ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions.

Pathological (ectopic) mineralization of soft tissues occurs during aging, in several common conditions such as diabetes, hypercholesterolemia, and renal failure and in certain genetic disorders. Pseudoxanthoma elasticum (PXE), a multi-organ disease affecting dermal, ocular, and cardiovascular tissues, is a model for ectopic mineralization disorders. ABCC6 dysfunction is the primary cause of PXE, but also some cases of generalized arterial calcification of infancy (GACI). ABCC6 deficiency in mice underlies an inducible dystrophic cardiac calcification phenotype (DCC). These calcification diseases are part of a spectrum of mineralization disorders that also includes Calcification of Joints and Arteries (CALJA). Since the identification of ABCC6 as the "PXE gene" and the development of several animal models (mice, rat, and zebrafish), there has been significant progress in our understanding of the molecular genetics, the clinical phenotypes, and pathogenesis of these diseases, which share similarities with more common conditions with abnormal calcification. ABCC6 facilitates the cellular efflux of ATP, which is rapidly converted into inorganic pyrophosphate (PPi) and adenosine by the ectonucleotidases NPP1 and CD73 (NT5E). PPi is a potent endogenous inhibitor of calcification, whereas adenosine indirectly contributes to calcification inhibition by suppressing the synthesis of tissue non-specific alkaline phosphatase (TNAP). At present, therapies only exist to alleviate symptoms for both PXE and GACI; however, extensive studies have resulted in several novel approaches to treating PXE and GACI. This review seeks to summarize the role of ABCC6 in ectopic calcification in PXE and other calcification disorders, and discuss therapeutic strategies targeting various proteins in the pathway (ABCC6, NPP1, and TNAP) and direct inhibition of calcification via supplementation by various compounds.

Generalized Arterial Calcification of Infancy: New Insights, Controversies, and Approach to Management.

PURPOSE OF REVIEW: This review summarizes current understanding of generalized arterial calcification of infancy (GACI), emphasizing pathophysiology, clinical presentation, and approaches and controversies in management. RECENT FINDINGS: Identification of causative ENPP1 mutations revealed that GACI arises from deficiencies in inorganic pyrophosphate (leading to calcifications) and adenosine monophosphate (leading to intimal proliferation). Identification of genotypic and phenotypic overlap with pseudoxanthoma elasticum and autosomal recessive hypophosphatemic rickets further advanced understanding of GACI as a complex, multisystemic disease. Clinical data is limited to small, retrospective samples; it is therefore unknown whether commonly used medications, such as bisphosphonates and hypophosphatemia treatment, are therapeutic or potentially harmful. ENPP1-Fc replacement represents a promising approach warranting further study. Knowledge gaps in natural history place clinicians at high risk of assigning causality to interventions that are correlated with changes in clinical status. There is thus a critical need for improved natural history studies to develop and test targeted therapies.

IMPAIRED DARK ADAPTATION ASSOCIATED WITH A DISEASED BRUCH MEMBRANE IN PSEUDOXANTHOMA ELASTICUM.

PURPOSE: To characterize dark adaptation in patients with pseudoxanthoma elasticum, a systemic disease leading to calcification of elastic tissue including the Bruch membrane. METHODS: In this prospective case-control study, dark adaptation thresholds were measured using a Goldmann-Weekers dark adaptometer. Additional assessments included best-corrected visual acuity testing, contrast sensitivity, low luminance deficit, and vision-related quality of life. RESULTS: Dark adaptation thresholds were significantly higher, and adaptation periods were prolonged in patients with pseudoxanthoma elasticum (n = 35; 33 with 2 ABCC6 mutations) compared with controls (n = 35). The time to adapt 4 log units (20.6 ± 8.6 vs. 8.0 ± 1.3 minutes) and the mean dark adaptation threshold after 15 minutes (3.5 ± 1.1 vs. 1.8 ± 0.2 log units) were significantly different between patients and controls (both P < 0.001). Low luminance deficits (12.3 ± 6.4 vs. 6.1 ± 4.3 ETDRS letters), contrast sensitivity (1.4 ± 0.3 vs. 1.9 ± 0.1), and low luminance-related quality of life (LLQ score: 1,286 ± 355 vs. 2,167 ± 68) were also significantly worse in patients with pseudoxanthoma elasticum (all, P < 0.001). Two patients were treated with high-dose vitamin A which partially reversed impaired dark adaptation. CONCLUSION: Patients with pseudoxanthoma elasticum often have impaired dark adaptation. Positive effects of vitamin A supplementation may indicate restricted retinal access of vitamin A through the Bruch membrane as one possible underlying pathogenic factor.

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.

Retinal imaging including optical coherence tomography angiography for detecting active choroidal neovascularization in pseudoxanthoma elasticum.

IMPORTANCE: The diagnostic accuracy of different retinal imaging modalities to detect active choroidal neovascularization (CNV) in pseudoxanthoma elasticum (PXE) is essential to enable a correct diagnosis but is currently poorly understood. BACKGROUND: Optical coherence tomography (OCT), fluorescein angiography (FA) and OCT angiography (OCT-A) are employed in daily practice, but a systematic comparison of these imaging techniques is lacking. DESIGN: Retrospective, observational study. PARTICIPANTS: Twenty patients (31 eyes) with PXE. METHODS: OCT, FA and OCT-A imaging was performed in each eye and graded separately by independent readers. MAIN OUTCOME MEASURES: Diagnostic accuracy, sensitivity and specificity to detect CNV-activity of each modality and longitudinal change of CNV size measured by OCT-A. RESULTS: OCT showed the highest diagnostic accuracy (kappa = 0.57) in comparison to OCT-A or FA (kappa = 0.39 and 0.37, respectively). OCT-A, OCT and FA showed a diagnostic sensitivity of 0.9, 0.85 and 0.6, and a diagnostic specificity of 0.45, 0.72 and 0.82, respectively. Evaluation of longitudinal OCT recordings (24 eyes) resulted in optimal sensitivity and specificity (kappa = 1.0). Although median CNV size assessed using OCT-A remained stable on longitudinal measures of seven eyes, two eyes showed a distinct increase over time despite anti-vascular endothelial growth factor treatment. CONCLUSIONS AND RELEVANCE: The systematic use of OCT, FA and OCT-A imaging can facilitate the diagnostic accuracy for detection and follow-up of CNV activity in PXE. While structural OCT is of high value, especially when longitudinal follow-up images are available, FA and OCT-A data might contribute to diagnostic accuracy in more complex cases.

Inborn Errors of Metabolism: Pseudoxanthoma Elasticum.

Pseudoxanthoma elasticum (PXE) is an autosomal recessive multisystem disorder that involves the skin, GI tract, and heart, as well as the eye. It affects approximately 1 in 50,000 people worldwide and is seen twice as frequently in females as in males. Fundus findings include angioid streaks (Fig. 38.1), reticular macular dystrophy, speckled appearance temporal to the macula (peau d'orange, like the dimpled texture of an orange peel), drusen of the optic nerve, and vitelliform-like deposits. Peau d'orange may precede the development of an angioid streak. "Comets," with or without a tail, are seen as solitary subretinal, nodular white bodies of retinal pigment epithelium (RPE) atrophy, usually present in the mid periphery (Fig. 38.2). The tail points toward the optic disc. Patients sometimes develop choroidal neovascular membrane. Skin changes (plucked chicken-like appearance) occur on the flexure areas, including the neck and axilla, as well as increased skin laxity with excessive skin folding. Cardiovascular changes include accelerated atherosclerosis with occlusive vascular disease leading to angina, hypertension, restrictive cardiomyopathy, mitral valve prolapse, and others. Progressive calcification and fragmentation of elastic fibers in the skin, eye, and cardiovascular system is the underlying pathophysiology.

ABCC6 knockdown in HepG2 cells induces a senescent-like cell phenotype.

BACKGROUND: Pseudoxanthoma elasticum (PXE) is characterized by progressive ectopic mineralization of elastic fibers in dermal, ocular and vascular tissues. No effective treatment exists. It is caused by inactivating mutations in the gene encoding for the ATP-binding cassette, sub-family C member 6 transporter (ABCC6), which is mainly expressed in the liver. The ABCC6 substrate (s) and the PXE pathomechanism remain unknown. Recent studies have shown that overexpression of ABCC6 in HEK293 cells results in efflux of ATP, which is rapidly converted into nucleoside monophosphates and pyrophosphate (PPi). Since the latter inhibits mineralization, it was proposed that the absence of circulating PPi in PXE patients results in the characteristic ectopic mineralization. These studies also demonstrated that the presence of ABCC6 modifies cell secretory activity and suggested that ABCC6 can change the cell phenotype. METHODS: Stable ABCC6 knockdown HepG2 clones were generated using small hairpin RNA (shRNA) technology. The intracellular glutathione and ROS levels were determined. Experiments using cell cycle analysis, real-time PCR and western blot were performed on genes involved in the senescence phenotype. RESULTS: To shed light on the physiological role of ABCC6, we focused on the phenotype of HepG2 cells that lack ABCC6 activity. Interestingly, we found that ABCC6 knockdown HepG2 cells show: 1) intracellular reductive stress; 2) cell cycle arrest in G1 phase; 3) upregulation of p21Cip p53 independent; and 4) downregulation of lamin A/C. CONCLUSIONS: These findings show that the absence of ABCC6 profoundly changes the HepG2 phenotype, suggesting that the PXE syndrome is a complex metabolic disease that is not exclusively related to the absence of pyrophosphate in the bloodstream.

CHORIOCAPILLARIS SIGNAL VOIDS IN MATERNALLY INHERITED DIABETES AND DEAFNESS AND IN PSEUDOXANTHOMA ELASTICUM.

PURPOSE: To evaluate the pattern of choriocapillaris signal voids in maternally inherited diabetes and deafness and in pseudoxanthoma elasticum in eyes before the development of any geographic atrophy. METHODS: The choriocapillaris under the central macula was imaged with the Optovue RTVue XR Avanti using a 10 µm slab thickness. Automatic local thresholding of the resultant raw data extracted areas of absent flow signal, called signal voids, and these were counted and logarithmically binned. The signal void patterns were analyzed in four eyes of two patients with maternally inherited diabetes and deafness and four eyes of three patients with pseudoxanthoma elasticum. None of the patients had geographic atrophy. These data were compared with 55 eyes of 38 healthy control subjects and analyzed with generalized estimating equations. RESULTS: The choriocapillaris images in maternally inherited diabetes and deafness and pseudoxanthoma elasticum show that the model of signal voids followed a power law distribution, but with a slope and offset much lower than the normal control group, adjusted for age (P < 0.001). The eyes in the disease group were much more likely to have signal voids greater than 40,000 µm. CONCLUSION: Before the development of any overt geographic atrophy, patients with maternally inherited diabetes and deafness and pseudoxanthoma elasticum show pronounced abnormalities of choriocapillaris flow. Current clinical measures of retinal pigment epithelial health only look for areas of cell death, as in geographic atrophy. It is not possible to determine from current imaging if the choriocapillaris loss precedes potential loss of function of the retinal pigment epithelium, such as secretion of vascular endothelial growth factor.

A case of pseudoxanthoma elasticum with proliferative diabetic retinopathy.

BACKGROUND: To report the case of a patient with pseudoxanthoma elasticum (PXE) and proliferative diabetic retinopathy (PDR), and discuss the relationship between PXE and diabetic retinopathy (DR). CASE PRESENTATION: A 47-year-old man with PXE presented with angioid streaks and DR in both eyes, and bilateral panretinal photocoagulation was performed for treatment. Vitrectomy had previously been performed in his right eye for vitreous hemorrhage due to PDR. Systemic findings included multiple, discrete, symmetrical, small yellow papules bilaterally in the axilla and inguinal region. Examination on presentation showed vitreous hemorrhage in his left eye, and vitrectomy was performed for treatment. Intraoperative findings showed fibrovascular membrane around the optic disc and vascular arcade. A mottled fundus (peau d'orange appearance) associated with angioid streaks was also present, yet there was no evident choroidal neovascularization (CNV). The postoperative course was satisfactory, and corrected visual acuity improved from 0.02 to 0.7 diopters. CONCLUSION: Despite the peau d'orange appearance in both eyes of this case, no CNV was evident. The vitreous hemorrhage was thus attributed to PDR. Moreover, we reviewed the published literature and discuss the relationship between PXE and DR.

Disseminated arterial calcification and enhanced myogenic response are associated with abcc6 deficiency in a mouse model of pseudoxanthoma elasticum.

OBJECTIVE: Pseudoxanthoma elasticum is an inherited metabolic disorder resulting from ABCC6 gene mutations. It is characterized by progressive calcification and fragmentation of elastic fibers in the skin, retina, and the arterial wall. Despite calcium accumulation in the arteries of patients with pseudoxanthoma elasticum, functional consequences remain unknown. In the present study, we investigated arterial structure and function in Abcc6(-/-) mice, a model of the human disease. APPROACH AND RESULTS: Arterial calcium accumulation was evaluated using alizarin red stain and atomic absorption spectrometry. Expression of genes involved in osteochondrogenic differentiation was measured by polymerase chain reaction. Elastic arterial properties were evaluated by carotid echotracking. Vascular reactivity was evaluated using wire and pressure myography and remodeling using histomorphometry. Arterial calcium accumulation was 1.5- to 2-fold higher in Abcc6(-/-) than in wild-type mice. Calcium accumulated locally leading to punctuate pattern. Old Abcc6(-/-) arteries expressed markers of both osteogenic (Runx2, osteopontin) and chondrogenic lineage (Sox9, type II collagen). Abcc6(-/-) arteries displayed slight increase in arterial stiffness and vasoconstrictor tone in vitro tended to be higher in response to phenylephrine and thromboxane A2. Pressure-induced (myogenic) tone was significantly higher in Abcc6(-/-) arteries than in wild type. Arterial blood pressure was not significantly changed in Abcc6(-/-), despite higher variability. CONCLUSIONS: Scattered arterial calcium depositions are probably a result of osteochondrogenic transdifferentiation of vascular cells. Lower elasticity and increased myogenic tone without major changes in agonist-dependent contraction evidenced in aged Abcc6(-/-) mice suggest a reduced control of local blood flow, which in turn may alter vascular homeostasis in the long term.

Anti-VEGF Treatment for Secondary Neovascularization in Pseudoxanthoma Elasticum - Age of Onset, Treatment Frequency, and Visual Outcome.

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, 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.

A novel animal model for pseudoxanthoma elasticum: the KK/HlJ mouse.

Pseudoxanthoma elasticum is a multisystem ectopic mineralization disorder caused by mutations in the ABCC6 gene. A mouse model with targeted ablation of the corresponding gene (Abcc6(tm1JfK)) develops ectopic mineralization on the dermal sheath of vibrissae as biomarker of the progressive mineralization disorder. Survey of 31 mouse strains in a longitudinal aging study has identified three mouse strains with similar ectopic mineralization of the vibrissae, particularly the KK/HlJ strain. We report here that this mouse strain depicts, in addition to ectopic mineralization of the dermal sheath of vibrissae, mineral deposits in a number of internal organs. Energy dispersive X-ray analysis and topographic mapping found the presence of calcium and phosphate as the principal ions in the mineral deposits, similar to that in Abcc6(tm1JfK) mice, suggesting the presence of calcium hydroxyapatite. The mineralization was associated with a splice junction mutation at the 3' end of exon 14 of the Abcc6 gene, resulting in a 5-bp deletion from the coding region and causing frame-shift of translation. As a consequence, essentially no Abcc6 protein was detected in the liver of the KK/HlJ mice, similar to that in Abcc6(tm1JfK) mice. Collectively, our studies found that the KK/HlJ mouse strain is characterized by ectopic mineralization due to a mutation in the Abcc6 gene and therefore provides a novel model system to study pseudoxanthoma elasticum.

Commentary on Variants in the ABCC6 Gene Implicated in Pseudoxanthoma Elasticum, a Heritable Ectopic Mineralization Disorder.

Significant progress has been made in understanding pseudoxanthoma elasticum (PXE), which results from mutations in ABCC6. The low prevalence of PXE and its heterotypic presentation confound genotype-phenotype correlations and the characterization of many identified variants. Kowal et al. (2022) present an in vivo model to characterize and annotate ABCC6 variants, establishing a novel system for allele annotation in the patient population.

Relationship between ankle brachial index and arterial remodeling in pseudoxanthoma elasticum.

OBJECTIVES: Pseudoxanthoma elasticum (PXE) is an inherited metabolic disease characterized by elastic fiber fragmentation and calcification in the cutaneous, ophthalmologic, and vascular tissues. Cardiovascular manifestations such as peripheral arterial disease (PAD) are frequent in PXE. Because of the changes in the elastic properties and medial calcification of the arterial wall in PXE, the impact of the arterial remodeling on the ankle brachial index (ABI), a well-established diagnostic method for the detection and follow-up of PAD, remains to be determined in this disease. METHODS: This was a cross-sectional, comparative, open study, which took place at the PXE Consultation Center, University Hospital of Angers. The subjects were 53 patients (mean age, 49 ± 14 years; 35 females) with PXE clinically proven on the basis of established criteria (skin changes, angioid streaks, and skin biopsy). The ABI at rest, symptoms of intermittent claudication (IC), carotid intima-media thickness (IMT), carotid-femoral pulse wave velocity (c-f PWV), compliance (CC), and ß stiffness index were measured in a single-center cohort. RESULTS: Forty-five percent of the PXE patients had an ABI ≤0.90, but only one patient had an ABI >1.40. IC was found in 23% of the patients with an ABI ≤0.90. There were no significant differences between the patients with a low and normal ABI in terms of IMT (P = .566) or ß stiffness index (P = .194), but differences were significant for c-f PWV (P = .010) and CC (P = .011). Adjusted multivariate linear regression for the Framingham-Laurier score showed that patients with a low ABI had less compliant carotid arteries (B = 0.318, P = .039). CONCLUSIONS: PAD detected by a low ABI is very frequent in PXE, although with limited prevalence of symptomatic claudication. Unexpectedly, ABI was low in such calcifying PAD and associated with lower CC, independently of atherosclerosis risk factors. These findings demonstrate that PXE represents a unique monogenic model of PAD in which the specific arterial wall remodeling could change the diagnostic value of the ABI to detect PAD.

Pseudoxanthoma elasticum: progress in diagnostics and research towards treatment : Summary of the 2010 PXE International Research Meeting.

Pseudoxanthoma elasticum (PXE), a prototypic heritable disorder with ectopic mineralization, manifests with characteristic skin findings, ocular involvement, and cardiovascular problems. The classic forms of PXE are due to loss-of-function mutations in the ABCC6 gene, which encodes ABCC6, a putative transmembrane efflux transporter expressed primarily in the liver. While considerable progress has recently been made in understanding the molecular genetics and pathomechanisms of PXE, no effective or specific treatment is currently available for this disorder. PXE International, the premiere patient advocacy organization, organized a workshop in November 2010 to assess the current state of diagnostics and research to develop an agenda towards treatment of PXE. This overview summarizes the progress in PXE research, with emphasis on molecular therapies for this, currently intractable, disorder.

Calcium may preferentially deposit in areas of elastic tissue damage.

BACKGROUND: Cutaneous calcification is an acquired disorder whereby insoluble, amorphous calcium salts deposit in the skin. Classically, cutaneous calcification is categorized as metastatic, dystrophic, idiopathic, or iatrogenic. OBJECTIVE: The purpose of this study was to further elucidate the underlying pathogenic mechanism for cutaneous calcification. METHODS: Three cases of cutaneous calcification, including clinical characteristics and associated histopathology, were reviewed. Previous reports of cutaneous calcification were searched for in the published literature and included. RESULTS: Calcium is distributed within areas of underlying tissue damage (ie, locus minoris resistentiae), and in our cases, occurred specifically at sites of chronic actinic damage and intravenous extravasation tissue injury. LIMITATIONS: A small number of clinical cases and previously published reports were reviewed. CONCLUSION: We hypothesize that cutaneous calcification may preferentially occur at anatomic sites where tissue integrity has been compromised (ie, locus minoris resistentiae). We suggest one potential mechanism: that cutaneous calcification occurs within dermis that contains damaged elastic fibers. Pseudoxanthoma elasticum may serve as a possible genetic disease model for this process.

Combination treatment with intravitreal injection of ranibizumab and reduced fluence photodynamic therapy for choroidal neovascularization secondary to angioid streaks: preliminary clinical results of 12-month follow-up.

BACKGROUND: To evaluate combination treatment with intravitreal ranibizumab injection and reduced fluence photodynamic therapy for choroidal neovascularization associated with angioid streaks. METHODS: This is an interventional case series of 10 previously untreated eyes of 10 patients with choroidal neovascularization secondary to angioid streaks. All eyes were treated with reduced fluence photodynamic therapy using 25 J/cm, immediately followed by intravitreal ranibizumab injection at baseline, and subsequent injections were performed on an as-needed basis thereafter. Treatment efficacy was assessed based on best-corrected visual acuity and optical coherence tomography findings. RESULTS: After 12 months of follow-up, the best-corrected visual acuity improved by >2 lines in 6 eyes (60%), remained within 2 lines of baseline in 3 eyes (30%), and decreased by ≥ 3 lines in only 1 eye (10%). The mean central foveal thickness decreased significantly from 332.2 µm at baseline to 235.7 µm at the last follow-up (P < 0.001), as measured by optical coherence tomography. CONCLUSION: The preliminary results of this prospective study indicate that combination treatment with intravitreal ranibizumab injection and reduced fluence photodynamic therapy for choroidal neovascularization associated with angioid streaks seems to be effective in reducing or eliminating retinal edema, regression of neovascularization, and improving or stabilizing visual acuity without any complications. Large controlled studies are needed to evaluate the long-term effects of this combination regimen.

Long-term effectiveness of intravitreal bevacizumab for choroidal neovascularization secondary to angioid streaks in pseudoxanthoma elasticum.

PURPOSE: To investigate the long-term effectiveness of intravitreal bevacizumab for treating active choroidal neovascularizations in pseudoxanthoma elasticum (PXE). METHODS: Fourteen patients (16 eyes) received intravitreal bevacizumab (1.5 mg) and were investigated monthly. Further treatments were administered depending on disease activity. Examinations included best-corrected visual acuity, biomicroscopy, optical coherence tomography, fluorescein angiography and indocyanine green angiography, fundus autofluorescence, and digital fundus photography. Areas of atrophy of the retinal pigment epithelium and retinal fibrosis were quantified using semiautomated detection on fundus autofluorescence images. RESULTS: Mean age of the cohort was 55 ± 13 years, and mean best-corrected visual acuity at baseline was 20/80 (logarithm of the minimum angle of resolution, 0.56, SD, 0.51). At last follow-up, after an average of 6.5 ± 5.7 injections over 28 months, best-corrected visual acuity was 20/40 (logarithm of the minimum angle of resolution, 0.31, SD, 0.32; P = 0.04). Central retinal thickness was reduced from 254 ± 45 µm to 214 ± 40 µm (P = 0.035). The size of retinal pigment epithelial atrophy and retinal fibrosis measured on fundus autofluorescence images increased in both the treated eye and the fellow eye (P < 0.05). Best-corrected visual acuity of patients with early disease compared with that of those with advanced disease improved significantly more over the treatment course (20/25 vs. 20/63; P = 0.008). CONCLUSION: Intravitreal bevacizumab therapy demonstrates long-term effectiveness by preserving function in advanced disease and improving function in early disease. Best results of treating active choroidal neovascularizations in PXE are achieved when treatment starts the earliest possible.

Clinical Characterization of Korean Patients with Pseudoxanthoma Elasticum and Angioid Streaks.

This study aimed to characterize Korean patients with pseudoxanthoma elasticum (PXE) presenting with angioid streaks. Retinal phenotypes were longitudinally evaluated by multimodal ophthalmic imaging, and targeted gene panel sequencing for inherited retinal diseases was conducted. Seven subjects from unrelated families (median age, 51.2 years) were enrolled and followed for a median of 3.2 years. Four asymptomatic patients were significantly younger than three symptomatic patients with decreased visual acuity at presentation (mean age; 38.1 vs. 61.5 years, p = 0.020). The asymptomatic patients maintained good vision (20/32 or better) and had no choroidal neovascularization (CNV) over the observation period. The symptomatic patients showed additional reduction in visual acuity and bilateral CNV occurrence during the longitudinal follow-up. Pathogenic ABCC6 variants were identified in all patients, leading to a diagnosis of PXE. Heterozygous monoallelic variants were identified in four patients and compound heterozygous variants were detected in three patients. Nine ABCC6 variants were identified, including one novel variant, c.2035G>T [p.Glu679Ter]. This is the first genetic study of Korean patients with PXE.

PSEUDOXANTHOMA ELASTICUM: SUCCESSFUL LONG-TERM MANAGEMENT OF CHOROIDAL NEOVASCULARIZATION SECONDARY TO ANGIOID STREAKS WITH PRO RE NATA INTRAVITREAL BEVACIZUMAB INJECTIONS.

PURPOSE: To demonstrate how a patient with recurrent episodes of choroidal neovascularization (CNV), secondary to angioid streaks, can be managed successfully with a pro re nata regime of intravitreal bevacizumab injection over an eight-year period. METHOD: A 32-year-old white woman with pseudoxanthoma elasticum has been followed up over an eight-year period for management of recurrent episodes of CNV in both eyes. She was educated to recognize the early signs and symptoms of CNV. Physical examination including visual acuity and slit-lamp examination as well as investigations such as macula optical coherence tomography and optical coherence tomography angiography were performed. Bevacizumab injections were given to her when she was diagnosed with CNV. RESULTS: Multiple episodes of CNV were successfully treated with pro re nata regimes of intravitreal bevacizumab injections. The patient was able to maintain excellent visual acuity of 0 logarithm of the minimum angle of resolution even after suffering recurrent episodes of CNV. CONCLUSION: This case report supports that a pro re nata regime of intravitreal bevacizumab injection therapy can be used successfully to treat recurrent episodes of CNV in a patient with pseudoxanthoma elasticum over an eight-year period. Early diagnosis through patient education and the use of appropriate diagnostic tools such as optical coherence tomography angiography have enabled us to deliver early treatment, resulting in an excellent outcome for this patient.