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Purpose Defects in MAK, encoding a protein localized to the photoreceptor connecting cilium, have recently been associated with autosomal recessive retinitis pigmentosa ( RP). The aim of this study is to describe our detailed clinical observations in patients with MAK-associated RP, including an assessment of syndromic symptoms frequently observed in ciliopathies. Methods In this international collaborative study, 11 patients carrying nonsense or missense mutations in MAK were clinically evaluated, including extensive assessment of the medical history, slit-lamp biomicroscopy, ophthalmoscopy, kinetic perimetry, electroretinography ( ERG), spectral-domain optical coherence tomography ( SD- OCT), autofluorescence imaging and fundus photography. Additionally, we used a questionnaire to evaluate the presence of syndromic features and tested the olfactory function. Results MAK-associated RP is not associated with syndromic features, not even with subclinical dysfunction of the olfactory apparatus. All patients experienced typical RP symptoms of night blindness followed by visual field constriction. Symptoms initiated between childhood and the age of 43 (mean: 23 years). Although some patients experienced vision loss, the visual acuity remained normal in most patients. ERG and ophthalmoscopy revealed classic RP characteristics, and SD- OCT demonstrated thinning of the overall retina, outer nuclear layer and photoreceptor-pigment epithelium complex. Conclusion Nonsense and missense mutations in MAK give rise to a non-syndromic recessive RP phenotype without apparent extra-ocular features. When compared to other retinal ciliopathies, MAK-associated RP appears to be relatively mild and shows remarkable resemblance to RP1-associated RP, which could be explained by the close functional relation of these proteins. [ABSTRACT FROM AUTHOR]

Purpose: To describe the clinical phenotype in a family with primary open angle glaucoma harboring a p.Gln368X mutation in MYOC. Materials and Methods: We identified a proband with primary open angle glaucoma and the p.Gln368X MYOC mutation. She and her six siblings were examined clinically, including Heidelberg Retina Tomography II, and venous blood samples were screened for other variants in MYOC, WDR36, OPTN, and CYP1B1. Results: Four individuals showed the p.Gln368X MYOC mutation, no other genetic variations were assessed. Two of these four siblings had glaucomatous optic disc changes with corresponding visual field losses and abnormal Heidelberg Retina Tomography results by the Moorfields regression analysis, one had abnormal results by the Moorfields regression analysis but no visual field loss, and one showed no glaucomatous signs or symptoms at all. These findings did not correlate with the age of the affected individuals. Conclusion: In the primary open angle glaucoma family described here, we documented a wide range in clinical symptoms, demonstrating a highly variable penetrance of the MYOC p.Gln368X mutation. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Does Dietary Lutein and Zeaxanthin Increase the Risk of Age Related macular Degeneration?," by H. T. V. Vu, L. Robman, C. A. McCarty and colleagues in the 2006 issue.

Aims: Atherosclerotic plaque hypoxia is detrimental for macrophage function. Prolyl hydroxylases (PHDs) initiate cellular hypoxic responses, possibly influencing macrophage function in plaque hypoxia. Thus, we aimed to elucidate the role of myeloid PHDs in atherosclerosis., Methods and Results: Myeloid-specific PHD knockout (PHDko) mice were obtained via bone marrow transplantation (PHD1ko, PHD3ko) or conditional knockdown through lysozyme M-driven Cre recombinase (PHD2cko). Mice were fed high cholesterol diet for 6-12 weeks to induce atherosclerosis. Aortic root plaque size was significantly augmented 2.6-fold in PHD2cko, and 1.4-fold in PHD3ko compared to controls but was unchanged in PHD1ko mice. Macrophage apoptosis was promoted in PHD2cko and PHD3ko mice in vitro and in vivo, via the hypoxia-inducible factor (HIF) 1α/BNIP3 axis. Bulk and single-cell RNA data of PHD2cko bone marrow-derived macrophages (BMDMs) and plaque macrophages, respectively, showed enhanced HIF1α/BNIP3 signalling, which was validated in vitro by siRNA silencing. Human plaque BNIP3 mRNA was positively associated with plaque necrotic core size, suggesting similar pro-apoptotic effects in human. Furthermore, PHD2cko plaques displayed enhanced fibrosis, while macrophage collagen breakdown by matrix metalloproteinases, collagen production, and proliferation were unaltered. Instead, PHD2cko BMDMs enhanced fibroblast collagen secretion in a paracrine manner. In silico analysis of macrophage-fibroblast communication predicted SPP1 (osteopontin) signalling as regulator, which was corroborated by enhanced plaque SPP1 protein in vivo. Increased SPP1 mRNA expression upon PHD2cko was preferentially observed in foamy plaque macrophages expressing 'triggering receptor expressed on myeloid cells-2' (TREM2hi) evidenced by single-cell RNA, but not in neutrophils. This confirmed enhanced fibrotic signalling by PHD2cko macrophages to fibroblasts, in vitro as well as in vivo., Conclusion: Myeloid PHD2cko and PHD3ko enhanced atherosclerotic plaque growth and macrophage apoptosis, while PHD2cko macrophages further activated collagen secretion by fibroblasts in vitro, likely via paracrine SPP1 signalling through TREM2hi macrophages., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Optical coherence tomography (OCT) is a high-resolution, three-dimensional, noninvasive imaging modality to examine the human retina. Since the introduction of spectral domain (SD-) OCT-the currently most used variant of OCT-previously unknown details of in vivo retinal morphology of a broad variety of pathologies have become visible. This chapter explains the basic principles of the OCT technology, deals with possible pitfalls in OCT examination or analysis, and hints at the use of OCT technology in functional imaging.

Angiogenesis is a critical feature of plaque development in atherosclerosis and might play a key role in both the initiation and later rupture of plaques. The precursory molecular or cellular pro-angiogenic events that initiate plaque growth and that ultimately contribute to plaque instability, however, cannot be detected directly with any current diagnostic modality. This study was designed to investigate the feasibility of ultrasound molecular imaging of endothelial αvβ3 expression in vitro and in vivo using αvβ3-targeted ultrasound contrast agents (UCAs). In the in vitro study, αvβ3 expression was confirmed by immunofluorescence in a murine endothelial cell line and detected using the targeted UCA and ultrasound imaging at 18-MHz transmit frequency. In the in vivo study, expression of endothelial αvβ3 integrin in murine carotid artery vessels and microvessels of the salivary gland was quantified using targeted UCA and high-frequency ultrasound in seven animals. Our results indicated that endothelial αvβ3 expression was significantly higher in the carotid arterial wall containing atherosclerotic lesions than in arterial segments without any lesions. We also found that the salivary gland can be used as an internal positive control for successful binding of targeted UCA to αvβ3 integrin. In conclusion, αvβ3-targeted UCA allows non-invasive assessment of the expression levels of αvβ3 on the vascular endothelium and may provide potential insights into early atherosclerotic plaque detection and treatment monitoring., (Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Prolonged endurance-type exercise is associated with elevated cardiac troponin (cTn) levels in asymptomatic recreational athletes. It is unclear whether exercise-induced cTn release mirrors a physiological or pathological underlying process. The aim of this study was to provide a direct comparison of the release kinetics of high-sensitivity cTnI (hs-cTnI) and T (hs-cTnT) after endurance-type exercise. In addition, the effect of remote ischemic preconditioning (RIPC), a cardioprotective strategy that limits ischemia-reperfusion injury, was investigated in a randomized controlled crossover manner. Twenty-five healthy volunteers completed an outdoor 30-km running trial preceded by RIPC (4 × 5 min 220 mm Hg unilateral occlusion) or control intervention. hs-cTnT, hs-cTnI, and sensitive cTnI (s-cTnI) concentrations were examined before, immediately after, 2 and 5 hours after the trial. The completion of a 30-km run resulted in a significant increase in circulating cTn (time: all p <0.001), with maximum hs-cTnT, hs-cTnI, and s-cTnI levels of 47 ± 27, 69 ± 62, and 82 ± 64 ng/L (mean ± SD), respectively. Maximum hs-cTnT concentrations were measured in 60% of the participants at 2 hours after exercise, compared with maximum hs-cTnI and s-cTnI concentrations at 5 hours in 84% and 80% of the participants. Application of an RIPC stimulus did not reduce exercise-induced cTn release (time × trial: all p >0.5). In conclusion, in contrast to acute myocardial infarction, maximum hs-cTnT levels after exercise precede maximum hs-cTnI levels. Distinct release kinetics of hs-cTnT and hs-cTnI and the absence of an effect of RIPC favors the concept that exercise-induced cTn release may be mechanistically distinct from cTn release in acute myocardial infarction., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Short term dietary nitrate or nitrite supplementation has nitric oxide (NO)-mediated beneficial effects on blood pressure and inflammation and reduces mitochondrial oxygen consumption, possibly preventing hypoxia. As these processes are implicated in atherogenesis, dietary nitrate was hypothesized to prevent plaque initiation, hypoxia and inflammation., Aims: Study prolonged nitrate supplementation on atherogenesis, hypoxia and inflammation in low density lipoprotein receptor knockout mice (LDLr(-/-))., Methods: LDLr(-/-) mice were administered sodium-nitrate or equimolar sodium-chloride in drinking water alongside a western-type diet for 14 weeks to induce atherosclerosis. Plasma nitrate, nitrite and hemoglobin-bound nitric oxide were measured by chemiluminescence and electron parametric resonance, respectively., Results: Plasma nitrate levels were elevated after 14 weeks of nitrate supplementation (NaCl: 40.29 ± 2.985, NaNO3: 78.19 ± 6.837, p < 0.0001). However, prolonged dietary nitrate did not affect systemic inflammation, hematopoiesis, erythropoiesis and plasma cholesterol levels, suggesting no severe side effects. Surprisingly, neither blood pressure, nor atherogenesis were altered. Mechanistically, plasma nitrate and nitrite were elevated after two weeks (NaCl: 1.0 ± 0.2114, NaNO3: 3.977 ± 0.7371, p < 0.0001), but decreased over time (6, 10 and 14 weeks). Plasma nitrite levels even reached baseline levels at 14 weeks (NaCl: 0.7188 ± 0.1072, NaNO3: 0.9723 ± 0.1279 p = 0.12). Also hemoglobin-bound NO levels were unaltered after 14 weeks. This compensation was not due to altered eNOS activity or conversion into peroxynitrite and other RNI, suggesting reduced nitrite formation or enhanced nitrate/nitrite clearance., Conclusion: Prolonged dietary nitrate supplementation resulted in compensation of nitrite and NO levels and did not affect atherogenesis or exert systemic side effects., (Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Objective: Angiopoietin-2 (Ang-2) blocking agents are currently undergoing clinical trials for use in cancer treatment. Ang-2 has also been associated with rupture-prone atherosclerotic plaques in humans, suggesting a role for Ang-2 in plaque stability. Despite the availability of Ang-2 blocking agents, their clinical use is still lacking. Our aim was to establish if Ang-2 has a role in atheroma development and in the transition of subclinical to clinically relevant atherosclerosis. We investigated the effect of antibody-mediated Ang-2 blockage on atherogenesis after in a mouse model of atherosclerosis., Methods: Hypercholesterolemic (low-density lipoprotein receptor(-/-) apolipoprotein B(100/100)) mice were subjected to high-cholesterol diet for eight weeks, one group with and one group without Ang-2 blocking antibody treatment during weeks 4-8.To enhance plaque development, a peri-adventitial collar was placed around the carotid arteries at the start of antibody treatment. Aortic root, carotid arteries and brachiocephalic arteries were analyzed to evaluate the effect of Ang-2 blockage on atherosclerotic plaque size and stable plaque characteristics., Results: Anti-Ang-2 treatment reduced the size of fatty streaks in the brachiocephalic artery (-72%, p < 0.05). In addition, antibody-mediated Ang-2 blockage reduced plasma triglycerides (-27%, p < 0.05). In contrast, Ang-2 blockage did not have any effect on the size or composition (collagen content, macrophage percentage, adventitial microvessel density) of pre-existing plaques in the aortic root or collar-induced plaques in the carotid artery., Conclusions: Ang-2 blockage was beneficial as it decreased fatty streak formation and plasma triglyceride levels, but had no adverse effect on pre-existing atherosclerosis in hypercholesterolemic mice., (Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Purpose: To investigate whether long-term protection from light exposure affects the rate of disease progression in patients with autosomal recessive Stargardt disease (STGD1), measured using fundus autofluorescence imaging., Design: Longitudinal, retrospective, interventional case series., Methods: Five patients with Stargardt disease protected 1 eye from light exposure by applying a black contact lens during waking hours for ≥12 months. Disease progression was followed by performing autofluorescence imaging at semi-regular intervals. Longitudinal changes in autofluorescence were studied by evaluating areas of decreased autofluorescence and areas of increased autofluorescence as a measure of retinal pigment epithelium damage and lipofuscin accumulation, respectively., Results: We observed less progression of decreased autofluorescence in 4 out of 5 light-protected eyes relative to their respective nonprotected eyes. The progression of increased autofluorescence, on the other hand, was highly variable and did not respond consistently to treatment., Conclusions: Areas of decreased autofluorescence may serve as a useful biomarker for measuring the progression of Stargardt disease. The reduced progression of decreased autofluorescence in the light-protected eyes suggests that light deprivation might be beneficial in patients with Stargardt disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: Defects in MAK, encoding a protein localized to the photoreceptor connecting cilium, have recently been associated with autosomal recessive retinitis pigmentosa (RP). The aim of this study is to describe our detailed clinical observations in patients with MAK-associated RP, including an assessment of syndromic symptoms frequently observed in ciliopathies., Methods: In this international collaborative study, 11 patients carrying nonsense or missense mutations in MAK were clinically evaluated, including extensive assessment of the medical history, slit-lamp biomicroscopy, ophthalmoscopy, kinetic perimetry, electroretinography (ERG), spectral-domain optical coherence tomography (SD-OCT), autofluorescence imaging and fundus photography. Additionally, we used a questionnaire to evaluate the presence of syndromic features and tested the olfactory function., Results: MAK-associated RP is not associated with syndromic features, not even with subclinical dysfunction of the olfactory apparatus. All patients experienced typical RP symptoms of night blindness followed by visual field constriction. Symptoms initiated between childhood and the age of 43 (mean: 23 years). Although some patients experienced vision loss, the visual acuity remained normal in most patients. ERG and ophthalmoscopy revealed classic RP characteristics, and SD-OCT demonstrated thinning of the overall retina, outer nuclear layer and photoreceptor-pigment epithelium complex., Conclusion: Nonsense and missense mutations in MAK give rise to a non-syndromic recessive RP phenotype without apparent extra-ocular features. When compared to other retinal ciliopathies, MAK-associated RP appears to be relatively mild and shows remarkable resemblance to RP1-associated RP, which could be explained by the close functional relation of these proteins., (© 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: To examine human performance and agreement on reticular pseudodrusen (RPD) detection and quantification by using single- and multimodality grading protocols and to describe and evaluate a machine learning system for the automatic detection and quantification of reticular pseudodrusen by using single- and multimodality information., Methods: Color fundus, fundus autofluoresence, and near-infrared images of 278 eyes from 230 patients with or without presence of RPD were used in this study. All eyes were scored for presence of RPD during single- and multimodality setups by two experienced observers and a developed machine learning system. Furthermore, automatic quantification of RPD area was performed by the proposed system and compared with human delineations., Results: Observers obtained a higher performance and better interobserver agreement for RPD detection with multimodality grading, achieving areas under the receiver operating characteristic (ROC) curve of 0.940 and 0.958, and a κ agreement of 0.911. The proposed automatic system achieved an area under the ROC of 0.941 with a multimodality setup. Automatic RPD quantification resulted in an intraclass correlation (ICC) value of 0.704, which was comparable with ICC values obtained between single-modality manual delineations., Conclusions: Observer performance and agreement for RPD identification improved significantly by using a multimodality grading approach. The developed automatic system showed similar performance as observers, and automatic RPD area quantification was in concordance with manual delineations. The proposed automatic system allows for a fast and accurate identification and quantification of RPD, opening the way for efficient quantitative imaging biomarkers in large data set analysis., (Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.)

Background: The purpose of this study is to compare the effects of mitomycin C (MMC) and triamcinolone acetonide (TAC) during and after glaucoma filtering surgery., Methods: Retrospective interventional consecutive case series. All eyes underwent primary guarded trabeculectomy with either MMC or sub-Tenon TAC injection. Intraoperative and postoperative complications up to 5 years after the filtering surgery were evaluated. Differences between the two regimens were tested for statistical significance., Results: A total of 64 trabeculectomies, of which 39 with MMC and 25 with TAC, were compared. At the 5-year follow-up examination three of the eyes treated with MMC (7.7 %) and none of the eyes treated with TAC had an intraocular pressure of more than 18 mmHg (p = 0.08). In the MMC group, three eyes required repeated glaucoma surgery (7.7 %; one trabeculectomy, one Baerveldt drainage implant, one cyclodiode laser treatment), while this was two eyes in the TAC group (8.0 %; one Baerveldt drainage implant, one cyclodiode laser treatment) (p = 0.97)., Conclusion: The present study demonstrates that in primary trabeculectomy, the 5-year risk profiles of MMC and purified TAC are comparable, suggesting that as an antifibrotic agent TAC is at least as effective as MMC. Prospective randomized trials will need to confirm the agents' relative long-term benefits.

This review article gives a state-of-the-art synopsis of current pathophysiological concepts in Sjögren-Larsson syndrome (SLS) mainly based upon original research data of the authors in one of the world's largest clinical SLS study cohorts. Clinical features are discussed in order of appearance, and diagnostic tests are set out to guide the clinician toward the diagnosis SLS. Furthermore, current and future treatment strategies are discussed to render a comprehensive review of the topic.

Purpose: To determine if small hard drusen in patients with basal laminar drusen show short-term changes., Design: Prospective observational case series., Methods: Ten subjects with basal laminar drusen were longitudinally followed during a period of 4 months by spectral-domain optical coherence tomography. Drusen that showed a spontaneous change in volume were further analyzed according to 5 morphologic parameters: shape, reflectivity, homogeneity, and concurring photoreceptor layer/retinal pigment epithelium damage. Odds ratios (OR) and risk for regression and progression of drusen volumes were calculated., Results: One hundred and five small hard drusen in 19 eyes showed a spontaneous change in volume over the period of follow-up. Drusen with a "pointed" shape were significantly associated (P = .031; OR 4.89; 95% confidence interval [CI] 1.16-20.67) with spontaneous progression in drusen volume, with a chance of 0.80 (95% CI 0.55-0.93) to progress. Drusen that showed a decreased reflectivity of overlying photoreceptor layer (P = .041; OR 7.67; 95% CI 1.09-54.24) or retinal pigment epithelium (P = .022; OR 12.38; 95% CI 1.44-106.57), showed a significant association with spontaneous regression in drusen volume, with chances of regression of 0.86 (95% CI 0.41-0.98) and 0.89 (95% CI 0.49-0.99), respectively., Conclusion: Small hard drusen in patients with the basal laminar drusen phenotype are subject to a process of short-term remodeling. The dynamic nature of this disease points to high biochemical activity that may be sensitive to future pharmacologic treatment strategies. In addition, these short-term changes of drusen may be a source of misclassification in disease staging., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Sjögren-Larsson syndrome (SLS), an autosomal recessive hereditary disorder with congenital ichthyosis, spastic diplegia or tetraplegia, and mental retardation, reveals a characteristic macular dystrophy with intraretinal crystals and foveal pseudocysts. Ophthalmic symptoms in SLS are reduced visual acuity and photophobia. This article reports the deficiency of macular pigment as a novel finding in this peculiar, congenital maculopathy., Design: Cross-sectional, observational case study., Participants: Patients with clinically and genetically proven SLS., Methods: Besides general ophthalmologic examination, 2 different methods were used, fundus autofluorescence (FAF) and fundus reflectometry with the macular pigment reflectometer (MPR), for measuring macular pigment (MP)., Main Outcome Measures: Distribution profiles and quantity of MP in eyes of SLS patients., Results: Twenty-eight eyes of 14 patients were included. The technique to measure MP depended on the ability of the mentally handicapped patients to cooperate. Fundus autofluorescence images providing qualitative estimates were obtained from 9 eyes of 5 patients, and MPR measures providing quantitative estimates were obtained from 19 eyes of 10 patients. Fundus autofluorescence images of SLS patients lacked the typical attenuation of macular FAF signal expected in normal eyes. Mean foveal MP levels measured by MPR showed significantly lower values in SLS patients (0.10+/-0.07) than in healthy individuals (0.69+/-0.17; P<0.001, Student t test)., Conclusions: The group of SLS patients studied here had significantly reduced levels of foveal MP. The crystalline macular dystrophy in SLS seems to be the first known disease with a genetically caused deficiency of MP., (Copyright 2010. Published by Elsevier Inc.)

Purpose: To evaluate the clinical characteristics, bacterial culture, and visual outcome of patients with acute endophthalmitis after cataract surgery., Design: Retrospective consecutive interventional case series., Methods: Clinical notes from patients treated for acute endophthalmitis after cataract surgery in a single center from 1996 to 2006 were reviewed. Patients with less than 1 month of follow-up and missing bacterial cultures were excluded. Vitreous biopsy or primary vitrectomy followed by intravitreal injection of vancomycin and ceftazidime (+/- prednisolone) was performed. Main outcome measures were bacterial culture and final visual acuity., Results: Bacterial cultures (total 250 cases) showed bacterial growth in 166 cases (66.4%). From these 166 cultures, 89 (53.6%) revealed gram-positive coagulase-negative, 63 (38.0%) other gram-positive, 10 (6.0%) gram-negative, and 4 (2.4%) polymicrobial cultures. Vitreous biopsy with intravitreal antibiotics injection was performed in 225 (90.0%) of cases. Primary vitrectomy with intravitreal antibiotics was performed in 25 eyes (10.0%). Final visual acuity >/=0.5 was achieved in 129 (51.6%) of all cases, 54 (60.7%) of the 89 gram-positive coagulase-negative cultures, 20 (31.7%) of the 63 other gram-positive cultures, 5 (50.0%) of the 10 gram-negative cultures, and 9 (45.0%) of the 20 Staphylococcus aureus cultures. There was no additional effect for treatment by primary vitrectomy or intravitreal prednisolone., Conclusions: Treatment outcome after endophthalmitis is highly dependent on the causative organism. Treatment outcomes for gram-negative bacteria and S. aureus may be better than previously reported. Prompt treatment of endophthalmitis remains essential and the role of complete primary vitrectomy remains subject to debate., ((c) 2010 Elsevier Inc. All rights reserved.)

Objective: To describe the clinical characteristics, follow-up data and molecular genetic background in a large group of patients with central areolar choroidal dystrophy (CACD)., Design: Retrospective case series study., Participants: One hundred three patients with CACD from the Netherlands., Methods: Ophthalmologic examination, including color vision testing, fundus photography, fluorescein angiography, fundus autofluorescence (FAF) imaging, optical coherence tomography, full-field electroretinography (ERG), multifocal ERG, and electrooculography. Blood samples were obtained for DNA extraction and subsequent analysis of the peripherin/RDS gene, as well as haplotype analysis., Main Outcome Measures: Clinical characteristics, phenotypic range, clinical follow-up data, and FAF findings., Results: The mean age at onset of visual loss was 46 years, with subsequent gradual deterioration in visual acuity. Ninety-eight patients carried a p.Arg142Trp mutation in peripherin/RDS, whereas 5 affected members of a CACD family carried a p.Arg172Gln peripherin/RDS mutation. A remarkable variation in disease severity was observed, and nonpenetrance was seen up to the age of 64 years, in up to 21% of mutation carriers. However, most macular lesions in mutation carriers displayed a typical stage of CACD. Substantial changes were seen on FAF imaging after a mean follow-up period of 11 months. Electrophysiologic data were consistent with a central cone dystrophy. The age at onset and phenotypic characteristics of CACD show considerable overlap with atrophic age-related macular degeneration (AMD). The great majority of p.Arg142Trp-carrying CACD patients originated from the southeast region of the Netherlands, and haplotype analysis strongly suggested a common founder mutation., Conclusions: When caused by a p.Arg142Trp mutation in the peripherin/RDS gene, CACD causes a central cone dystrophy phenotype. This mutation, which most likely originates from a common founder in most patients, is associated with a significant degree of nonpenetrance. In the elderly patient, CACD may be confused with AMD, especially in cases with decreased penetrance.

Purpose: Glaucoma is the second most prevalent cause of blindness worldwide, projected to affect more than 60 million people by 2010, 75% of which represents primary open angle glaucoma (POAG). Of the three genes, namely, Myocilin (MYOC), Optineurin (OPTN), and WD repeat-containing protein 36 (WDR36), which have been shown to cause POAG when defective, MYOC is the most frequently mutated gene, accounting for 3%-4% of all POAG cases. The purpose of this study was identification and functional characterization of MYOC mutations in adult-onset, high-pressure POAG patients from The Netherlands., Methods: The following criteria were required for study participants to be included: have at least two affected family members, an age of diagnosis of more than 35 years, intraocular pressure (IOP) of more than 22 mmHg, glaucomatous optic neuropathy in both eyes, visual field loss consistent with assessed optic neuropathy in at least one eye, and an open anterior chamber angle without morphological abnormalities by gonioscopy. Sequence analysis was performed in genomic DNA of 30 probands for the protein coding region of the MYOC gene. A Chinese hamster ovarian cell line (CHO-K1) was used to express wild type and mutant MYOC protein. Detergent solubility of MYOC was assayed and its secretory property was analyzed by immunoprecipitation., Results: We recruited 250 individuals from 30 families (120 affected and 130 unaffected family members) with a positive history of POAG. We identified a novel mutation c.1288T>C (p.Phe430Leu) in exon 3 of MYOC in two unrelated families showing the same haplotype around the mutant allele. The novel mutation segregated completely with the disease in these families and was absent in 250 ethnically matched controls. All patients harboring this mutation showed severe glaucomatous damage, pointing to the deleterious effect of this mutation. Compared to the wild type, the mutant protein was less soluble when extracted with Triton X-100 and was secretion-defective., Conclusions: The novel MYOC mutation, p.Phe430Leu, has the same origin in both POAG families from The Netherlands. The pathogenic nature of this mutation is suggested by the severe phenotype of mutant patients and mistrafficking of mutant protein as observed for other severe disease-causing mutations of MYOC.