced bone age. Around the age of 4YO she was diagnosed with bilateral macular and papillary edema and despite treatment with methotrexate and adalimumab, she continued to experience persistent ocular inflammation and progressive vision loss; hands and feet deformities stopped evolving around age of 6-7YO; at 12YO, due to worsening of macular edema and optic disc swelling, her treatment regimen was modified to include rituximab, which led to modest improvements. Her diagnostic odyssey culminated at 15YO with the identification of the pathogenic variant p.Tyr254Cys in ALPK1 . Recently, tocilizumab, an IL-6 receptor antagonist, was added, resulting in significant reduction in macular edema and optic disc swelling just within one month. However, visual function did not improve due to pre-existing retinal damage. Conclusion: Tocilizumab showed significant anatomical benefit in this ROSAH syndrome patient, suggesting a role for IL-6 in disease pathophysiology. Although vision could not be restored, the response supports the use of targeted biologics in managing ROSAH. Broader clinical studies are needed to confirm efficacy. This case also highlights the importance of including ALPK1 in genetic panels for optic neuropathies, retinal disorders, and unexplained arthropathies to improve diagnosis and treatment strategies.

Background/Objectives: Diabetic retinopathy (DR) is the leading cause of preventable blindness among working-age adults. Early detection through screening programs is essential for managing the condition and preventing visual impairment. In Portugal, the national DR screening program (DR SP) targets diabetic patients, aiming to detect DR at an early stage and refer patients requiring intervention for an ophthalmology appointment. This study aims to assess the effectiveness of the Portuguese DR SP by analyzing patients referred for a hospital appointment following a positive screening result. Methods: An observational retrospective cohort study was conducted at Unidade Local de Saúde de São João (ULS-SJ), including patients referred to a DR SP hospital appointment between January 2020 and December 2023. Data were collected from hospital records upon approval by the Hospital Ethics Committee. Screening and hospital diagnoses were compared for agreement. The Chi-Square test and Cohen’s Kappa were used to assess the association between screening and hospital diagnoses. Results: A total of 1126 patients (2251 retinographies) were analyzed. The median time from screening to hospital consultation was 63 days (Interquartile Range = 39–99), though referral times varied widely within the same classifications (ranging from 8 to 354 days). The most common screening classifications were R2 (pre-proliferative DR, 47.8%) and M1 (maculopathy, 24.6%). In eyes with DR, agreement between screening and hospital diagnoses was highest for R2 (40.1%) and M1 (32.3%), while proliferative DR (R3) showed 30% agreement. The positive predictive value (PPV) of the screening program was 55.9%, with a false positive rate of 44.1%. A statistically significant association between screening and hospital diagnoses was observed (p < 0.001, Chi-Square test), though Cohen’s Kappa values (0.167 Right Eye, 0.157 Left eye) indicated only slight agreement. Conclusions: Our study found that DR SP effectively identifies patients needing ophthalmologic evaluation with moderate diagnostic agreement and a relatively high false positive rate, leading to unnecessary referrals. While this ensures that sight-threatening cases are not missed, improvements in grader training, classification protocols, and Optical Coherence Tomography (OCT) integration could improve results. Strengthening screening adherence and optimizing referral pathways would further improve the program’s impact on early DR detection and management.