Background/Objectives: To assess the frequency, extent, localization and potential progression of optic disc drusen (ODD) and the correlation with the angioid streak (AS) length and retinal atrophy in patients with pseudoxanthoma elasticum (PXE). Methods: This retrospective study included patient data from a dedicated PXE clinic at the Department of Ophthalmology, University of Bonn, Germany (observation period from February 2008 to July 2023). Two readers evaluated the presence, localization, and the extent of the ODD on fundus autofluorescence (FAF) imaging at baseline and the follow-up assessments. Additionally, we measured the length of the longest AS visible at baseline and follow-up and the area of atrophy at baseline, both on FAF. Results: A total of 150 eyes of 75 PXE patients (median age at baseline 51.8 years, IRQ 46.3; 57.5 years, 49 female) underwent retrospective analysis. At baseline, 23 of 75 patients exhibited ODD in a minimum of one eye, resulting in an ODD prevalence of 30.7% in our cohort of PXE patients. Among these, 14 patients showed monocular and 9 binocular ODD that were localized predominantly nasally (46.9%). During the observational period (mean 97.5 ± 44.7 months), only one patient developed de novo ODD in one eye and one other patient showed a progression in the size of the existing ODD. The group of patients with ODD had significantly longer ASs (median 7020 µm, IQR 4604; 9183, vs. AS length without ODD: median 4404 µm, IQR 3512; 5965, p < 0.001). No association with the size of the atrophy was found at baseline (p = 0.27). Conclusions: This study demonstrates a prevalence of ODD of 30.7%. ODD presence is associated with longer ASs (an indicator of the severity and extent of ocular Bruch\'s membrane calcification), suggesting that ODD formation is tightly related to ectopic calcification-possibly secondary to calcification of the lamina cribrosa. Prospective studies investigating the impact of ODD (in conjunction with intraocular pressure) on visual function in PXE warrant consideration.

Pseudoxanthoma elasticum (PXE) is a rare inherited systemic disease responsible for a juvenile peripheral arterial calcification disease. The clinical diagnosis of PXE is only based on a complex multi-organ phenotypic score and/or genetical analysis. Reduced plasma inorganic pyrophosphate concentration [PPi]p has been linked to PXE. In this study, we used a novel and accurate method to measure [PPi]p in one of the largest cohorts of PXE patients, and we reported the valuable contribution of a cutoff value to PXE diagnosis. Plasma samples and clinical records from two French reference centers for PXE (PXE Consultation Center, Angers, and FAVA-MULTI South Competent Center, Nice) were assessed. Plasma PPi were measured in 153 PXE and 46 non-PXE patients. The PPi concentrations in the plasma samples were determined by a new method combining enzymatic and ion chromatography approaches. The best match between the sensitivity and specificity (Youden index) for diagnosing PXE was determined by ROC analysis. [PPi]p were lower in PXE patients (0.92 ± 0.30 µmol/L) than in non-PXE patients (1.61 ± 0.33 µmol/L, p < 0.0001), corresponding to a mean reduction of 43 ± 19% (SD). The PPi cutoff value for diagnosing PXE in all patients was 1.2 µmol/L, with a sensitivity of 83.3% and a specificity of 91.1% (AUC = 0.93), without sex differences. In patients aged <50 years (i.e., the age period for PXE diagnosis), the cutoff PPi was 1.2 µmol/L (sensitivity, specificity, and AUC of 93%, 96%, and 0.97, respectively). The [PPi]p shows high accuracy for diagnosing PXE; thus, quantifying plasma PPi represents the first blood assay for diagnosing PXE.

Pseudoxanthoma elasticum (PXE) is an autosomal-recessively inherited multisystem disease. Mutations in the ABCC6-gene are causative, coding for a transmembrane transporter mainly expressed in hepatocytes, which promotes the efflux of adenosine triphosphate (ATP). This results in low levels of plasma inorganic pyrophosphate (PPi), a critical anti-mineralization factor. The clinical phenotype of PXE is characterized by the effects of elastic fiber calcification in the skin, the cardiovascular system, and the eyes. In the eyes, calcification of Bruch\'s membrane results in clinically visible lesions, including peau d\'orange, angioid streaks, and comet tail lesions. Frequently, patients must be treated for secondary macular neovascularization. No effective therapy is available for treating the cause of PXE, but several promising approaches are emerging. Finding appropriate outcome measures remains a significant challenge for clinical trials in this slowly progressive disease. This review article provides an in-depth summary of the current understanding of PXE and its multi-systemic manifestations. The article offers a detailed overview of the ocular manifestations, including their morphological and functional consequences, as well as potential complications. Lastly, previous and future clinical trials of causative treatments for PXE are discussed.

BACKGROUND: To characterize and monitor choroidal neovascularisation (CNV) secondary to angioid streaks (AS) using multimodal imaging and to compare the results with conventional fluorescein angiography (FA).
METHODS: A total of 11 eyes with CNV secondary to AS were included in this retrospective study. Multimodal morphological and functional assessment, including spectral-domain optical coherence tomography (SD-OCT), spectral-domain optical coherence tomography angiography (SD-OCTA), and fundus autofluorescence (FAF), were used to assess for evidence of CNV activity and compared with conventional FA. Morphological features of CNV were analyzed and treatment was continuously monitored using SD-OCT and SD-OCTA.
RESULTS: Our results showed that SD-OCTA provided reliable results for the detection of secondary CNV in AS that were comparable to conventional FA. With SD-OCTA, a total of 13 CNVs were detected in 11 eyes and analyzed by means of outer retinal choriocapillaris depth (ORCC) segmentation and the corresponding B-scans. Twelve of the 13 CNVs were classified as active and therefore required treatment. For treatment monitoring during intravitreal therapy (IVT), SD-OCTA was found to be a valuable diagnostic tool over a mean follow-up of 76 weeks.
CONCLUSIONS: Our study demonstrates that SD-OCTA can be routinely used to identify ill-defined CNV without dye-based angiography, especially in cases of CNV secondary to AS, where Bruch\'s membrane (BM) defects limit the diagnostic value of FA. Our results showed that non-invasive multimodal imaging facilitates sufficient CNV monitoring and treatment guidance. Further studies are warranted to provide more evidence in this rare retinal disease.

Pseudoxanthoma elasticum (PXE) is a rare disease characterized by ectopic calcification, however, despite the widely spread effect of pro/anti-calcifying systemic factors associated with this genetic metabolic condition, it is not known why elastic fibers in the same patient are mainly fragmented or highly mineralized in clinically unaffected (CUS) and affected (CAS) skin, respectively. Cellular morphology and secretome are investigated in vitro in CUS and CAS fibroblasts. Here we show that, compared to CUS, CAS fibroblasts exhibit: a) differently distributed and organized focal adhesions and stress fibers; b) modified cell-matrix interactions (i.e., collagen gel retraction); c) imbalance between matrix metalloproteinases and tissue inhibitor of metalloproteinases; d) differentially expressed pro- and anti-calcifying proteoglycans and elastic-fibers associated glycoproteins. These data emphasize that in the development of pathologic mineral deposition fibroblasts play an active role altering the stability of elastic fibers and of the extracellular matrix milieu creating a local microenvironment guiding the level of matrix remodeling at an extent that may lead to degradation (in CUS) or to degradation and calcification (in CAS) of the elastic component. In conclusion, this study contributes to a better understanding of the mechanisms of the mineral deposition that can be also associated with several inherited or age-related diseases (e.g., diabetes, atherosclerosis, chronic kidney diseases).

Angioid streaks (AS) are recognized as irregular, linear dehiscences of Bruch\'s membrane, often associated with systemic diseases. We present the case of a 50-year-old woman initially diagnosed with AS during a routine optometric examination. Subsequent ophthalmological evaluation revealed bilateral AS with calcified drusen. Two years post-diagnosis, she developed blurred vision in her right eye due to the choroidal neovascular membrane adjacent to the macular AS. Further evaluation uncovered clinical signs consistent with pseudoxanthoma elasticum (PXE), including characteristic skin lesions. A multidisciplinary approach involving ophthalmology, dermatology, and cardiovascular specialists was initiated. Histopathological confirmation of PXE was obtained through a skin biopsy. PXE, an autosomal recessive disorder characterized by elastin calcification, presents systemic manifestations necessitating comprehensive evaluation and monitoring. This case demonstrates the importance of recognizing ocular complications in PXE and advocates for early multidisciplinary intervention to mitigate potential vision and life-threatening outcomes.

A 42-year-old female with a known case of hypertension for three years, symptoms of metamorphopsia, and decreased vision in both eyes reported to the ophthalmology outpatient department. There was no recorded history of ocular injury or surgery. Several observational techniques, such as fundus inspection, fundus camera photography, and optical coherence tomography (OCT), were utilized to assess the patient. We referred her to the Department of Dermatology for additional assessment because of her symptoms as well as the appearance of her neck\'s skin, which matched \"plucked chicken skin.\" There, the diagnosis of pseudoxanthoma elasticum (PE) was confirmed. She was subsequently scheduled for an intravitreal bevacizumab injection called Avastin, which improved her visual acuity.

UNASSIGNED: To describe the ocular findings of murine pseudoxanthoma elasticum (PXE) models with ATP-binding cassette subfamily C member 6 (Abcc6) gene knockout.
UNASSIGNED: This experiment was conducted in four Abcc6-/- rats and compared with six wild-type Abcc6+/+ control rats. The animals underwent necropsy at 6 months of age. Histological examination of the eyes was performed.
UNASSIGNED: Histological examination of eight eyes from four Abcc6-/- rats revealed multiple nodular foci of calcification in the uvea, sclera, and conjunctiva, focally in perivascular distribution, as well as linear and nodular calcification of Bruch\'s membrane. Calcific foci were not associated with inflammation in the knockout rats. There was no evidence of calcification in control eyes.
UNASSIGNED: The Abcc6-/- rat model shows that PXE can affect multiple ocular tissues beyond the calcification in Bruch\'s membrane noted in human eyes. Nodular calcific foci probably correspond to comet lesions seen in patients with PXE. The presence of ectopic calcium without inflammation distinguishes it from inflammatory calcium deposition in atherosclerosis. Further studies are needed to determine why PXE does not cause inflammatory infiltration.
UNASSIGNED: The Abcc6-/- murine model may be suitable for studying ocular PXE pathophysiology and ectopic calcification and developing effective therapies.

OBJECTIVE: To assess the onset, treatment frequency, and visual outcome of anti-vascular endothelial growth factor (anti-VEGF) treatment due to secondary choroidal neovascularization (CNV) in patients with pseudoxanthoma elasticum (PXE).
METHODS: Retrospective cohort study METHODS: One-hundred six eyes of 53 patients with PXE were analyzed. The assessment of CNV activity relied on hemorrhage visible on funduscopy and intra- / subretinal fluid on optical coherence tomography (OCT), individually defining a shortening or extension of treatment interval. Best-corrected visual acuity (BCVA) at baseline, age at anti-VEGF therapy initiation, and BCVA-drop events at exudation onset (worsening of BCVA of 2 or more lines) were documented. Further, we assessed the number of injections during the first year and the total number of injections, the time to treatment initiation of the fellow eye, and BCVA over time.
RESULTS: During a median observation period of 77 months (IQR 49; 126) patients received a median number of 28.0 anti-VEGF-injections (IQR 9.8; 43.5). Eight patients received no injection (median age at baseline 38.1 years), 11 patients underwent anti-VEGF treatment in one eye (median age 47.2 years) and 34 patients in both eyes (median age 51.8 years). The median age at the first anti-VEGF treatment was 52.80 years (IQR 47.2-57.6). Applying Cox regression models, the median \"survival\" time of fellow eye until treatment initiation was 16.8 months. In the group of bilateral treated patients, the median time difference was 9.6 months (IQR 2.1- 32.4, range 0-122) The median number of injections was 5.5 per eye in the first year of treatment (IQR 3-7) and was associated with the total number of injections in the observation period (2.33, CI 1.22-3.44, P < .001). A better BCVA at the last follow-up visit was associated with a better baseline BCVA (P < .001, R2 = 0.318) and with the absence of a BCVA drop at the onset of exudation (P = 0.035, R2 = 0.339).
CONCLUSIONS: The results of this study indicate that anti-VEGF treatment is required for most PXE patients at a relatively young age. Once treatment in one eye is initiated, the time to fellow eye treatment is relatively short. A BCVA drop before treatment initiation is a risk factor for worse visual outcomes, suggesting that treatment is prudent before exudation affects the central retina. Given the young age of onset and intensive treatment needs, patients with PXE might particularly benefit from longer-acting anti-VEGF therapeutics.

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