Pseudoxanthoma elasticum - Genetics, pathophysiology, and clinical presentation.

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.

Bruch's Membrane Calcification in Pseudoxanthoma Elasticum: Comparing Histopathology and Clinical Imaging.

Purpose: To investigate the histology of Bruch's membrane (BM) calcification in pseudoxanthoma elasticum (PXE) and correlate this to clinical retinal imaging. Design: Experimental study with clinicopathological correlation. Subjects and Controls: Six postmortem eyes from 4 PXE patients and 1 comparison eye from an anonymous donor without PXE. One of the eyes had a multimodal clinical image set for comparison. Methods: Calcification was labeled with OsteSense 680RD, a fluorescent dye specific for hydroxyapatite, and visualized with confocal microscopy. Scanning electron microscopy coupled with energy-dispersive x-ray spectroscopy (SEM-EDX) and time-of-flight secondary ion mass spectrometry (TOF-SIMs) were used to analyze the elemental and ionic composition of different anatomical locations. Findings on cadaver tissues were compared with clinical imaging of 1 PXE patient. Main Outcome Measures: The characteristics and topographical distribution of hydroxyapatite in BM in eyes with PXE were compared with the clinical manifestations of the disease. Results: Analyses of whole-mount and sectioned PXE eyes revealed an extensive, confluent OsteoSense labeling in the central and midperipheral BM, transitioning to a speckled labeling in the midperiphery. These areas corresponded to hyperreflective and isoreflective zones on clinical imaging. Scanning electron microscopy coupled with energy-dispersive x-ray spectroscopy and TOF-SIMs analyses identified these calcifications as hydroxyapatite in BM of PXE eyes. The confluent fluorescent appearance originates from heavily calcified fibrous structures of both the collagen and the elastic layers of BM. Calcification was also detected in an aged comparison eye, but this was markedly different from PXE eyes and presented as small snowflake-like deposits in the posterior pole. Conclusions: Pseudoxanthoma elasticum eyes show extensive hydroxyapatite deposition in the inner and outer collagenous and elastic BM layers in the macula with a gradual change toward the midperiphery, which seems to correlate with the clinical phenotype. The snowflake-like calcification in BM of an aged comparison eye differed markedly from the extensive calcification in PXE. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Plasma Level of Pyrophosphate Is Low in Pseudoxanthoma Elasticum Owing to Mutations in the ABCC6 Gene, but It Does Not Correlate with ABCC6 Genotype.

BACKGROUND: Pseudoxanthoma elasticum (PXE), a monogenic disorder resulting in calcification affecting the skin, eyes and peripheral arteries, is caused by mutations in the ABCC6 gene, and is associated with low plasma inorganic pyrophosphate (PPi). It is unknown how ABCC6 genotype affects plasma PPi. METHODS: We studied the association of ABCC6 genotype (192 patients with biallelic pathogenic ABCC6 mutations) and PPi levels, and its association with the severity of arterial and ophthalmological phenotypes. ABCC6 variants were classified as truncating or non-truncating, and three groups of the 192 patients were formed: those with truncating mutations on both chromosomes (n = 121), those with two non-truncating mutations (n = 10), and a group who had one truncating and one non-truncating ABCC6 mutation (n = 61). The hypothesis formulated before this study was that there was a negative association between PPi level and disease severity. RESULTS: Our findings confirm low PPi in PXE compared with healthy controls (0.53 ± 0.15 vs. 1.13 ± 0.29 µM, p < 0.01). The PPi of patients correlated with increasing age (ß: 0.05 µM, 95% CI: 0.03-0.06 per 10 years) and was higher in females (0.55 ± 0.17 vs. 0.51 ± 0.13 µM in males, p = 0.03). However, no association between PPi and PXE phenotypes was found. When adjusted for age and sex, no association between PPi and ABCC6 genotype was found. CONCLUSIONS: Our data suggest that the relationship between ABCC6 mutations and reduced plasma PPi may not be as direct as previously thought. PPi levels varied widely, even in patients with the same ABCC6 mutations, further suggesting a lack of direct correlation between them, even though the ABCC6 protein-mediated pathway is responsible for ~60% of this metabolite in the circulation. We discuss potential factors that may perturb the expected associations between ABCC6 genotype and PPi and between PPi and disease severity. Our findings support the argument that predictions of pathogenicity made on the basis of mutations (or on the structure of the mutated protein) could be misleading.

IS VAGINAL DELIVERY HARMFUL TO PATIENTS WITH PSEUDOXANTHOMA ELASTICUM?

BACKGROUND/PURPOSE: To investigate the effect of a vaginal delivery (VD) on retinal pathology in patients with pseudoxanthoma elasticum. METHODS: Retrospective case series. All 14 consecutive women with pseudoxanthoma elasticum who visited the ophthalmology department during pregnancy and after delivery between 2010 and 2018 were included. Prepartum and postpartum imaging consisted of color imaging, near-infrared imaging, and optical coherence tomography and was assessed on occurrence of (sub)retinal hemorrhages and change in angioid streaks. RESULTS: Fourteen patients (15 deliveries) were included, of whom 11 patients (79%) had a VD and three patients (21%) a secondary caesarian section. Data of three patients with VD (four deliveries) could not be assessed for (sub)retinal hemorrhage within 10 weeks postpartum. The median age at delivery was 31 years (IQR 29-37). One patient with VD (9%) had a choroidal neovascularization and was treated with anti-VEGF injections before assisted delivery. All patients had angioid streaks in the central 5,500 µ m of the posterior pole of both eyes. After delivery, no patient in the VD or caesarian section group presented with progression of angioid streaks or (sub)retinal hemorrhage. CONCLUSION: Pushing during the expulsion phase of VD seems safe in pseudoxanthoma elasticum patients without active choroidal neovascularization, and the presence of angioid streaks alone should not be an indication for elective caesarian section.

Genotype-phenotype correlation in pseudoxanthoma elasticum.

BACKGROUND AND AIMS: Pseudoxanthoma elasticum (PXE) is caused by variants in the ABCC6 gene. It results in calcification in the skin, peripheral arteries and the eyes, but has considerable phenotypic variability. We investigated the association between the ABCC6 genotype and calcification and clinical phenotypes in these different organs. METHODS: ABCC6 sequencing was performed in 289 PXE patients. Genotypes were grouped as two truncating, mixed, or two non-truncating variants. Arterial calcification mass was quantified on whole body, low dose CT scans; and peripheral arterial disease was measured with the ankle brachial index after treadmill test. The presence of pseudoxanthoma in the skin was systematically scored. Ophthalmological phenotypes were the length of angioid streaks as a measure of Bruchs membrane calcification, the presence of choroidal neovascularizations, severity of macular atrophy and visual acuity. Regression models were built to test the age and sex adjusted genotype-phenotype association. RESULTS: 158 patients (median age 51 years) had two truncating variants, 96 (median age 54 years) a mixed genotype, 18 (median age 47 years) had two non-truncating variants. The mixed genotype was associated with lower peripheral (ß: 0.39, 95%CI:-0.62;-0.17) and total (ß: 0.28, 95%CI:-0.47;-0.10) arterial calcification mass scores, and lower prevalence of choroidal neovascularizations (OR: 0.41 95%CI:0.20; 0.83) compared to two truncating variants. No association with pseudoxanthomas was found. CONCLUSIONS: PXE patients with a mixed genotype have less severe arterial and ophthalmological phenotypes than patients with two truncating variants in the ABCC6 gene. Research into environmental and genetic modifiers might provide further insights into the unexplained phenotypic variability.

The Natural History of Bruch's Membrane Calcification in Pseudoxanthoma Elasticum.

Purpose: To describe the natural history of Bruch's membrane (BM) calcification in patients with pseudoxanthoma elasticum (PXE). Design: Retrospective cohort study. Participants: Both eyes of 120 PXE patients younger than 50 years, 78 of whom had follow-up imaging after more than 1 year. Methods: All patients underwent multimodal imaging, including color fundus photography, near-infrared reflectance (NIR) imaging, and late phase indocyanine green angiography (ICGA). We determined the distance from the optic disc to the central and temporal border of peau d'orange on NIR, expressed in horizontal optic disc diameter (ODD). The length of the longest angioid streak was classified into 5 zones. Main Outcome Measures: Age-specific changes of peau d'orange, angioid streaks, and ICGA hypofluorescence as surrogate markers for the extent of BM calcification. Results: In cross-sectional analysis, longer angioid streaks were associated with increasing age (P < 0.001 for trend). The temporal border of peau d'orange showed a weak association with increasing age (ß = 0.02; 95% confidence interval [CI], 0.00-0.04), whereas the central border showed a strong association (ß = 0.12; 95% CI, 0.09-0.15). Longitudinal analysis revealed a median shift of the central border to the periphery of 0.08 ODD per year (interquartile range [IQR], 0.00-0.17; P < 0.001). This shift was more pronounced in patients younger than 20 years (0.12 ODD per year [IQR, 0.08-0.28]) than in patients older than 40 years (0.07 ODD per year [IQR, -0.05 to 0.15]). The temporal border did not shift during follow-up (P = 0.69). New or growing angioid streaks were detected in 39 of 156 eyes (25%). The hypofluorescent area on ICGA was visible only in the fourth or fifth decade and correlated with longer angioid streaks. Conclusions: In PXE patients, the speckled BM calcification slowly confluences during life. The location of the temporal border of peau d'orange remains rather constant, whereas the central border shifts to the periphery. This suggests the presence of a predetermined area for BM calcification. A larger ICGA hypofluorescent area correlates with older age and longer angioid streaks, which implies that it depends on the degree of BM calcification.

The effect of etidronate on choroidal neovascular activity in patients with pseudoxanthoma elasticum.

AIM: To assess the effect of the bisphosphonate etidronate on choroidal neovascular (CNV) activity in patients with pseudoxanthoma elasticum (PXE). METHODS: This is an ancillary study in a single center, randomized, double-blind placebo-controlled trial (RCT) in which 74 patients with PXE were assigned to either one-year etidronate or placebo treatment. Spectral domain optical coherence tomography (SD-OCT) imaging and color fundus photography were performed every three months for one year and were systematically assessed on signs of CNV activity. RESULTS: In the etidronate group, 11 (30%) of the patients had CNV activity at baseline, compared to 25 (67%) of the patients in the placebo group (P = 0.005). The proportion of eyes with CNV activity during the study ranged from 18-33% in the etidronate group and 42-56% in the placebo group and no significant difference in improvement or worsening of CNV activity was found (P = 0.168). Using a generalized mixed model for repeated measures, there was a protective effect of etidronate in crude analysis (RR 0.86, 95% CI 0.75-0.98) that disappeared when adjusting for baseline CNV activity (RR 0.97, 95% CI 0.84-1.13). CONCLUSION: In this post-hoc RCT analysis we did not observe a protecting or deteriorating effect of etidronate on CNV activity in patients with PXE after adjustment for baseline CNV.

A Reflectivity Measure to Quantify Bruch's Membrane Calcification in Patients with Pseudoxanthoma Elasticum Using Optical Coherence Tomography.

Purpose: Progressive calcification of Bruch's membrane (BM) causes considerable visual morbidity in patients with pseudoxanthoma elasticum (PXE). Since calcification is hyperreflective on optical coherence tomography (OCT), our aim was to measure BM calcification with OCT imaging. Methods: Case-control study with 45 patients with PXE under 40 years (range, 11-39) and 25 controls (range, 14-39). Spectralis HRA-OCT imaging consisted of seven macular B-scans with 250-µm spacing. Retinal segmentation was performed with the IOWA Reference Algorithms. MATLAB was used to extract and average z-axis reflectivity profiles. Layer reflectivities were normalized to the ganglion cell and inner plexiform layers. Both median and peak layer reflectivities were compared between patients with PXE and controls. The discriminative value of the retinal pigment epithelium (RPE)-BM peak reflectivity was analyzed using receiver operating characteristic analysis. Results: The reflectivity profile of patients with PXE differed from controls in the outer retinal layers. The normalized median RPE-BM reflectivity was 41.1 (interquartile range [IQR], 26.3-51.9) in patients with PXE, compared with 22.5 (IQR, 19.3-29.5) in controls (P = 2.09 × 10-3). The normalized RPE-BM peak reflectivity was higher in patients with PXE (67.5; IQR, 42.1-84.2) than in controls (32.7; IQR, 25.7-38.9; P = 2.43 × 10-5) and had a high discriminative value with an area under the curve of 0.85 (95% confidence interval, 0.76-0.95). In patients with PXE under 40 years, increasing age did not have a statistically significant effect on the RPE-BM peak reflectivity (patients under 20 years: 44.2 [IQR, 40.5-74.6]; 20-30 years: 66.0 [IQR, 45.1-83.8]; 30-40 years: 70.8 [IQR, 49.0-88.0], P = 0.47). Conclusions: BM calcification can be measured as increased RPE-BM reflectivity in young patients with PXE and has a high discriminative value. Translational Relevance: In patients with PXE, the OCT reflectivity of Bruch's membrane may be the first biomarker for Bruch's membrane calcification and a valuable ophthalmologic endpoint in clinical trials.

The Extent of Angioid Streaks Correlates With Macular Degeneration in Pseudoxanthoma Elasticum.

PURPOSE: To investigate whether the extent of Bruch's membrane calcification is associated with choroidal neovascularization (CNV) and macular atrophy in patients with pseudoxanthoma elasticum (PXE) by using the extent of angioid streaks as a surrogate marker for the degree of Bruch's membrane calcification. DESIGN: Retrospective cross-sectional study. METHODS: We investigated 301 patients with PXE (median age, 52 years; range, 9-79 years) in a tertiary referral center. For both eyes, we graded the extent of angioid streaks, that is, their distance from the optic disc, into 5 groups. Imaging was systematically assessed for signs of CNV and macular atrophy. Associations between the extent of angioid streaks and CNV or macular atrophy were investigated using regression analysis. RESULTS: CNV was present in 148 patients (49%) and retinal atrophy in 71 patients (24%). The extent of angioid streaks was associated with older age (P for trend = 1.92 × 10-15) and a higher prevalence of CNV and/or macular atrophy (P for trend = 4.22 × 10-10 and P for trend = 5.17 × 10-6, respectively). In addition, the extent of angioid streaks was associated with the presence of CNV when adjusted for age and sex (odds ratio, 1.9; 95% confidence interval, 1.3-2.9) and with more severe macular atrophy (proportional odds ratio, 2.3; 95% confidence interval, 1.5-3.6). CONCLUSIONS: In patients with PXE, longer angioid streaks are associated with an increased risk of CNV and macular atrophy, even after adjustment for age. These findings are relevant when counseling PXE patients on their visual prognosis.

Is arterial stiffness in the carotid artery associated with choroidal thinning in patients with pseudoxanthoma elasticum or controls?

PURPOSE: Patients with pseudoxanthoma elasticum (PXE) develop calcification of Bruch's membrane (BM) and choroidal thinning, as well as calcification of intracranial arteries, leading to arterial stiffness. We investigated whether arterial stiffness is associated with choroidal thinning in PXE patients, besides the presumed effect of BM calcification. METHODS: Cross-sectional study with 75 PXE patients and 40 controls. Macular choroidal thickness was measured using optical coherence tomography scans. Functional magnetic resonance imaging was used to calculate the pulsatility index (PI) of the carotid siphon as a measure of arterial stiffness. Associations between PI and choroidal thickness were investigated using linear mixed effects models adjusted for age and ocular axial length. Furthermore, we investigated choroidal thickness in relation to the presence of retinal pigment epithelium (RPE) atrophy, its topographical distribution and age. RESULTS: Median age was 58 years (IQR 53-66) in PXE patients and 62 years (IQR 56-67) in controls (p = 0.08). Pseudoxanthoma elasticum (PXE) patients had a thinner choroid than controls (138 µm versus 248 µm, p < 0.01). No association was observed between PI and choroidal thickness in PXE patients (ß = -1.6, 95% CI -59.4 to 54.5) nor in controls (ß =-47.6, 95% CI -129.7 to 31.9). In PXE patients, RPE atrophy was associated with a thinner choroid (p < 0.01). Also, the nasal choroid was thinner than the temporal choroid, and choroidal thickness already decreased with age in PXE eyes without RPE atrophy. CONCLUSION: There was no independent association between measures of arterial stiffness and choroidal thinning in PXE patients and controls. Probably, changes in BM lead to choroidal thinning in PXE.

Risk of Rhegmatogenous Retinal Detachment in Acute Retinal Necrosis With and Without Prophylactic Intervention.

PURPOSE: To study whether preventive laser or preventive vitrectomy is able to lower the risk of rhegmatogenous retinal detachment (RRD) in patients with acute retinal necrosis (ARN). DESIGN: A retrospective, interventional case series. METHODS: We performed a retrospective study of 59 patients (63 eyes) with ARN treated in a single tertiary referral center. We analyzed different groups with either no prophylaxis, prophylactic laser, or prophylactic vitrectomy. Main outcome measure was incidence of RRD. RESULTS: Overall incidence of RRD was 44.4%, including 13% at presentation. In a crude analysis, the risk of RRD was highest in 33 patients with prophylactic laser (45.5%), lower in 15 patients with no prophylaxis (26.7%), and lowest in 7 patients with prophylactic vitrectomy (14.3%). Baseline best-corrected visual acuity differed between these groups, but zone and percentage of involved retina did not. In a multivariable model including prophylactic laser and ARN severity, only zone was predictive of RRD. CONCLUSION: When correcting for severity of disease, we did not observe a reduction in the risk of RRD by prophylactic laser in eyes with ARN. Therefore, prophylactic laser may be abandoned. The role of prophylactic vitrectomy is still unclear, but deserves further investigation.

VISUAL ACUITY IN PSEUDOXANTHOMA ELASTICUM.

PURPOSE: To assess the age-specific proportion of visual impairment in patients with pseudoxanthoma elasticum (PXE) and to compare this with foveal abnormality and similar data of late age-related macular degeneration patients. METHODS: Cross-sectional data of 195 patients with PXE were reviewed, including best-corrected visual acuity and imaging. The World Health Organisation criteria were used to categorize bilateral visual impairment. These results were compared with similar data of 131 patients with late age-related macular degeneration from the Rotterdam study. RESULTS: Overall, 50 PXE patients (26.0%) were visually impaired, including 21 (11%) with legal blindness. Visual functioning declined with increasing age. In patients older than 50 years, 37% was visually impaired and 15% legally blind. Foveal choroidal neovascularization was found in 84% of eyes with a best-corrected visual acuity lower than 20/70 (0.30) and macular atrophy in the fovea in 16%. In late age-related macular degeneration patients, 40% were visually impaired and 13% legally blind. Visual impairment started approximately 20 years later as compared with PXE patients. CONCLUSION: Visual impairment and blindness are frequent in PXE, particularly in patients older than 50 years. Although choroidal neovascularization is associated with the majority of vision loss, macular atrophy is also common. The proportion of visual impairment in PXE is comparable with late age-related macular degeneration but manifests earlier in life.

Etidronate for Prevention of Ectopic Mineralization in Patients With Pseudoxanthoma Elasticum.

BACKGROUND: In pseudoxanthoma elasticum (PXE), low pyrophosphate levels may cause ectopic mineralization, leading to skin changes, visual impairment, and peripheral arterial disease. OBJECTIVES: The authors hypothesized that etidronate, a pyrophosphate analog, might reduce ectopic mineralization in PXE. METHODS: In the Treatment of Ectopic Mineralization in Pseudoxanthoma Elasticum trial, adults with PXE and leg arterial calcifications (n = 74) were randomly assigned to etidronate or placebo (cyclical 20 mg/kg for 2 weeks every 12 weeks). The primary outcome was ectopic mineralization, quantified with 18fluoride positron emission tomography scans as femoral arterial wall target-to-background ratios (TBRfemoral). Secondary outcomes were computed tomography arterial calcification and ophthalmological changes. Safety outcomes were bone density, serum calcium, and phosphate. RESULTS: During 12 months of follow-up, the TBRfemoral increased 6% (interquartile range [IQR]: -12% to 25%) in the etidronate group and 7% (IQR: -9% to 32%) in the placebo group (p = 0.465). Arterial calcification decreased 4% (IQR: -11% to 7%) in the etidronate group and increased 8% (IQR: -1% to 20%) in the placebo group (p = 0.001). Etidronate treatment was associated with significantly fewer subretinal neovascularization events (1 vs. 9, p = 0.007). Bone density decreased 4% ± 12% in the etidronate group and 6% ± 9% in the placebo group (p = 0.374). Hypocalcemia (<2.20 mmol/l) occurred in 3 versus 1 patient (8.1% vs. 2.7%, p = 0.304). Eighteen patients (48.6%) treated with etidronate, compared with 0 patients treated with placebo (p < 0.001), experienced hyperphosphatemia (>1.5 mmol/l) and recovered spontaneously. CONCLUSIONS: In patients with PXE, etidronate reduced arterial calcification and subretinal neovascularization events but did not lower femoral 18fluoride sodium positron emission tomography activity compared with placebo, without important safety issues. (Treatment of Ectopic Mineralization in Pseudoxanthoma elasticum; NTR5180).