RARE DISEASE
Pseudoxanthoma elasticum
Pseudoxanthoma elasticum
Pseudoxanthoma elasticum
Synonyms: Gronblad-Strandberg-Touraine syndrome, PXE
Synonyms: Gronblad-Strandberg-Touraine syndrome, PXE
Synonyms: Gronblad-Strandberg-Touraine syndrome, PXE
Drug discovery
3
drugs
With orphan designations
Overview
Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive disorder caused by ABCC6 mutations, leading to ectopic mineralization of elastic fibers in skin, eyes, and cardiovascular tissues. Clinical features include yellowish skin papules, angioid streaks with risk of choroidal neovascularization, and vascular complications like claudication. Diagnosis combines clinical findings, histopathology (calcified elastic fibers), and genetic testing. Management focuses on symptom mitigation, as no disease-modifying therapies exist [1][2][4][17].
Therapies
Ocular: Intravitreal anti-VEGF agents (e.g., bevacizumab) for choroidal neovascularization [4][11][18].
Cardiovascular: Lipid-lowering agents, blood pressure control, and vascular surgery for severe arteriosclerosis [2][16][17].
Symptomatic**: Cosmetic surgery for skin laxity; magnesium supplementation and bisphosphonates under investigation [6][16][20].
Categories: rare cardiac diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare neurological diseases, rare ophthalmic disorders, rare renal diseases, rare skin diseases, rare transplant-related disorders
Research Papers
298 drug discovery papers about Pseudoxanthoma elasticum, with 5 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
298 drug discovery papers about Pseudoxanthoma elasticum, with 5 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2024-10-14 | Successful Pedal Bypass in a Patient With Pseudoxanthoma Elasticum.
Pseudoxanthoma elasticum (PXE) is a rare metabolic disease, causing calcification in the arterial media layer and further peripheral artery disease (PAD). A high rate of failure has been reported after endovascular and open surgical management of PAD among patients with PXE. Critical limb ischemia (CLI) rarely develops in PXE, and there are only few reports of its treatment. We present a case report of a 57 year-old female diagnosed with pseudoxanthoma elasticum (PXE). She presented with critical limb ischemia (CLI) and was successfully treated with pedal bypass using the great saphenous vein. Despite obtaining suboptimal outcomes through the initial approach of percutaneous transluminal angioplasty to treat critical limb ischemia, the subsequent bypass operation proved to be a success. At the first follow-up appointment at 1 month, the patient was asymptomatic and the ulceration had almost healed. The patient underwent an ultrasound examination at 3, 6, 12, and 24 months after discharge, and the surveillance was uncomplicated. With a clear indication for surgery, limb-threatening ischemia can be successfully treated with distal bypass, if necessary, in patients with PXE similarly to atherosclerotic PADs. Appropriate diagnostic and surveillance imaging and the utilization of a multidisciplinary team are key components for effective management of PAD in patients with PXE.
2015-07-21 | Heart transplant and 2-year follow up in a child with generalized arterial calcification of infancy.
Generalized arterial calcification of infancy (GACI, OMIM 208000) and pseudoxanthoma elasticum (PXE, OMIM 264800) are rare autosomal-recessive disorders which represent the opposite ends of the same spectrum of pathologies characterized by progressive ectopic calcification and degeneration of elastic fibers at skin, eyes, and cardiovascular level. Patients with GACI suffer from hypertension, severe myocardial ischemia, and congestive heart failure and often die within 6 months of life. On the other end, PXE is associated with considerable morbidity, rarely with mortality. GACI and PXE are associated with biallelic mutations in ENPP1 and in ABCC6. We report the case of a 4-year-old Italian child submitted to heart transplant, at 18 months old, for end-stage heart failure due to extensive myocardial infarction of the left ventricle and diffuse coronary calcifications. The histology showed generalized arterial calcification and the molecular analysis identified mutations in ABCC6. Two years after transplantation, the child shows good clinical conditions and growth with no recurrence of calcium deposits in the heart. Bisphosphonate therapy at present is the treatment of choice for systemic arterial involvement in GACI, and heart transplant has proven to be the definitive treatment in case with extensive myocardial infarction, as in our. Molecular analysis is mandatory for a complete diagnosis and familial counseling.
2012-11-26 | Administration of bone marrow derived mesenchymal stem cells into the liver: potential to rescue pseudoxanthoma elasticum in a mouse model (Abcc6-/-).
Pseudoxanthoma elasticum (PXE) is a heritable ectopic mineralization disorder caused by loss-of-function mutations in the ABCC6 gene which is primarily expressed in the liver. There is currently no effective treatment for PXE. In this study, we characterized bone marrow derived mesenchymal stem cells (MSCs) and evaluated their ability to contribute to liver regeneration, with the aim to rescue PXE phenotype. The MSCs, isolated from GFP-transgenic mice by magnetic cell sorting, were shown to have high potential for hepatic differentiation, with expression of Abcc6 , in culture. These cells were transplanted into the livers of 4-week-old immunodeficient Abcc6 −/− mice by intrasplenic injection one day after partial hepatectomy, when peak expression of the stromal cell derived factor-1 (SDF-1) in the liver was observed. Fluorescent bioimaging analyses indicated that transplanted MSCs homed into liver between day 1 and 7, and significant numbers of GFP-positive cells were confirmed in the liver by immunofluorescence. Moreover, enhanced engraftment efficiency was observed with MSCs with high expression levels of the chemokine receptor Cxcr4, a receptor for SDF-1. These data suggest that purified MSCs have the capability of differentiating into hepatic lineages relevant to PXE pathogenesis and may contribute to partial correction of the PXE phenotype.
1997-08-01 | New Report of Severe Coronary Artery Disease in an Eighteen-Year-Old Girl with Pseudoxanthoma Elasticum
An eighteen-year-old woman with pseudoxanthoma elasticum (PXE) suffered from mild angina pectoris over a ten-year period. Severe triple-vessel disease with mild left ventric ular dysfunction was demonstrated on angiography. No revascularization was feasible. Despite a reported high frequency of angina pectoris among patients with PXE, only 10 convincing reports have appeared in the literature. Careful coronary artery evaluation is required in young patients with PXE, even though asymptomatic, because coronary artery disease (CAD) seems to be frequent and because no precise feature can be distinguished between types with or without severe vascular disease. Through very rare reports, surgical revascularization appears feasible and beneficial in a less severe form of CAD in patients with PXE. The risk of premature and severe diffuse CAD in PXE does not seem to be explained only by the combination of increased Lp [a] (or any other risk factor) and PXE.
1975-10-01 | Coronary artery disease in an 18 year old girl with pseudoxanthoma elasticum: Successful surgical therapy
An 18 year old girl with pseudoxanthoma elasticum, a 7 year history of angina pectoris and evidence of an old anteroseptal myocardial infarction was found on coronary angiography to have three vessel coronary artery disease. A triple coronary artery-saphenous vein bypass graft was performed, and she has been asymptomatic for 1 year. Histologic examination of a segment of the right coronary artery revealed changes consistent with the vascular lesion of pseudoxanthoma elasticum.
small molecules
2026-08-10 | Ectopic calcification is inhibited by minocycline also in PARP-1-independent in vitro models
Ectopic calcification (EC) is a still untreatable hallmark of genetic and acquired diseases. Recent findings suggested that minocycline (Mi) retains several biological impacts beyond its antibiotic function, including anti-inflammatory and antioxidant effects, modulation of the nucleus-mitochondria crosstalk, inhibition of the stress-induced over-activation of the poly(ADP-ribose) polymerase-1 (PARP-1) involved in DNA repair and possibly in EC. Interestingly, some of these pathways are involved in the pathogenesis of Pseudoxanthoma elasticum (PXE), a genetic disease considered a paradigm of EC. Notably, data have been provided indicating an association between anti-calcifying effects of Mi and PARP-1 inhibition, although the involved pathways remain unclear. Therefore, we have investigated through integrated approaches which molecular pathways can be involved in the proposed anti-calcifying potential of Mi. This study shows that Mi inhibits mineralization acting both in the extracellular (i.e., acellular model of coacervated elastin fibrils) and in the intracellular (i.e., cultured PXE dermal fibroblasts) environments. Results support and broaden the calcification inhibitory capability of Mi suggesting that, also in PARP-1 independent in vitro models of calcification, mineral deposition can be inhibited through the calcium chelating properties of the drug and the action on mitochondria mainly preserving Δψ m although oxidative stress is not affected.
2026-07-29 | Phosphocitrate Is Superior to Pyrophosphate in Preventing Soft Connective Tissue Calcification in a Mouse Model of Pseudoxanthoma Elasticum.
Pseudoxanthoma elasticum (PXE) is a rare inherited disorder characterized by progressive ectopic calcification of soft connective tissues, including skin, arteries, and eyes, leading to significant morbidity. PXE results from loss of functional ABCC6, a liver specific ATP efflux conduit. Reduced ATP release into the circulation limits its conversion into AMP and the mineralization inhibitor pyrophosphate (PPi). Consequently, low plasma PPi levels drive ectopic calcification in PXE. Although oral PPi supplementation can inhibit ectopic calcification in Abcc6-/- mice, impractically high doses are needed, due to its rapid hydrolysis in the gastrointestinal tract. Here, we evaluated phosphocitrate, an exceedingly more potent mineralization inhibitor, in vitro and in Abcc6-/- mice. In ATDC5 cells, 1 μM phosphocitrate significantly inhibited mineralization following induction, comparable to approximately tenfold higher concentrations of PPi. In vivo, daily intraperitoneal administration of phosphocitrate (4.7 μmol/kg bw) markedly reduced calcification in muzzle skin and kidneys, whereas an at least fivefold higher dose of PPi was needed to achieve a similar effect. Oral administration required substantially higher doses of both compounds (~2.4 mmol/kg bw), but PC remained more effective than PPi at inhibiting soft tissue calcification in Abcc6-/- mice. Importantly, unlike PPi, oral phosphocitrate did not adversely affect skeletal strength or stiffness, even at supraphysiological doses. In summary, phosphocitrate is a more potent inhibitor of ectopic calcification than PPi in Abcc6-/- mice. While optimization of oral delivery remains necessary, its increased potency supports the potential of alternative administration routes, including subcutaneous delivery, as a practical therapeutic strategy for PXE.
2026-07-27 | SCAMP – an open-source tool for the quantification of calcification in fish larvae
Abstract Quantifying skeletal mineralization phenotypes in larval fish is complicated by the natural curvature of the notochord and by sample-to-sample variability in orientation, staining and imaging. Consequently, many studies rely on summary measures such as vertebral counts or total stain intensity. Here we present SCAMP (Spinal Calcification & Mineralization Profiler), an open-source, GUI-based Python tool that computationally straightens the curved notochord of Alizarin Red S-stained fish larvae and generates standardized mineralization profiles along the spinal axis. This approach reduces positional and shape variability, allowing direct, quantitative comparison of calcification patterns within and between experimental cohorts, without requiring programming expertise. We validate SCAMP using a zebrafish model of Pseudoxanthoma elasticum ( abcc6a elu15/elu15 ), recovering genotype-specific differences in the intensity, extent and spatial distribution of ectopic calcification. Using SCAMP, we further show that inorganic pyrophosphate (PPi) supplementation of the medium suppresses ectopic notochord calcification, alters the anterior–posterior distribution of mineralized regions in homozygous mutants, and promotes mineralization at physiological vertebral sites. We also show that methylene blue, a routine antifungal additive in fish medium, reduces baseline calcification, with the most pronounced effects observed in heterozygous controls. SCAMP is freely available and has the potential to be adapted to other fish species used in skeletal and mineralization research.
2026-06-15 | Chronic Total Occlusion Recanalization in a 14-Year-Old Girl With Pseudoxanthoma Elasticum: IVUS-Guided Stentless Strategy.
Pseudoxanthoma elasticum (PXE) is a hereditary disorder causing progressive arterial mineralization that may cause premature coronary disease in children. A 14-year-old girl with exertional angina since age 8 was diagnosed with PXE after her mother used an artificial intelligence tool to identify skin lesions. Coronary imaging revealed mid-left anterior descending artery chronic total occlusion without CT macrocalcification. Intravascular ultrasound (IVUS) demonstrated concentric high-echoic wall thickening without acoustic shadowing, consistent with mineralized elastic lamina rather than atherosclerosis. A stentless drug-coated balloon strategy was chosen. At 10 months, she was asymptomatic with sustained left anterior descending artery patency by scheduled angiography. This is the first reported IVUS-guided chronic total occlusion recanalization in a pediatric PXE patient, illustrating how intravascular imaging can characterize disease biology and guide individualized device selection. In children with unexplained exertional symptoms and skin lesions, PXE should be considered. When IVUS identifies a nonatherosclerotic substrate, a stentless strategy may preserve vessel growth potential.
2026-03-10 | The liver regulates ectopic calcification in Abcc6-deficient models of pseudoxanthoma elasticum.
Pseudoxanthoma Elasticum (PXE) is a rare disease caused by loss of function of the ATP-binding cassette C (ABC) member 6 (Abcc6) gene and characterized by ectopic calcification of multiple tissues, but the physiological reasons underlying ectopic calcification in PXE remain unclear. In a murine model of Abcc6-deficient PXE in which animals developed robust cardiac calcification after heart injury, we show the critical importance of the liver in mediating ectopic cardiac calcification. Tissue-specific deletion of Abcc6 in the liver, but not in the heart, was sufficient to cause post-injury cardiac calcification. Metabolomics and gene expression analysis demonstrated deficiencies in nucleotide metabolism, cellular energetics, and defects in cellular respiration underlying ectopic calcification in PXE. Functional abnormalities in cellular respiration in the injured heart were similar in animals with global or liver-specific Abcc6 deficiency, showing that hepatic Abcc6 expression regulated cellular respiration in the injured heart. We show that ectopic calcification in PXE was primarily dystrophic and that treatment with clodronate or etidronate, which prevent the growth of calcium hydroxyapatite mineralization, was sufficient to rescue the phenotype of ectopic cardiac calcification in Abcc6-deficient states. Taken together, these observations highlight the role of the liver in regulating target tissue metabolic and mitochondrial function in causing ectopic calcification in Abcc6-deficient states.
antibodies
2026-04-25 | Asymmetric functional evolution of bilateral giant angioid streaks after 14 years of follow-up: A case report
• Bilateral giant subfoveal angioid streaks with pseudoxanthoma elasticum • High risk of choroidal neovascularization and severe hemorrhagic complications • 14-year follow-up showing asymmetric functional evolution between both eyes • Earlier switch to treat-and-extend regimen was associated with preserved vision Angioid streaks are rare, dark red, radiating fundus lesions surrounding the optic nerve head caused by breaks in Bruch's membrane. They predispose to choroidal neovascularization and recurrent hemorrhages requiring proactive management. We report a 44-year-old pseudoxanthoma elasticum patient with bilateral, atypical macular angioid streaks and a 14-year follow-up. In 2011, fundus examination revealed horizontal angioid streaks traversing the macula bilaterally without evidence of choroidal neovascularization; best-corrected visual acuity was 10/10 Parinaud 2 both eyes. The left eye subsequently developed neovascularization complicated by macular hemorrhages. Within two years, bilateral neovascularization with recurrent macular hemorrhages developed, prompting transition from a PRN to a treat-and-extend regimen. After 11 years of intravitreal ranibizumab therapy, the right eye maintained baseline visual acuity, while the left eye progressively declined to 1/10 (Parinaud 16) due to fibrotic sequelae. This case illustrates an interesting angioid streak pattern, characterized by giant horizontal streaks crossing the fovea, an anatomical configuration associated with particularly high risk of choroidal neovascularization and submacular hemorrhages. The 14-year follow up demonstrates the limitations of a pro re nata regimen in these high-risk presentations, as delayed transition to treat-and-extend failed to prevent subfoveal fibrosis and severe visual loss in the left eye. Conversely, earlier treatment initiation and earlier transition to treat-and-extend protocol was associated with preserved vision in the right eye. This case could suggest that a proactive approach may optimize visual outcomes as in age related macular degeneration. There is a lack of guidelines and studies on this therapeutic strategy. Close monitoring, assessment with optical coherence tomography angiography, and preventive education are essential, particularly regarding the risk of neovascularization and hemorrhage in patients with foveal-spanning angioid streaks. A proactive regimen may represent a more suitable and effective option for these patients when complications appear.
2026-03-31 | Angioid Streaks with Choroidal Neovascularization: An Ophthalmic Window to the Diagnosis of Pseudoxanthoma Elasticum
The most common systemic association of Angioid streaks is Pseudoxanthoma Elasticum (PXE), which is defined by the progressive mineralization of elastic tissue in the epidermis, eyes, and vascular system. We present the case of a 45-year-old female who presented with findings consistent with Angioid streaks complicated by choroidal neovascularization (CNV) in association with PXE. The patient presented with bilateral asymmetric painless vision loss, with an active CNV in the left eye, and a disciform scar in the right eye. Skin biopsy from neck confirmed PXE as the systemic cause. Intravitreal Ranibizumab was given in the left eye, which resulted in significant anatomical and functional improvement. This case demonstrates the need for systemic examination in Angioid streak patients, as well as the efficacy of anti-VEGF therapy in salvaging vision.
2026-01-15 | Anti-vascular Endothelial Growth Factor Therapy (anti-VEGF) in the Treatment of Neovascular Membrane Secondary to Angioid Streaks – Case Report
Angioid streaks, a rare defect of Bruch’s membrane, are most typically characterized by an asymptomatic course. However, when complications such as submacular hemorrhage or a neovascular membrane develop, visual acuity may deteriorate markedly, requiring therapeutic intervention. Angioid streaks can be associated with a number of systemic diseases, the most common being pseudoxanthoma elasticum, Paget’s disease, Ehlers–Danlos syndrome, beta thalassemia, and sickle cell anemia. This underscores the need for comprehensive systemic evaluation to identify potential comorbid conditions. We present the case of a 29-year-old patient in whom visual deterioration accompanied by image distortion was the first manifestation of angioid streaks complicated by a neovascular membrane. We demonstrate the positive therapeutic effects of intravitreal anti-vascular endothelial growth factor injections with ranibizumab. A total of five injections were required to stabilize the disease process, resulting in full visual acuity and complete resolution of subjective symptoms such as image distortion. Neoangiogenesis is the most common and most serious complication of angioid streaks. The fact that the disorder is rare, and at the same time linked to numerous systemic diseases, continues to hinder the development of standardized treatment protocols. The primary therapeutic method, yielding good results, is intravitreal anti-vascular endothelial growth factor treatment. Inhibition of vascular endothelial growth factor, the main mediator of angiogenesis and vascular permeability, plays a key role in stabilizing the disease. Moreover, early intervention is associated with markedly better outcomes and enables favorable anatomical and functional results.
2025-12-24 | Intravitreal faricimab treatment for traumatic choroidal rupture and macular neovascularization in angioid streaks: A case report.
IntroductionAngioid streaks is a rare retinal condition with pathological fissures in Bruch's membrane due to an abnormal and calcified Bruch's membrane. The condition can occur idiopathic or in association to other conditions. Development of macular neovascularization (MNV) in these angioid streaks, and MNV-related exudation, development of atrophy or in rare cases traumatic rupture can lead to visual symptoms.Case descriptionThis report describes a case of angioid streaks which was diagnosed after a blunt trauma that lead to visual symptoms and further examination revealed MNV with traumatic rupture. Anti-vascular endothelial growth factor treatment using faricimab was commenced with three injections at four weeks intervals. Family history raised suspicion of a systemic disease, and genetic work-up led to a diagnosis of pseudoxanthoma elasticum. The MNV treated with faricimab led to excellent visual results and no exudative recurrence during a follow-up period of 8 months after the last injection.ConclusionThis case report presents a clinical approach for managing MNV with traumatic rupture secondary to angioid streaks and is also the first case to present results of faricimab use for these lesions.
2025-11-17 | Angioid Streaks Revealing Pseudoxanthoma Elasticum: About Three Cases
Purpose: To describe three cases of angioid streaks revealing pseudoxanthoma elasticum (PXE) and to discuss the diagnostic, clinical, and therapeutic aspects of this uncommon association. Methods: Observational study of three patients managed at the Ophthalmology Departments of the Specialty Hospital of Rabat and Hassan II Military Hospital of Laâyoune. Results: Three patients (two men and one woman, aged 58, 55, and 42 years) presented with progressive bilateral visual loss. Fundus examination revealed dark, radially oriented lines emerging from the optic disc, consistent with angioid streaks. Fluorescein angiography confirmed the diagnosis. Dermatologic evaluation revealed pseudoxanthoma elasticum, while cardiovascular and skeletal investigations were unremarkable. Conclusion: Angioid streaks represent a rare manifestation of Bruch’s membrane rupture, most frequently associated with PXE (Grönblad–Strandberg syndrome). Early detection of choroidal neovascularization and prompt anti-VEGF therapy are essential to preserve visual function.
gene therapies
2025-12-09 | Liver-directed base editing of ABCC6 prevents ectopic calcification in a variant-humanized mouse model of pseudoxanthoma elasticum.
Pseudoxanthoma elasticum (PXE) is an autosomal recessive connective tissue disorder characterized by ectopic calcification of elastic fibers throughout the skin, retina, and arteries. It is caused by pathogenic variants in ABCC6, which encodes a transmembrane transporter that primarily localizes to hepatocytes. Loss of ABCC6 function in hepatocytes leads to systemic deficiency of inorganic pyrophosphate (PPi), a potent inhibitor of calcification; such depletion of PPi from the circulation is responsible for multisystemic ectopic calcification seen in PXE. Therefore, liver-targeted variant correction by genome editing and subsequent restoration of systemic PPi may offer a one-and-done therapeutic approach for PXE. The ABCC6 c.3490C>T (p.R1164X) variant is one of the most common variants found in PXE patients. Here, we show that liver-directed correction of the R1164X variant by adenine base editing restores plasma PPi and prevents ectopic skin calcification in mice fed a standard diet or an "acceleration diet" that exacerbates ectopic calcification. These results provide fundamental insight into the molecular etiology of PXE and provide a proof-of-principle that genetic correction of ABCC6 defects through adenine base editing may represent a novel, permanent therapy for the treatment of PXE.
2025-08-03 | Data from: Improved specificity and efficiency of in vivo adenine base editing therapies with hybrid guide RNAs
Phenylketonuria (PKU), pseudoxanthoma elasticum (PXE), and hereditary tyrosinemia type 1 (HT1) are autosomal recessive disorders linked to the PAH, ABCC6, and FAH and HPD genes, respectively. Here we evaluated the off-target editing profiles of clinical lead guide RNAs (gRNAs) that, when combined with adenine base editors (ABEs), correct the recurrent PAH P281L variant, PAH R408W variant, or ABCC6 R1164X variant or disrupt either of two sites in the HPD gene (a modifier gene of HT1) in human hepatocytes. To mitigate off-target mutagenesis, we systematically screened hybrid gRNAs with DNA nucleotide substitutions. Comprehensive and variant-aware specificity profiling of these hybrid gRNAs revealed dramatically reduced off-target editing and reduced bystander editing in cells. In humanized PAH P281L and ABCC6 R1164X mouse models of PKU and PXE, we showed that when formulated in lipid nanoparticles (LNPs) with ABE mRNA, selected hybrid gRNAs reverted disease phenotypes, reduced off-target editing, increased on-target editing, and reduced bystander editing in vivo. These studies highlight the utility of hybrid gRNAs to improve the safety and efficiency of adenine base editing therapies. We performed ONE‑seq in this manuscript, and here is the original dataset for all the ONE‑seq experiments conducted for this study.
2025-04-25 | Investigation on ABCC6-Deficient Human Hepatocytes Generated by CRISPR-Cas9 Genome Editing.
Patients affected by the rare disease pseudoxanthoma elasticum (PXE) exhibit the calcification of elastic fibers in ocular, dermal, and vascular tissues. These symptoms are triggered by mutations in the ATP-binding cassette transporter subfamily C member 6 (ABCC6), whose substrate remains unknown. Interestingly, ABCC6 is predominantly expressed in the liver tissue, leading to the hypothesis that PXE is a metabolic disorder. We developed a genome-editing system targeting ABCC6 in human immortalized hepatocytes (HepIms) for further investigations. The HepIms were transfected with an ABCC6-specific clustered regulatory interspaced short palindromic repeat (CRISPR-Cas9) genome-editing plasmid, resulting in the identification of a heterozygous (htABCC6HepIm) and a compound heterozygous (chtABCC6HepIm) clone. These clones were analyzed for key markers associated with the PXE pathobiochemistry. Hints of impaired lipid trafficking, defects in the extracellular matrix remodeling, the induction of calcification inhibitor expression, and the down regulation of senescence and inflammatory markers in ABCC6-deficienct HepIms were found. Our ABCC6 knock-out model of HepIms provides a valuable tool for studying the metabolic characteristics of PXE in vitro. The initial analysis of the clones mirrors various features of the PXE pathobiochemistry and provides an outlook on future research approaches.
2025-03-17 | P177: Evaluation of the genotypic and phenotypic spectrum of pediatric ABCC6 deficiency
ABCC6 is a transmembrane protein involved in the metabolic pyrophosphate (PPi)-adenosine pathway that produces PPi, an inhibitor of skeletal mineralization, and adenosine, a regulator of vascular intimal proliferation. Dysfunctional ABCC6 results in accumulation of mineralized deposits in the soft tissue and arterial intimal proliferation. Pseudoxanthoma elasticum (PXE) due to ABCC6 Deficiency is characterized by calcification of the skin, retina, and peripheral arteries, with symptom onset typically in adolescence or early adulthood.
2025-03-14 | Arterial Calcification as a Pseudoxanthoma Elasticum-like Manifestation in Beta-Thalassemia: Molecular Mechanisms and Significance
Thalassemia, once associated with limited survival, now sees extended life expectancy due to treatment advancements, but new complications such as pseudoxanthoma elasticum (PXE)-like syndrome are emerging. In fact, thalassemia patients develop PXE-like features more frequently than the general population. These features include skin lesions, ocular changes, and vascular issues like arterial calcifications, all linked to oxidative damage from iron overload. PXE-like syndrome in thalassemia mimics inherited PXE but is acquired. The underlying cause is thought to be oxidative stress due to iron overload, which induces free radicals and damages elastic tissues. Unlike inherited PXE, this form does not involve mutations in the ABCC6 gene, suggesting different pathogenic mechanisms, including abnormal fibroblast metabolism and oxidative processes. The vascular calcification seen in this syndrome often follows elastic fiber degeneration, with proteoglycans and glycoproteins acting as nucleation sites for mineralization. The condition can lead to severe cardiovascular and gastrointestinal complications. Studies have shown a significant incidence of PXE-like skin lesions in thalassemia patients, with some dying from cardiovascular complications. Research on ABCC6, a transporter protein involved in ectopic mineralization, has highlighted its role in various conditions, including PXE, beta-thalassemia, and generalized arterial calcification of infancy. ABCC6 mutations or reduced expression led to ectopic mineralization, affecting cardiovascular, ocular, and dermal tissues. The exact molecular mechanisms linking ABCC6 deficiency to ectopic mineralization remain unclear, though it is known to influence calcification-modulating proteins. This review focuses on the role of ABCC6 in the pathogenesis of calcifications, especially intracranial vascular calcifications in PXE and beta-thalassemia.
other
2021-12-07 | Elastin calcification in in vitro models and its prevention by MGP's N-terminal peptide.
Medial calcification has been associated with diabetes, chronic kidney disease, and genetic disorders like pseudoxanthoma elasticum. Recently, we showed that genetic reduction of arterial elastin content reduces the severity of medial calcification in matrix Gla protein (MGP)-deficient and Eln haploinsufficient Mgp-/-;Eln+/- mice. This study suggests that there might be a direct effect of elastin amount on medial calcification. We studied this using novel in vitro systems, which are based on elastin or elastin-like polypeptides. We first examined the mineral deposition properties of a transfected pigmented epithelial cell line that expresses elastin and other elastic lamina proteins. When grown in inorganic phosphate-supplemented medium, these cells deposited calcium phosphate minerals, which could be prevented by an N'-terminal peptide of MGP (m3pS) carrying phosphorylated serine residues. We next confirmed these findings using a cell-free elastin-like polypeptide (ELP3) scaffold, where the peptide prevented mineral maturation. Overall, this work describes a novel cell culture model for elastocalcinosis and examines the inhibition of mineral deposition by the m3pS peptide in this and a cell-free elastin-based scaffold. Our study provides strong evidence suggesting the critical functional roles of MGP's phosphorylated serine residues in the prevention of elastin calcification and proposes a possible mechanism of their action.
2021-10-18 | Safety and efficacy of rt-PA treatment for acute stroke in pseudoxanthoma elasticum: the first report.
Pseudoxanthoma elasticum is a rare cause for ischaemic stroke. Little is known about acute and secondary prevention strategies in these subjects given the increased risk of gastrointestinal and urinary bleedings. Here we present the case of a 62 years old man affected by pseudoxanthoma elasticum who presented with acute ischaemic stroke and was successfully treated with intravenous thrombolysis. Neurological signs improved after intravenous thrombolysis without bleeding complication. To our knowledge, this is the first case of pseudoxanthoma elasticum-related stroke undergoing intravenous thrombolysis.
2021-06-26 | The 3-step Greek protocol of neck skin rejuvenation inspired by a case of pseudoxanthoma elasticum: combination of laser skin resurfacing, collagen booster and PRP
Aim: The physiological ageing process causes significant changes in the extracellular matrix (ECM) of the neck skin, which are the first signs of ageing witness for women. We are inspired by a young woman, who suffers from a rare genetic disorder called pseudoxanthoma elasticum (PXE), which manifests irregular, thickened, fragmented and haphazardly orientated elastic fibers. We herein present a combination of three different therapies (laser skin resurfacing, type I horse collagen boosters and platelet rich plasma)as an approach to ameliorate neck skin sagging. Methods: A 28-year-old Roma woman with a clinically diagnosed PXE, verified by ophthalmologic evidence and skin biopsy, underwent 3 sessions of this combined protocol every 3 weeks. One month after the last treatment session, a new biopsy was taken. During this period, the patient was encouraged for daily topical application of collagen mousse and vitamin C combined with sun block SPF50, along with limited exposure to sunlight. Results: Clinical assessment supported by photographic documentation was performed at each session. Severe changes in hydration and tightening of the neck skin were obvious 3 weeks after the second session, although the verification of the results was substantiated with the pathology of the post treatment skin biopsy obtained 1 month following the completion of the protocol. The elastic fibers in the mid-dermis were dense, non-fragmented and parallel oriented. The aesthetic performance was evident until the final follow-up visit. Conclusions: Nowadays, the primary goal of aesthetic medical research is oriented to the dermis bio-reconstruction, where specific treatments try to improve the dermis quality from the inside to repair imperfections of skin ageing. The key of success is attributed to the best possible treatment combination capable of fibroblast stimulation.
2021-06-04 | From membrane to mineralization: the curious case of the ABCC6 transporter.
ATP-binding cassette subfamily C member 6 gene/protein (ABCC6) is an ATP-dependent transmembrane transporter predominantly expressed in the liver and the kidney. ABCC6 first came to attention in human medicine when it was discovered in 2000 that mutations in its encoding gene, ABCC6, caused the autosomal recessive multisystemic mineralization disease pseudoxanthoma elasticum (PXE). Since then, the physiological and pathological roles of ABCC6 have been the subject of intense research. In the last 20 years, significant findings have clarified ABCC6 structure as well as its physiological role in mineralization homeostasis in humans and animal models. Yet, several facets of ABCC6 biology remain currently incompletely understood, ranging from the precise nature of its substrate(s) to the increasingly complex molecular genetics. Nonetheless, advances in our understanding of pathophysiological mechanisms causing mineralization lead to several treatment options being suggested or already tested in pilot clinical trials for ABCC6 deficiency. This review highlights current knowledge of ABCC6 and the challenges ahead, particularly the attempts to translate basic science into clinical practice.
2020-11-20 | The Human Face of ABCC6
Researchers working on basic and translational clinical science related to ABC transporters are enthusiastic and dedicated investigators. As the field has grown, so has its contribution to human disease. Pseudoxanthoma elasticum (PXE) International, an advocacy organization established by non‐scientists, began supporting research and convenings on these transporters, specifically ABCC6, the gene associated with PXE, 20 years ago. As a patient advocacy organization, we have spent more than 25 years creating a large research consortium, initiating, funding and conducting research. Years of basic modelling and vigorous hypothesis testing have resulted in some important advances leading to clinical trials. The synergy of basic scientists, lay advocates, clinicians and translational scientists has dramatically accelerated research on PXE and progress towards better and more effective treatments for PXE patients.
cell therapies
2024-10-14 | Successful Pedal Bypass in a Patient With Pseudoxanthoma Elasticum.
Pseudoxanthoma elasticum (PXE) is a rare metabolic disease, causing calcification in the arterial media layer and further peripheral artery disease (PAD). A high rate of failure has been reported after endovascular and open surgical management of PAD among patients with PXE. Critical limb ischemia (CLI) rarely develops in PXE, and there are only few reports of its treatment. We present a case report of a 57 year-old female diagnosed with pseudoxanthoma elasticum (PXE). She presented with critical limb ischemia (CLI) and was successfully treated with pedal bypass using the great saphenous vein. Despite obtaining suboptimal outcomes through the initial approach of percutaneous transluminal angioplasty to treat critical limb ischemia, the subsequent bypass operation proved to be a success. At the first follow-up appointment at 1 month, the patient was asymptomatic and the ulceration had almost healed. The patient underwent an ultrasound examination at 3, 6, 12, and 24 months after discharge, and the surveillance was uncomplicated. With a clear indication for surgery, limb-threatening ischemia can be successfully treated with distal bypass, if necessary, in patients with PXE similarly to atherosclerotic PADs. Appropriate diagnostic and surveillance imaging and the utilization of a multidisciplinary team are key components for effective management of PAD in patients with PXE.
2015-07-21 | Heart transplant and 2-year follow up in a child with generalized arterial calcification of infancy.
Generalized arterial calcification of infancy (GACI, OMIM 208000) and pseudoxanthoma elasticum (PXE, OMIM 264800) are rare autosomal-recessive disorders which represent the opposite ends of the same spectrum of pathologies characterized by progressive ectopic calcification and degeneration of elastic fibers at skin, eyes, and cardiovascular level. Patients with GACI suffer from hypertension, severe myocardial ischemia, and congestive heart failure and often die within 6 months of life. On the other end, PXE is associated with considerable morbidity, rarely with mortality. GACI and PXE are associated with biallelic mutations in ENPP1 and in ABCC6. We report the case of a 4-year-old Italian child submitted to heart transplant, at 18 months old, for end-stage heart failure due to extensive myocardial infarction of the left ventricle and diffuse coronary calcifications. The histology showed generalized arterial calcification and the molecular analysis identified mutations in ABCC6. Two years after transplantation, the child shows good clinical conditions and growth with no recurrence of calcium deposits in the heart. Bisphosphonate therapy at present is the treatment of choice for systemic arterial involvement in GACI, and heart transplant has proven to be the definitive treatment in case with extensive myocardial infarction, as in our. Molecular analysis is mandatory for a complete diagnosis and familial counseling.
2012-11-26 | Administration of bone marrow derived mesenchymal stem cells into the liver: potential to rescue pseudoxanthoma elasticum in a mouse model (Abcc6-/-).
Pseudoxanthoma elasticum (PXE) is a heritable ectopic mineralization disorder caused by loss-of-function mutations in the ABCC6 gene which is primarily expressed in the liver. There is currently no effective treatment for PXE. In this study, we characterized bone marrow derived mesenchymal stem cells (MSCs) and evaluated their ability to contribute to liver regeneration, with the aim to rescue PXE phenotype. The MSCs, isolated from GFP-transgenic mice by magnetic cell sorting, were shown to have high potential for hepatic differentiation, with expression of Abcc6 , in culture. These cells were transplanted into the livers of 4-week-old immunodeficient Abcc6 −/− mice by intrasplenic injection one day after partial hepatectomy, when peak expression of the stromal cell derived factor-1 (SDF-1) in the liver was observed. Fluorescent bioimaging analyses indicated that transplanted MSCs homed into liver between day 1 and 7, and significant numbers of GFP-positive cells were confirmed in the liver by immunofluorescence. Moreover, enhanced engraftment efficiency was observed with MSCs with high expression levels of the chemokine receptor Cxcr4, a receptor for SDF-1. These data suggest that purified MSCs have the capability of differentiating into hepatic lineages relevant to PXE pathogenesis and may contribute to partial correction of the PXE phenotype.
1997-08-01 | New Report of Severe Coronary Artery Disease in an Eighteen-Year-Old Girl with Pseudoxanthoma Elasticum
An eighteen-year-old woman with pseudoxanthoma elasticum (PXE) suffered from mild angina pectoris over a ten-year period. Severe triple-vessel disease with mild left ventric ular dysfunction was demonstrated on angiography. No revascularization was feasible. Despite a reported high frequency of angina pectoris among patients with PXE, only 10 convincing reports have appeared in the literature. Careful coronary artery evaluation is required in young patients with PXE, even though asymptomatic, because coronary artery disease (CAD) seems to be frequent and because no precise feature can be distinguished between types with or without severe vascular disease. Through very rare reports, surgical revascularization appears feasible and beneficial in a less severe form of CAD in patients with PXE. The risk of premature and severe diffuse CAD in PXE does not seem to be explained only by the combination of increased Lp [a] (or any other risk factor) and PXE.
1975-10-01 | Coronary artery disease in an 18 year old girl with pseudoxanthoma elasticum: Successful surgical therapy
An 18 year old girl with pseudoxanthoma elasticum, a 7 year history of angina pectoris and evidence of an old anteroseptal myocardial infarction was found on coronary angiography to have three vessel coronary artery disease. A triple coronary artery-saphenous vein bypass graft was performed, and she has been asymptomatic for 1 year. Histologic examination of a segment of the right coronary artery revealed changes consistent with the vascular lesion of pseudoxanthoma elasticum.
small molecules
2026-08-10 | Ectopic calcification is inhibited by minocycline also in PARP-1-independent in vitro models
Ectopic calcification (EC) is a still untreatable hallmark of genetic and acquired diseases. Recent findings suggested that minocycline (Mi) retains several biological impacts beyond its antibiotic function, including anti-inflammatory and antioxidant effects, modulation of the nucleus-mitochondria crosstalk, inhibition of the stress-induced over-activation of the poly(ADP-ribose) polymerase-1 (PARP-1) involved in DNA repair and possibly in EC. Interestingly, some of these pathways are involved in the pathogenesis of Pseudoxanthoma elasticum (PXE), a genetic disease considered a paradigm of EC. Notably, data have been provided indicating an association between anti-calcifying effects of Mi and PARP-1 inhibition, although the involved pathways remain unclear. Therefore, we have investigated through integrated approaches which molecular pathways can be involved in the proposed anti-calcifying potential of Mi. This study shows that Mi inhibits mineralization acting both in the extracellular (i.e., acellular model of coacervated elastin fibrils) and in the intracellular (i.e., cultured PXE dermal fibroblasts) environments. Results support and broaden the calcification inhibitory capability of Mi suggesting that, also in PARP-1 independent in vitro models of calcification, mineral deposition can be inhibited through the calcium chelating properties of the drug and the action on mitochondria mainly preserving Δψ m although oxidative stress is not affected.
2026-07-29 | Phosphocitrate Is Superior to Pyrophosphate in Preventing Soft Connective Tissue Calcification in a Mouse Model of Pseudoxanthoma Elasticum.
Pseudoxanthoma elasticum (PXE) is a rare inherited disorder characterized by progressive ectopic calcification of soft connective tissues, including skin, arteries, and eyes, leading to significant morbidity. PXE results from loss of functional ABCC6, a liver specific ATP efflux conduit. Reduced ATP release into the circulation limits its conversion into AMP and the mineralization inhibitor pyrophosphate (PPi). Consequently, low plasma PPi levels drive ectopic calcification in PXE. Although oral PPi supplementation can inhibit ectopic calcification in Abcc6-/- mice, impractically high doses are needed, due to its rapid hydrolysis in the gastrointestinal tract. Here, we evaluated phosphocitrate, an exceedingly more potent mineralization inhibitor, in vitro and in Abcc6-/- mice. In ATDC5 cells, 1 μM phosphocitrate significantly inhibited mineralization following induction, comparable to approximately tenfold higher concentrations of PPi. In vivo, daily intraperitoneal administration of phosphocitrate (4.7 μmol/kg bw) markedly reduced calcification in muzzle skin and kidneys, whereas an at least fivefold higher dose of PPi was needed to achieve a similar effect. Oral administration required substantially higher doses of both compounds (~2.4 mmol/kg bw), but PC remained more effective than PPi at inhibiting soft tissue calcification in Abcc6-/- mice. Importantly, unlike PPi, oral phosphocitrate did not adversely affect skeletal strength or stiffness, even at supraphysiological doses. In summary, phosphocitrate is a more potent inhibitor of ectopic calcification than PPi in Abcc6-/- mice. While optimization of oral delivery remains necessary, its increased potency supports the potential of alternative administration routes, including subcutaneous delivery, as a practical therapeutic strategy for PXE.
2026-07-27 | SCAMP – an open-source tool for the quantification of calcification in fish larvae
Abstract Quantifying skeletal mineralization phenotypes in larval fish is complicated by the natural curvature of the notochord and by sample-to-sample variability in orientation, staining and imaging. Consequently, many studies rely on summary measures such as vertebral counts or total stain intensity. Here we present SCAMP (Spinal Calcification & Mineralization Profiler), an open-source, GUI-based Python tool that computationally straightens the curved notochord of Alizarin Red S-stained fish larvae and generates standardized mineralization profiles along the spinal axis. This approach reduces positional and shape variability, allowing direct, quantitative comparison of calcification patterns within and between experimental cohorts, without requiring programming expertise. We validate SCAMP using a zebrafish model of Pseudoxanthoma elasticum ( abcc6a elu15/elu15 ), recovering genotype-specific differences in the intensity, extent and spatial distribution of ectopic calcification. Using SCAMP, we further show that inorganic pyrophosphate (PPi) supplementation of the medium suppresses ectopic notochord calcification, alters the anterior–posterior distribution of mineralized regions in homozygous mutants, and promotes mineralization at physiological vertebral sites. We also show that methylene blue, a routine antifungal additive in fish medium, reduces baseline calcification, with the most pronounced effects observed in heterozygous controls. SCAMP is freely available and has the potential to be adapted to other fish species used in skeletal and mineralization research.
2026-06-15 | Chronic Total Occlusion Recanalization in a 14-Year-Old Girl With Pseudoxanthoma Elasticum: IVUS-Guided Stentless Strategy.
Pseudoxanthoma elasticum (PXE) is a hereditary disorder causing progressive arterial mineralization that may cause premature coronary disease in children. A 14-year-old girl with exertional angina since age 8 was diagnosed with PXE after her mother used an artificial intelligence tool to identify skin lesions. Coronary imaging revealed mid-left anterior descending artery chronic total occlusion without CT macrocalcification. Intravascular ultrasound (IVUS) demonstrated concentric high-echoic wall thickening without acoustic shadowing, consistent with mineralized elastic lamina rather than atherosclerosis. A stentless drug-coated balloon strategy was chosen. At 10 months, she was asymptomatic with sustained left anterior descending artery patency by scheduled angiography. This is the first reported IVUS-guided chronic total occlusion recanalization in a pediatric PXE patient, illustrating how intravascular imaging can characterize disease biology and guide individualized device selection. In children with unexplained exertional symptoms and skin lesions, PXE should be considered. When IVUS identifies a nonatherosclerotic substrate, a stentless strategy may preserve vessel growth potential.
2026-03-10 | The liver regulates ectopic calcification in Abcc6-deficient models of pseudoxanthoma elasticum.
Pseudoxanthoma Elasticum (PXE) is a rare disease caused by loss of function of the ATP-binding cassette C (ABC) member 6 (Abcc6) gene and characterized by ectopic calcification of multiple tissues, but the physiological reasons underlying ectopic calcification in PXE remain unclear. In a murine model of Abcc6-deficient PXE in which animals developed robust cardiac calcification after heart injury, we show the critical importance of the liver in mediating ectopic cardiac calcification. Tissue-specific deletion of Abcc6 in the liver, but not in the heart, was sufficient to cause post-injury cardiac calcification. Metabolomics and gene expression analysis demonstrated deficiencies in nucleotide metabolism, cellular energetics, and defects in cellular respiration underlying ectopic calcification in PXE. Functional abnormalities in cellular respiration in the injured heart were similar in animals with global or liver-specific Abcc6 deficiency, showing that hepatic Abcc6 expression regulated cellular respiration in the injured heart. We show that ectopic calcification in PXE was primarily dystrophic and that treatment with clodronate or etidronate, which prevent the growth of calcium hydroxyapatite mineralization, was sufficient to rescue the phenotype of ectopic cardiac calcification in Abcc6-deficient states. Taken together, these observations highlight the role of the liver in regulating target tissue metabolic and mitochondrial function in causing ectopic calcification in Abcc6-deficient states.
antibodies
2026-04-25 | Asymmetric functional evolution of bilateral giant angioid streaks after 14 years of follow-up: A case report
• Bilateral giant subfoveal angioid streaks with pseudoxanthoma elasticum • High risk of choroidal neovascularization and severe hemorrhagic complications • 14-year follow-up showing asymmetric functional evolution between both eyes • Earlier switch to treat-and-extend regimen was associated with preserved vision Angioid streaks are rare, dark red, radiating fundus lesions surrounding the optic nerve head caused by breaks in Bruch's membrane. They predispose to choroidal neovascularization and recurrent hemorrhages requiring proactive management. We report a 44-year-old pseudoxanthoma elasticum patient with bilateral, atypical macular angioid streaks and a 14-year follow-up. In 2011, fundus examination revealed horizontal angioid streaks traversing the macula bilaterally without evidence of choroidal neovascularization; best-corrected visual acuity was 10/10 Parinaud 2 both eyes. The left eye subsequently developed neovascularization complicated by macular hemorrhages. Within two years, bilateral neovascularization with recurrent macular hemorrhages developed, prompting transition from a PRN to a treat-and-extend regimen. After 11 years of intravitreal ranibizumab therapy, the right eye maintained baseline visual acuity, while the left eye progressively declined to 1/10 (Parinaud 16) due to fibrotic sequelae. This case illustrates an interesting angioid streak pattern, characterized by giant horizontal streaks crossing the fovea, an anatomical configuration associated with particularly high risk of choroidal neovascularization and submacular hemorrhages. The 14-year follow up demonstrates the limitations of a pro re nata regimen in these high-risk presentations, as delayed transition to treat-and-extend failed to prevent subfoveal fibrosis and severe visual loss in the left eye. Conversely, earlier treatment initiation and earlier transition to treat-and-extend protocol was associated with preserved vision in the right eye. This case could suggest that a proactive approach may optimize visual outcomes as in age related macular degeneration. There is a lack of guidelines and studies on this therapeutic strategy. Close monitoring, assessment with optical coherence tomography angiography, and preventive education are essential, particularly regarding the risk of neovascularization and hemorrhage in patients with foveal-spanning angioid streaks. A proactive regimen may represent a more suitable and effective option for these patients when complications appear.
2026-03-31 | Angioid Streaks with Choroidal Neovascularization: An Ophthalmic Window to the Diagnosis of Pseudoxanthoma Elasticum
The most common systemic association of Angioid streaks is Pseudoxanthoma Elasticum (PXE), which is defined by the progressive mineralization of elastic tissue in the epidermis, eyes, and vascular system. We present the case of a 45-year-old female who presented with findings consistent with Angioid streaks complicated by choroidal neovascularization (CNV) in association with PXE. The patient presented with bilateral asymmetric painless vision loss, with an active CNV in the left eye, and a disciform scar in the right eye. Skin biopsy from neck confirmed PXE as the systemic cause. Intravitreal Ranibizumab was given in the left eye, which resulted in significant anatomical and functional improvement. This case demonstrates the need for systemic examination in Angioid streak patients, as well as the efficacy of anti-VEGF therapy in salvaging vision.
2026-01-15 | Anti-vascular Endothelial Growth Factor Therapy (anti-VEGF) in the Treatment of Neovascular Membrane Secondary to Angioid Streaks – Case Report
Angioid streaks, a rare defect of Bruch’s membrane, are most typically characterized by an asymptomatic course. However, when complications such as submacular hemorrhage or a neovascular membrane develop, visual acuity may deteriorate markedly, requiring therapeutic intervention. Angioid streaks can be associated with a number of systemic diseases, the most common being pseudoxanthoma elasticum, Paget’s disease, Ehlers–Danlos syndrome, beta thalassemia, and sickle cell anemia. This underscores the need for comprehensive systemic evaluation to identify potential comorbid conditions. We present the case of a 29-year-old patient in whom visual deterioration accompanied by image distortion was the first manifestation of angioid streaks complicated by a neovascular membrane. We demonstrate the positive therapeutic effects of intravitreal anti-vascular endothelial growth factor injections with ranibizumab. A total of five injections were required to stabilize the disease process, resulting in full visual acuity and complete resolution of subjective symptoms such as image distortion. Neoangiogenesis is the most common and most serious complication of angioid streaks. The fact that the disorder is rare, and at the same time linked to numerous systemic diseases, continues to hinder the development of standardized treatment protocols. The primary therapeutic method, yielding good results, is intravitreal anti-vascular endothelial growth factor treatment. Inhibition of vascular endothelial growth factor, the main mediator of angiogenesis and vascular permeability, plays a key role in stabilizing the disease. Moreover, early intervention is associated with markedly better outcomes and enables favorable anatomical and functional results.
2025-12-24 | Intravitreal faricimab treatment for traumatic choroidal rupture and macular neovascularization in angioid streaks: A case report.
IntroductionAngioid streaks is a rare retinal condition with pathological fissures in Bruch's membrane due to an abnormal and calcified Bruch's membrane. The condition can occur idiopathic or in association to other conditions. Development of macular neovascularization (MNV) in these angioid streaks, and MNV-related exudation, development of atrophy or in rare cases traumatic rupture can lead to visual symptoms.Case descriptionThis report describes a case of angioid streaks which was diagnosed after a blunt trauma that lead to visual symptoms and further examination revealed MNV with traumatic rupture. Anti-vascular endothelial growth factor treatment using faricimab was commenced with three injections at four weeks intervals. Family history raised suspicion of a systemic disease, and genetic work-up led to a diagnosis of pseudoxanthoma elasticum. The MNV treated with faricimab led to excellent visual results and no exudative recurrence during a follow-up period of 8 months after the last injection.ConclusionThis case report presents a clinical approach for managing MNV with traumatic rupture secondary to angioid streaks and is also the first case to present results of faricimab use for these lesions.
2025-11-17 | Angioid Streaks Revealing Pseudoxanthoma Elasticum: About Three Cases
Purpose: To describe three cases of angioid streaks revealing pseudoxanthoma elasticum (PXE) and to discuss the diagnostic, clinical, and therapeutic aspects of this uncommon association. Methods: Observational study of three patients managed at the Ophthalmology Departments of the Specialty Hospital of Rabat and Hassan II Military Hospital of Laâyoune. Results: Three patients (two men and one woman, aged 58, 55, and 42 years) presented with progressive bilateral visual loss. Fundus examination revealed dark, radially oriented lines emerging from the optic disc, consistent with angioid streaks. Fluorescein angiography confirmed the diagnosis. Dermatologic evaluation revealed pseudoxanthoma elasticum, while cardiovascular and skeletal investigations were unremarkable. Conclusion: Angioid streaks represent a rare manifestation of Bruch’s membrane rupture, most frequently associated with PXE (Grönblad–Strandberg syndrome). Early detection of choroidal neovascularization and prompt anti-VEGF therapy are essential to preserve visual function.
gene therapies
2025-12-09 | Liver-directed base editing of ABCC6 prevents ectopic calcification in a variant-humanized mouse model of pseudoxanthoma elasticum.
Pseudoxanthoma elasticum (PXE) is an autosomal recessive connective tissue disorder characterized by ectopic calcification of elastic fibers throughout the skin, retina, and arteries. It is caused by pathogenic variants in ABCC6, which encodes a transmembrane transporter that primarily localizes to hepatocytes. Loss of ABCC6 function in hepatocytes leads to systemic deficiency of inorganic pyrophosphate (PPi), a potent inhibitor of calcification; such depletion of PPi from the circulation is responsible for multisystemic ectopic calcification seen in PXE. Therefore, liver-targeted variant correction by genome editing and subsequent restoration of systemic PPi may offer a one-and-done therapeutic approach for PXE. The ABCC6 c.3490C>T (p.R1164X) variant is one of the most common variants found in PXE patients. Here, we show that liver-directed correction of the R1164X variant by adenine base editing restores plasma PPi and prevents ectopic skin calcification in mice fed a standard diet or an "acceleration diet" that exacerbates ectopic calcification. These results provide fundamental insight into the molecular etiology of PXE and provide a proof-of-principle that genetic correction of ABCC6 defects through adenine base editing may represent a novel, permanent therapy for the treatment of PXE.
2025-08-03 | Data from: Improved specificity and efficiency of in vivo adenine base editing therapies with hybrid guide RNAs
Phenylketonuria (PKU), pseudoxanthoma elasticum (PXE), and hereditary tyrosinemia type 1 (HT1) are autosomal recessive disorders linked to the PAH, ABCC6, and FAH and HPD genes, respectively. Here we evaluated the off-target editing profiles of clinical lead guide RNAs (gRNAs) that, when combined with adenine base editors (ABEs), correct the recurrent PAH P281L variant, PAH R408W variant, or ABCC6 R1164X variant or disrupt either of two sites in the HPD gene (a modifier gene of HT1) in human hepatocytes. To mitigate off-target mutagenesis, we systematically screened hybrid gRNAs with DNA nucleotide substitutions. Comprehensive and variant-aware specificity profiling of these hybrid gRNAs revealed dramatically reduced off-target editing and reduced bystander editing in cells. In humanized PAH P281L and ABCC6 R1164X mouse models of PKU and PXE, we showed that when formulated in lipid nanoparticles (LNPs) with ABE mRNA, selected hybrid gRNAs reverted disease phenotypes, reduced off-target editing, increased on-target editing, and reduced bystander editing in vivo. These studies highlight the utility of hybrid gRNAs to improve the safety and efficiency of adenine base editing therapies. We performed ONE‑seq in this manuscript, and here is the original dataset for all the ONE‑seq experiments conducted for this study.
2025-04-25 | Investigation on ABCC6-Deficient Human Hepatocytes Generated by CRISPR-Cas9 Genome Editing.
Patients affected by the rare disease pseudoxanthoma elasticum (PXE) exhibit the calcification of elastic fibers in ocular, dermal, and vascular tissues. These symptoms are triggered by mutations in the ATP-binding cassette transporter subfamily C member 6 (ABCC6), whose substrate remains unknown. Interestingly, ABCC6 is predominantly expressed in the liver tissue, leading to the hypothesis that PXE is a metabolic disorder. We developed a genome-editing system targeting ABCC6 in human immortalized hepatocytes (HepIms) for further investigations. The HepIms were transfected with an ABCC6-specific clustered regulatory interspaced short palindromic repeat (CRISPR-Cas9) genome-editing plasmid, resulting in the identification of a heterozygous (htABCC6HepIm) and a compound heterozygous (chtABCC6HepIm) clone. These clones were analyzed for key markers associated with the PXE pathobiochemistry. Hints of impaired lipid trafficking, defects in the extracellular matrix remodeling, the induction of calcification inhibitor expression, and the down regulation of senescence and inflammatory markers in ABCC6-deficienct HepIms were found. Our ABCC6 knock-out model of HepIms provides a valuable tool for studying the metabolic characteristics of PXE in vitro. The initial analysis of the clones mirrors various features of the PXE pathobiochemistry and provides an outlook on future research approaches.
2025-03-17 | P177: Evaluation of the genotypic and phenotypic spectrum of pediatric ABCC6 deficiency
ABCC6 is a transmembrane protein involved in the metabolic pyrophosphate (PPi)-adenosine pathway that produces PPi, an inhibitor of skeletal mineralization, and adenosine, a regulator of vascular intimal proliferation. Dysfunctional ABCC6 results in accumulation of mineralized deposits in the soft tissue and arterial intimal proliferation. Pseudoxanthoma elasticum (PXE) due to ABCC6 Deficiency is characterized by calcification of the skin, retina, and peripheral arteries, with symptom onset typically in adolescence or early adulthood.
2025-03-14 | Arterial Calcification as a Pseudoxanthoma Elasticum-like Manifestation in Beta-Thalassemia: Molecular Mechanisms and Significance
Thalassemia, once associated with limited survival, now sees extended life expectancy due to treatment advancements, but new complications such as pseudoxanthoma elasticum (PXE)-like syndrome are emerging. In fact, thalassemia patients develop PXE-like features more frequently than the general population. These features include skin lesions, ocular changes, and vascular issues like arterial calcifications, all linked to oxidative damage from iron overload. PXE-like syndrome in thalassemia mimics inherited PXE but is acquired. The underlying cause is thought to be oxidative stress due to iron overload, which induces free radicals and damages elastic tissues. Unlike inherited PXE, this form does not involve mutations in the ABCC6 gene, suggesting different pathogenic mechanisms, including abnormal fibroblast metabolism and oxidative processes. The vascular calcification seen in this syndrome often follows elastic fiber degeneration, with proteoglycans and glycoproteins acting as nucleation sites for mineralization. The condition can lead to severe cardiovascular and gastrointestinal complications. Studies have shown a significant incidence of PXE-like skin lesions in thalassemia patients, with some dying from cardiovascular complications. Research on ABCC6, a transporter protein involved in ectopic mineralization, has highlighted its role in various conditions, including PXE, beta-thalassemia, and generalized arterial calcification of infancy. ABCC6 mutations or reduced expression led to ectopic mineralization, affecting cardiovascular, ocular, and dermal tissues. The exact molecular mechanisms linking ABCC6 deficiency to ectopic mineralization remain unclear, though it is known to influence calcification-modulating proteins. This review focuses on the role of ABCC6 in the pathogenesis of calcifications, especially intracranial vascular calcifications in PXE and beta-thalassemia.
other
2021-12-07 | Elastin calcification in in vitro models and its prevention by MGP's N-terminal peptide.
Medial calcification has been associated with diabetes, chronic kidney disease, and genetic disorders like pseudoxanthoma elasticum. Recently, we showed that genetic reduction of arterial elastin content reduces the severity of medial calcification in matrix Gla protein (MGP)-deficient and Eln haploinsufficient Mgp-/-;Eln+/- mice. This study suggests that there might be a direct effect of elastin amount on medial calcification. We studied this using novel in vitro systems, which are based on elastin or elastin-like polypeptides. We first examined the mineral deposition properties of a transfected pigmented epithelial cell line that expresses elastin and other elastic lamina proteins. When grown in inorganic phosphate-supplemented medium, these cells deposited calcium phosphate minerals, which could be prevented by an N'-terminal peptide of MGP (m3pS) carrying phosphorylated serine residues. We next confirmed these findings using a cell-free elastin-like polypeptide (ELP3) scaffold, where the peptide prevented mineral maturation. Overall, this work describes a novel cell culture model for elastocalcinosis and examines the inhibition of mineral deposition by the m3pS peptide in this and a cell-free elastin-based scaffold. Our study provides strong evidence suggesting the critical functional roles of MGP's phosphorylated serine residues in the prevention of elastin calcification and proposes a possible mechanism of their action.
2021-10-18 | Safety and efficacy of rt-PA treatment for acute stroke in pseudoxanthoma elasticum: the first report.
Pseudoxanthoma elasticum is a rare cause for ischaemic stroke. Little is known about acute and secondary prevention strategies in these subjects given the increased risk of gastrointestinal and urinary bleedings. Here we present the case of a 62 years old man affected by pseudoxanthoma elasticum who presented with acute ischaemic stroke and was successfully treated with intravenous thrombolysis. Neurological signs improved after intravenous thrombolysis without bleeding complication. To our knowledge, this is the first case of pseudoxanthoma elasticum-related stroke undergoing intravenous thrombolysis.
2021-06-26 | The 3-step Greek protocol of neck skin rejuvenation inspired by a case of pseudoxanthoma elasticum: combination of laser skin resurfacing, collagen booster and PRP
Aim: The physiological ageing process causes significant changes in the extracellular matrix (ECM) of the neck skin, which are the first signs of ageing witness for women. We are inspired by a young woman, who suffers from a rare genetic disorder called pseudoxanthoma elasticum (PXE), which manifests irregular, thickened, fragmented and haphazardly orientated elastic fibers. We herein present a combination of three different therapies (laser skin resurfacing, type I horse collagen boosters and platelet rich plasma)as an approach to ameliorate neck skin sagging. Methods: A 28-year-old Roma woman with a clinically diagnosed PXE, verified by ophthalmologic evidence and skin biopsy, underwent 3 sessions of this combined protocol every 3 weeks. One month after the last treatment session, a new biopsy was taken. During this period, the patient was encouraged for daily topical application of collagen mousse and vitamin C combined with sun block SPF50, along with limited exposure to sunlight. Results: Clinical assessment supported by photographic documentation was performed at each session. Severe changes in hydration and tightening of the neck skin were obvious 3 weeks after the second session, although the verification of the results was substantiated with the pathology of the post treatment skin biopsy obtained 1 month following the completion of the protocol. The elastic fibers in the mid-dermis were dense, non-fragmented and parallel oriented. The aesthetic performance was evident until the final follow-up visit. Conclusions: Nowadays, the primary goal of aesthetic medical research is oriented to the dermis bio-reconstruction, where specific treatments try to improve the dermis quality from the inside to repair imperfections of skin ageing. The key of success is attributed to the best possible treatment combination capable of fibroblast stimulation.
2021-06-04 | From membrane to mineralization: the curious case of the ABCC6 transporter.
ATP-binding cassette subfamily C member 6 gene/protein (ABCC6) is an ATP-dependent transmembrane transporter predominantly expressed in the liver and the kidney. ABCC6 first came to attention in human medicine when it was discovered in 2000 that mutations in its encoding gene, ABCC6, caused the autosomal recessive multisystemic mineralization disease pseudoxanthoma elasticum (PXE). Since then, the physiological and pathological roles of ABCC6 have been the subject of intense research. In the last 20 years, significant findings have clarified ABCC6 structure as well as its physiological role in mineralization homeostasis in humans and animal models. Yet, several facets of ABCC6 biology remain currently incompletely understood, ranging from the precise nature of its substrate(s) to the increasingly complex molecular genetics. Nonetheless, advances in our understanding of pathophysiological mechanisms causing mineralization lead to several treatment options being suggested or already tested in pilot clinical trials for ABCC6 deficiency. This review highlights current knowledge of ABCC6 and the challenges ahead, particularly the attempts to translate basic science into clinical practice.
2020-11-20 | The Human Face of ABCC6
Researchers working on basic and translational clinical science related to ABC transporters are enthusiastic and dedicated investigators. As the field has grown, so has its contribution to human disease. Pseudoxanthoma elasticum (PXE) International, an advocacy organization established by non‐scientists, began supporting research and convenings on these transporters, specifically ABCC6, the gene associated with PXE, 20 years ago. As a patient advocacy organization, we have spent more than 25 years creating a large research consortium, initiating, funding and conducting research. Years of basic modelling and vigorous hypothesis testing have resulted in some important advances leading to clinical trials. The synergy of basic scientists, lay advocates, clinicians and translational scientists has dramatically accelerated research on PXE and progress towards better and more effective treatments for PXE patients.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
3 orphan drug designations for Pseudoxanthoma elasticum.
3 orphan drug designations for Pseudoxanthoma elasticum.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Etidronate disodium | small molecules | EMA | Haltex Therapeutics B.V. | |
Recombinant human ectonucleotide pyrophosphatase/phosphodiesterase 1-Fc (rhENPP1-Fc) enzyme | proteins | FDA | Inozyme Pharma, Inc. | |
a small molecule tissue-nonspecific alkaline phosphatase inhibitor | small molecules | FDA | Daiichi Sankyo, Inc. |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.