Hypertensive retinopathy and choroidopathy have important short- and long-term implications on patients' overall health and mortality. Eye care professionals should be familiar with the severity ...staging of these entities and be able to readily recognize and refer patients who are in need of systemic blood pressure control. This paper will review the diagnosis, staging, treatment, and long-term implications for vision and mortality of patients with hypertensive retinopathy and choroidopathy.
Retinitis pigmentosa (RP) is a major cause of blindness that affects 1.5 million people worldwide. Mutations in cyclic nucleotide-gated channel β 1 (CNGB1) cause approximately 4% of autosomal ...recessive RP. Gene augmentation therapy shows promise for treating inherited retinal degenerations; however, relevant animal models and biomarkers of progression in patients with RP are needed to assess therapeutic outcomes. Here, we evaluated RP patients with CNGB1 mutations for potential biomarkers of progression and compared human phenotypes with those of mouse and dog models of the disease. Additionally, we used gene augmentation therapy in a CNGβ1-deficient dog model to evaluate potential translation to patients. CNGB1-deficient RP patients and mouse and dog models had a similar phenotype characterized by early loss of rod function and slow rod photoreceptor loss with a secondary decline in cone function. Advanced imaging showed promise for evaluating RP progression in human patients, and gene augmentation using adeno-associated virus vectors robustly sustained the rescue of rod function and preserved retinal structure in the dog model. Together, our results reveal an early loss of rod function in CNGB1-deficient patients and a wide window for therapeutic intervention. Moreover, the identification of potential biomarkers of outcome measures, availability of relevant animal models, and robust functional rescue from gene augmentation therapy support future work to move CNGB1-RP therapies toward clinical trials.
Mitochondrial respiratory chain (RC) disease therapies directed at intra-mitochondrial pathology are largely ineffective. Recognizing that RC dysfunction invokes pronounced extra-mitochondrial ...transcriptional adaptations, particularly involving dysregulated translation, we hypothesized that translational dysregulation is itself contributing to the pathophysiology of RC disease. Here, we investigated the activities, and effects from direct inhibition, of a central translational regulator (mTORC1) and its downstream biological processes in diverse genetic and pharmacological models of RC disease. Our data identify novel mechanisms underlying the cellular pathogenesis of RC dysfunction, including the combined induction of proteotoxic stress, the ER stress response and autophagy. mTORC1 inhibition with rapamycin partially ameliorated renal disease in B6.Pdss2(kd/kd) mice with complexes I-III/II-III deficiencies, improved viability and mitochondrial physiology in gas-1(fc21) nematodes with complex I deficiency, and rescued viability across a variety of RC-inhibited human cells. Even more effective was probucol, a PPAR-activating anti-lipid drug that we show also inhibits mTORC1. However, directly inhibiting mTORC1-regulated downstream activities yielded the most pronounced and sustained benefit. Partial inhibition of translation by cycloheximide, or of autophagy by lithium chloride, rescued viability, preserved cellular respiratory capacity and induced mitochondrial translation and biogenesis. Cycloheximide also ameliorated proteotoxic stress via a uniquely selective reduction of cytosolic protein translation. RNAseq-based transcriptome profiling of treatment effects in gas-1(fc21) mutants provide further evidence that these therapies effectively restored altered translation and autophagy pathways toward that of wild-type animals. Overall, partially inhibiting cytosolic translation and autophagy offer novel treatment strategies to improve health across the diverse array of human diseases whose pathogenesis involves RC dysfunction.
This report highlights a case of irreversible bilateral cicatricial keratoconjunctivitis related to dupilumab therapy for the treatment of severe atopic dermatitis (AD). After 38 years of AD, the ...patient began dupilumab therapy and achieved disease control. Two years into treatment, his ophthalmic examination was significant for bilateral cicatricial keratoconjunctivitis with severe foreshortening of the inferior conjunctival fornices, symblepharon, and ankyloblepharon, which persisted even after topical steroid eye drops and discontinuation of dupilumab. Treating dermatologists should be aware of this potential irreversible adverse effect, and we recommend that patients are monitored for ocular complications while on dupilumab therapy.
Purpose. To report a case of postoperative endophthalmitis after combined cataract extraction and iStent inject implantation. Observation. A 70-year-old male with a nuclear sclerotic cataract and ...primary open-angle glaucoma underwent an uneventful phacoemulsification cataract extraction with implantation of an intraocular lens and an iStent inject trabecular bypass stent. The patient was prescribed a postoperative regimen of ofloxacin 0.3% and prednisolone acetate 1%, 1 drop four times a day each. On postoperative day five, he presented to the emergency room for eye pain and had 4+ mixed cells in the anterior chamber (AC) without hypopyon or vitritis on exam. Prednisolone 1% eye drops were increased from four times a day to every two hours while awake. Overnight, he developed worsening vision and severe eye pain. The next morning, he was found to have increased AC cells, vitritis, and intraretinal hemorrhages and was diagnosed with endophthalmitis. The patient underwent a vitreous tap and intravitreal injections of vancomycin (1 mg/0.1 mL) and amikacin (0.4 mg/0.1 mL). Cultures grew Staphylococcus epidermidis. Lab work-up revealed underlying neutropenia. Visual acuity eventually recovered to 20/20. Conclusion and Importance. This report highlights a case of endophthalmitis associated with placement of the iStent inject. The infection was well-controlled after administration of intravitreal antibiotics without removal of the iStent inject, and visual acuity eventually recovered to 20/20. Surgeons should be aware of endophthalmitis risk following combined iStent inject placement, and good recovery is possible without removal of the implant.
Primary mitochondrial respiratory chain (RC) diseases are heterogeneous in etiology and manifestations but collectively impair cellular energy metabolism. Mechanism(s) by which RC dysfunction causes ...global cellular sequelae are poorly understood. To identify a common cellular response to RC disease, integrated gene, pathway, and systems biology analyses were performed in human primary RC disease skeletal muscle and fibroblast transcriptomes. Significant changes were evident in muscle across diverse RC complex and genetic etiologies that were consistent with prior reports in other primary RC disease models and involved dysregulation of genes involved in RNA processing, protein translation, transport, and degradation, and muscle structure. Global transcriptional and post-transcriptional dysregulation was also found to occur in a highly tissue-specific fashion. In particular, RC disease muscle had decreased transcription of cytosolic ribosomal proteins suggestive of reduced anabolic processes, increased transcription of mitochondrial ribosomal proteins, shorter 5'-UTRs that likely improve translational efficiency, and stabilization of 3'-UTRs containing AU-rich elements. RC disease fibroblasts showed a strikingly similar pattern of global transcriptome dysregulation in a reverse direction. In parallel with these transcriptional effects, RC disease dysregulated the integrated nutrient-sensing signaling network involving FOXO, PPAR, sirtuins, AMPK, and mTORC1, which collectively sense nutrient availability and regulate cellular growth. Altered activities of central nodes in the nutrient-sensing signaling network were validated by phosphokinase immunoblot analysis in RC inhibited cells. Remarkably, treating RC mutant fibroblasts with nicotinic acid to enhance sirtuin and PPAR activity also normalized mTORC1 and AMPK signaling, restored NADH/NAD(+) redox balance, and improved cellular respiratory capacity. These data specifically highlight a common pathogenesis extending across different molecular and biochemical etiologies of individual RC disorders that involves global transcriptome modifications. We further identify the integrated nutrient-sensing signaling network as a common cellular response that mediates, and may be amenable to targeted therapies for, tissue-specific sequelae of primary mitochondrial RC disease.
Uveal melanoma is the most common primary intraocular malignancy and can occur in the choroid, the ciliary body, or the iris. It is most often diagnosed based on clinical examination by an ...ophthalmologist. Nearly all patients present with visual symptoms. Characteristic findings on clinical examination include pigmented or pale choroidal masses with serous retinal detachments and acoustic hollowness seen with ocular ultrasonography. CT and MRI of the orbits are not traditionally utilized for the diagnosis of uveal melanoma. We present 3 cases in which uveal melanoma was an incidental finding on neuroimaging for unrelated conditions in asymptomatic patients. Radiologists should maintain a high suspicion for uveal melanoma when an intraocular mass of greater than 2 mm in thickness is seen on CT or MRI.
Oxidative stress is a known contributing factor in mitochondrial respiratory chain (RC) disease pathogenesis. Yet, no efficient means exists to objectively evaluate the comparative therapeutic ...efficacy or toxicity of different antioxidant compounds empirically used in human RC disease. We postulated that pre-clinical comparative analysis of diverse antioxidant drugs having suggested utility in primary RC disease using animal and cellular models of RC dysfunction may improve understanding of their integrated effects and physiologic mechanisms, and enable prioritization of lead antioxidant molecules to pursue in human clinical trials. Here, lifespan effects of N-acetylcysteine (NAC), vitamin E, vitamin C, coenzyme Q10 (CoQ10), mitochondrial-targeted CoQ10 (MS010), lipoate, and orotate were evaluated as the primary outcome in a well-established, short-lived C. elegans gas-1(fc21) animal model of RC complex I disease. Healthspan effects were interrogated to assess potential reversal of their globally disrupted in vivo mitochondrial physiology, transcriptome profiles, and intermediary metabolic flux. NAC or vitamin E fully rescued, and coenzyme Q, lipoic acid, orotic acid, and vitamin C partially rescued gas-1(fc21) lifespan toward that of wild-type N2 Bristol worms. MS010 and CoQ10 largely reversed biochemical pathway expression changes in gas-1(fc21) worms. While nearly all drugs normalized the upregulated expression of the “cellular antioxidant pathway”, they failed to rescue the mutant worms' increased in vivo mitochondrial oxidant burden. NAC and vitamin E therapeutic efficacy were validated in human fibroblast and/or zebrafish complex I disease models. Remarkably, rotenone-induced zebrafish brain death was preventable partially with NAC and fully with vitamin E. Overall, these pre-clinical model animal data demonstrate that several classical antioxidant drugs do yield significant benefit on viability and survival in primary mitochondrial disease, where their major therapeutic benefit appears to result from targeting global cellular, rather than intramitochondria-specific, oxidative stress. Clinical trials are needed to evaluate whether the two antioxidants, NAC and vitamin E, that show greatest efficacy in translational model animals significantly improve the survival, function, and feeling of human subjects with primary mitochondrial RC disease.
•NAC and vitamin E rescue short lifespan in gas-1(fc21) complex I mutant C. elegans.•Several antioxidants partially rescue lifespan but improve healthspan in gas-1(fc21) worms.•Vitamin E, and partially NAC, prevents brain death in complex I inhibited D. rerio.•NAC improves cell viability in fibroblasts from complex I ND5 disease human subject.•Cellular OXIDATIVE stress is a highly relevant treatment target in mitochondrial disease.
The retina-specific ABCA transporter, ABCA4, plays an essential role in translocating retinoids required by the visual cycle.
genetic variants are known to cause a wide range of inherited retinal ...disorders, including Stargardt disease and cone-rod dystrophy. More than 1,400
missense variants have been identified; however, more than half of these remain variants of uncertain significance (VUS). The purpose of this study was to employ a predictive strategy to assess the pathogenicity of
variants in inherited retinal diseases using protein modeling and computational approaches.
We studied 13 clinically well-defined patients with
retinopathies and identified the presence of 10 missense variants, including one novel variant in the
gene, by next-generation sequencing (NGS). All variants were structurally analyzed using AlphaFold2 models and existing experimental structures of human ABCA4 protein. The results of these analyses were compared with patient clinical presentations to test the effectiveness of the methods employed in predicting variant pathogenicity.
We conducted a phenotype-genotype comparison of 13 genetically and phenotypically well-defined retinal disease patients. The in silico protein structure analyses we employed successfully detected the deleterious effect of missense variants found in this affected patient cohort. Our study provides American College of Medical Genetics and Genomics (ACMG)-defined supporting evidence of the pathogenicity of nine missense
variants, aligning with the observed clinical phenotypes in this cohort.
In this report, we describe a systematic approach to predicting the pathogenicity of
variants by means of three-dimensional (3D) protein modeling and in silico structure analysis. Our results demonstrate concordance between disease severity and structural changes in protein models induced by genetic variations. Furthermore, the present study suggests that in silico protein structure analysis can be used as a predictor of pathogenicity and may facilitate the assessment of genetic VUS.
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