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Progress in Retinal and Eye Research May 2024Pseudoxanthoma elasticum (PXE) is an autosomal-recessively inherited multisystem disease. Mutations in the ABCC6-gene are causative, coding for a transmembrane... (Review)
Review
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.
PubMed: 38815804
DOI: 10.1016/j.preteyeres.2024.101274 -
European Journal of Ophthalmology May 2024To characterize and monitor choroidal neovascularisation (CNV) secondary to angioid streaks (AS) using multimodal imaging and to compare the results with conventional...
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.
PubMed: 38803209
DOI: 10.1177/11206721241257976 -
Communications Biology May 2024Pseudoxanthoma elasticum (PXE) is a rare disease characterized by ectopic calcification, however, despite the widely spread effect of pro/anti-calcifying systemic...
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).
Topics: Pseudoxanthoma Elasticum; Humans; Elastin; Fibroblasts; Calcinosis; Dermis; Middle Aged; Female; Male; Adult; Cells, Cultured; Extracellular Matrix; Elastic Tissue
PubMed: 38755434
DOI: 10.1038/s42003-024-06283-6 -
Cureus Apr 2024Angioid 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...
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.
PubMed: 38741802
DOI: 10.7759/cureus.58104 -
Mediterranean Journal of Rheumatology Mar 2024Wilson disease is a rare genetic disorder, characterised by excessive deposition of copper in the liver, brain, and other tissues. Penicillamine, a copper-chelating...
INTRODUCTION
Wilson disease is a rare genetic disorder, characterised by excessive deposition of copper in the liver, brain, and other tissues. Penicillamine, a copper-chelating agent, is used in high doses in the treatment of Wilson disease leading to a variety of cutaneous reactions, including hyper-sensitivity reactions, pseudoxanthoma elasticum, elastosis perforans serpiginosa, anetoderma, and cutis laxa (CL). We present a rare case of localised CL induced by penicillamine for Wilson disease, in the absence of elastosis perforans serpiginosa.
CASE DESCRIPTION
A 41-year-old male with Wilson disease treated with long-term high-dose penicillamine was referred to us for a basal cell carcinoma on the scalp. On physical examination, diffusely flaccid and redundant skin on the right side of the neck were observed. Histopathology revealed findings consistent with CL.
CONCLUSION
Long-term treatment with penicillamine for Wilson disease may induce localized CL, possibly by direct inhibition of cross-linkage of collagen fibres.
PubMed: 38736957
DOI: 10.31138/mjr.280223.pil -
International Journal of Ophthalmology 2024Multiple evanescent white dot syndrome (MEWDS) is a rare fundus disease, characterized by acute vision loss and visual field defects. Many previous studies have... (Review)
Review
Multiple evanescent white dot syndrome (MEWDS) is a rare fundus disease, characterized by acute vision loss and visual field defects. Many previous studies have explained the possible pathogenesis and clinical features of primary MEWDS. However, as the number of reported cases increases, secondary MEWDS occurs in other related retinal diseases and injuries, exhibiting some special characteristics. The associated retinal diseases include multifocal choroiditis/punctate inner choroidopathy (MFC/PIC), acute zonal occult outer retinopathy, best vitelliform macular dystrophy, pseudoxanthoma elasticum, and ocular toxoplasmosis. The related retinal injury is laser photocoagulation, surgery, and trauma. Although primary MEWDS often have a self-limiting course, secondary MEWDS may require treatment in some cases, according to the severity of concomitant diseases and complications. Notably, MEWDS secondary to MFC/PIC that is prone to forming choroidal neovascularization and focal choroidal excavation, needs positive treatment with corticosteroids. The possible underlying pathogenesis of secondary MEWDS is the exposure of choroidal antigen after the disruption of Bruch's membrane. The MEWDS-related features in secondary MEWDS are still evanescent under most circumstances. Its prognosis and treatment depend on the severity of complications. Current studies propose that the etiology is associated with immune factors, including viral infection, inflammation in choroid and Bruch's membrane, and antigen exposure caused by retinal and/or choroidal insults. More pathogenic studies should be conducted in the future. Accurate diagnosis for secondary MEWDS could benefit patients in aspects of management and prognosis.
PubMed: 38721509
DOI: 10.18240/ijo.2024.03.23 -
Cureus Mar 2024A 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...
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.
PubMed: 38690509
DOI: 10.7759/cureus.57342 -
Translational Vision Science &... Apr 2024To describe the ocular findings of murine pseudoxanthoma elasticum (PXE) models with ATP-binding cassette subfamily C member 6 (Abcc6) gene knockout.
PURPOSE
To describe the ocular findings of murine pseudoxanthoma elasticum (PXE) models with ATP-binding cassette subfamily C member 6 (Abcc6) gene knockout.
METHODS
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.
RESULTS
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.
DISCUSSION
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.
TRANSLATIONAL RELEVANCE
The Abcc6-/- murine model may be suitable for studying ocular PXE pathophysiology and ectopic calcification and developing effective therapies.
Topics: Animals; Male; Rats; Bruch Membrane; Calcinosis; Disease Models, Animal; Gene Knockout Techniques; Multidrug Resistance-Associated Proteins; Pseudoxanthoma Elasticum
PubMed: 38656313
DOI: 10.1167/tvst.13.4.29 -
American Journal of Ophthalmology Apr 2024To assess the onset, treatment frequency, and visual outcome of anti-vascular endothelial growth factor (anti-VEGF) treatment due to secondary choroidal...
PURPOSE
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).
DESIGN
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, R = 0.318) and with the absence of a BCVA drop at the onset of exudation (P = 0.035, R = 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.
PubMed: 38614195
DOI: 10.1016/j.ajo.2024.03.026 -
Internal Medicine (Tokyo, Japan) Apr 2024
PubMed: 38599872
DOI: 10.2169/internalmedicine.3050-23