Peripheral Interventions in Patients with Pseudoxanthoma Elasticum (PXE).

OBJECTIVE: Pseudoxanthoma elasticum (PXE) is an autosomal recessive metabolic disorder that may be associated with a high prevalence of peripheral artery disease (PAD) and related symptoms. However, the evidence supporting this association is weak, as only small cohort studies are available. Furthermore, limited data are available on the outcome of lower limb peripheral arterial interventions (PAI) in patients with PXE. It was the aim of this study to clarify the prevalence of PAD, and the occurrence and outcome of PAI in patients with PXE. METHODS: This was a retrospective review of prospectively collected data from the Dutch Expertise Centre for PXE database. Clinical data of consecutive patients with a definitive diagnosis of PXE were examined. The primary endpoint was the prevalence of PAD (defined as an ankle brachial index of < 0.9). The secondary endpoint was to report an overview of PAI and target lesion revascularisations. RESULTS: In 285 PXE patients (median age 58 years), 50.9% of patients (n = 145) met the criteria for PAD. Seventeen patients underwent a PAI, mostly for intermittent claudication, at a median age of 51 years. The incidence of PAI was 2.25 per 1 000 patient years in patients with PAD and PXE. A total of 58 interventions was recorded, of which 35 were target lesion revascularisations in nine patients. Twenty one revascularisations were performed within a year following the primary intervention, in 16 cases due to an acute occlusion. CONCLUSION: Within a well phenotyped and large PXE cohort, the diagnosis of PAD was prevalent in one in two patients. The observed rate of peripheral interventions was low, while the re-intervention rate was unfavourable after endovascular or bypass surgical procedures, with over half of these re-interventions indicated within a year.

INZ-701, a recombinant ENPP1 enzyme, prevents ectopic calcification in an Abcc6-/- mouse model of pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE), a heritable multisystem ectopic calcification disorder, is predominantly caused by inactivating mutations in ABCC6. The encoded protein, ABCC6, is a hepatic efflux transporter and a key regulator of extracellular inorganic pyrophosphate (PPi). Recent studies demonstrated that deficiency of plasma PPi, a potent endogenous calcification inhibitor, is the underlying cause of PXE. This study examined whether restoring plasma PPi levels by INZ-701, a recombinant human ENPP1 protein, the principal PPi-generating enzyme, prevents ectopic calcification in an Abcc6-/- mouse model of PXE. Abcc6-/- mice, at 6 weeks of age, the time of earliest stages of ectopic calcification, were injected subcutaneously with INZ-701 at 2 or 10 mg/kg for 2 or 8 weeks. INZ-701 at both doses increased steady-state plasma ENPP1 activity and PPi levels. In the 8-week treatment study, histopathologic examination and quantification of the calcium content in INZ-701-treated Abcc6-/- mice revealed significantly reduced calcification in the muzzle skin containing vibrissae, a biomarker of the calcification process in these mice. The extent of calcification corresponds to the local expression of two calcification inhibitors, osteopontin and fetuin-A. These results suggest that INZ-701 might provide a therapeutic approach for PXE, a disease with high unmet needs and no approved treatment.

Inorganic Pyrophosphate Deficiency Syndromes and Potential Treatments for Pathologic Tissue Calcification.

Pathologic soft tissue calcification can occur in both genetic and acquired clinical conditions, causing significant morbidity and mortality. Although the pathomechanisms of pathologic calcification are poorly understood, major progress has been made in recent years in defining the underlying genetic defects in Mendelian disorders of ectopic calcification. This review presents an overview of the pathophysiology of five monogenic disorders of pathologic calcification: pseudoxanthoma elasticum, generalized arterial calcification of infancy, arterial calcification due to deficiency of CD73, ankylosis, and progeria. These hereditary disorders, caused by mutations in genes encoding ATP binding cassette subfamily C member 6, ectonucleotide pyrophosphatase/phosphodiesterase 1, CD73, progressive ankylosis protein, and lamin A/C proteins, respectively, are inorganic pyrophosphate (PPi) deficiency syndromes with reduced circulating levels of PPi, the principal physiologic inhibitor of calcium hydroxyapatite deposition in soft connective tissues. In addition to genetic diseases, PPi deficiency has been encountered in acquired clinical conditions accompanied by pathologic calcification. Because specific and effective treatments are lacking for pathologic calcification, the unifying finding of PPi deficiency suggests that PPi-targeted therapies may be beneficial to counteract pathologic soft tissue calcification in both genetic and acquired diseases.

[Angioid streaks in systemic disease]. / Szemfenéki angioid csíkok szisztémás betegségekben.

Angioid streaks are defined as the special morphological alteration of the fundus; the most common clinical manifestations are irregular, reddish brownish stripes around the optic nerve head or on the posterior pole. On the basis of histological examination, the cause of this phenomenon is the breaks and continuity deficiencies in the thin layer of Bruch membrane caused by the degeneration of elastic fibers. The aim of this study is to present the ocular complication of this rare entity through the description of three cases, and to draw attention to systemic diseases in the background. In our first and third cases, pseudoxanthoma elasticum (Grönblad-Strandberg syndrome) was in the background, while in our second case, hematological disease was confirmed. In our first and second cases, the ocular complication was the choroidal neovascularization, which we treated with intravitreal anti-VEGF injection. In our third case, the choroidal rupture was the ocular complication, caused by trauma. Angioid streaks on the fundus may be sub-phenomena of systemic diseases, the detection, differential diagnosis and treatment require interdisciplinary collaboration between associate physicians. Orv Hetil. 2019; 160(25): 994-1000.

Adenovirus-Mediated ABCC6 Gene Therapy for Heritable Ectopic Mineralization Disorders.

Loss-of-function mutations in the ABCC6 gene cause pseudoxanthoma elasticum and type 2 generalized arterial calcification of infancy, heritable ectopic mineralization disorders without effective treatment. ABCC6 encodes the putative efflux transporter ABCC6, which is predominantly expressed in the liver. Although the substrate of ABCC6 remains unknown, recent studies showed that pseudoxanthoma elasticum is a metabolic disorder caused by reduced circulating levels of pyrophosphate, a potent mineralization inhibitor. We hypothesized that reconstitution of ABCC6 might counteract ectopic mineralization in an Abcc6-/- mouse model of pseudoxanthoma elasticum. Intravenous administration of a recombinant adenovirus expressing wild-type human ABCC6 in Abcc6-/- mice showed sustained high-level expression of human ABCC6 in the liver for up to 4 weeks, increasing pyrophosphate levels in plasma. In addition, adenovirus injection every 4 weeks restored plasma pyrophosphate levels and, consequently, significantly reduced ectopic mineralization in the skin of young mice. By contrast, the same treatment in old mice with already established mineral deposits failed to reduce mineralization. These results suggest that adenovirus-mediated ABCC6 gene delivery, when initiated early, is a promising prevention therapy for pseudoxanthoma elasticum and generalized arterial calcification of infancy, diseases that currently lack preventive or therapeutic options.

Premature termination codon read-through in the ABCC6 gene: potential treatment for pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder manifesting with ectopic connective tissue mineralization, caused by mutations in the ABCC6 gene, with ~35% of all mutations being premature termination mutations. In this study, we investigated the therapeutic potential of the nonsense codon read-through-inducing drug, PTC124, in treating PXE. The ability of this drug to facilitate read-through of nonsense mutations was examined in HEK293 cells transfected with human ABCC6 expression constructs harboring seven different PXE-associated nonsense mutations, and was evaluated by immunofluorescence and In-Cell ELISA. Our data demonstrated that PTC124 did not exhibit cytotoxicity in concentrations up to 20 µg ml(-1), and the facilitated read-through varied not only with dose but also with sequence context. Considering the redundancy of the genetic code, it was postulated that in case of the most common recurrent nonsense mutation, p.R1141X, the read-through may result in substitution of the arginine 1,141 by glycine, tryptophan, or cysteine. Their potential pathogenicity was tested in a recently developed zebrafish messenger RNA (mRNA) rescue assay, and demonstrated that all three mRNA transcripts were able to rescue abcc6a morpholino-induced phenotype of zebrafish. Thus, our results suggest that read-through of nonsense mutations in ABCC6 by PTC124 may have potential for pharmacologic treatment of PXE.

Nonuremic calciphylaxis associated with histologic changes of pseudoxanthoma elasticum.

Calciphylaxis is a rare condition characterized by medial calcification of small- and medium-sized vessels that subsequently leads to ischemic necrosis. Calciphylaxis most often occurs in patients with end-stage renal disease and secondary hyperparathyroidism. We present a unique case of calciphylaxis in which the patient did not have end-stage renal disease. Instead, primary hyperparathyroidism and/or alcoholic cirrhosis were the more likely causes of her calciphylaxis. In addition, our case demonstrated not only calciphylaxis but also fragmentation and calcification of elastic fibers within the dermis, changes that are most often seen in pseudoxanthoma elasticum. This is the first reported case of calciphylaxis, to our knowledge, with histopathologic changes of pseudoxanthoma elasticum in a patient who is nonuremic.

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.

[Angioid streaks complicated by choroidal neovascularization secondary to pseudoxanthoma elasticum: diagnosis and treatment. Case report]. / Stries angioïdes compliquées de néovaisseaux choroïdiens révélant un pseudoxanthome élastique : diagnostic et stratégie thérapeutique. À propos d'un cas.

Angioid streaks represent linear breaks in Bruch's membrane secondary to a change in the elastic layer. They are often associated with pseudoxanthoma elasticum. We report the case of a 36-year-old man with no prior history who was seen for a macular problem in the left eye, eventually involving the right eye after 3 months. He was diagnosed with pseudoxanthoma elasticum, associated with angioid streaks, complicated by choroidal neovascularization in both eyes. He was treated with intravitreal ranibizumab injections (0.5 mg/0.05 mL). His course in the right eye was remarkable for stable improvement at 3 months after the final injection. In the left eye, after initial improvement, recurrence was noted 2.5 months after injection, with subfoveal progression of the choroidal neovascularisation, unresponsive to a fourth ranibizumab injection. Angioid streaks represent a degenerative retinal pathology of elastic tissue with the potential for ingrowth of choroidal neovascularization. Various therapeutic approaches such as photodynamic therapy or laser photocoagulation have been proposed, with variable and sometimes limited results. Intravitreal ranibizumab injections currently remain the best treatment and should be studied with a longer-term, larger series.

Complications of thalassemia major and their treatment.

The life of patients with thalassemia has improved both in duration and in quality in industrialized countries. Complications are still common and include heart disease (heart failure and arrhythmias), chronic liver hepatitis, which can evolve in cirrhosis and, rarely, in hepatocellular carcinoma, endocrine problems (hypogonadism, hypothyroidism, diabetes, hypoparathyroidism), stunted growth, osteoporosis, thrombophilia and pseudoxanthoma elasticum. The incidence of complications is decreasing in younger cohorts of patients who have been transfused with blood that has been screened for viruses and thanks to the introduction of new oral iron chelators and imaging methods. The accurate measurement of iron deposits allows better management of iron overload. In addition, therapy for several complications is available. Specialized competence in treating patients with thalassemia is of great importance.

Pseudoxanthoma elasticum, ocular manifestations, complications and treatment.

Pseudoxanthoma elasticum (PXE), also known as Groenblad syndrome, is an inherited disorder characterised by mineralisation and fragmentation of elastic fibres in a number of organs including the skin, eyes and arterial blood vessels. The clinical manifestations of PXE centre on three major organ systems: skin, cardiovascular system and the eyes. This review focuses on the ocular manifestations of pseudoxanthoma elasticum, namely, peau d'orange, angioid streaks and choroidal neovascularisation, the clinical course of patients, the diagnostic approaches and current therapeutic strategies, such as laser photocoagulation whether transpupillary thermotherapy or photodynamic therapy, macular translocation surgery and anti-vascular endothelial growth factor treatment.

Overexpression of fetuin-a counteracts ectopic mineralization in a mouse model of pseudoxanthoma elasticum (abcc6(-/-)).

The pathologic hallmark of pseudoxanthoma elasticum (PXE) is ectopic mineralization of soft connective tissues. Recent studies have suggested that PXE is a metabolic disease, and perturbations in a number of circulatory factors have been postulated. One of them is fetuin-A, a 60-kDa glycoprotein synthesized in the liver and secreted into blood. Observations in targeted mutant mice (Ahsg(-/-)) and in cell culture model systems have shown that fetuin-A is a powerful anti-mineralization factor in circulation, and the serum levels of fetuin-A in patients with PXE as well as in a mouse model of PXE (Abcc6(-/-)) have been shown to be reduced by up to 30%. In this study, we tested the hypothesis that overexpression of fetuin-A in Abcc6(-/-) mice counteracts the ectopic mineralization. Delivery of an expression construct containing full-length mouse fetuin-A complementary DNA (cDNA), linked to a His-tag, to the liver of these mice resulted in elevated serum levels of this protein. As a consequence, soft tissue mineralization, which is a characteristic of Abcc6(-/-) mice, was reduced by approximately 70% at 12 weeks of age, but the effect was transient when examined 4 weeks later. The results suggest that normalization of serum fetuin-A, either through gene therapy approaches or by direct protein delivery to the circulation, may offer strategies for treating PXE and perhaps other heritable disorders of soft tissue mineralization.

Membranoproliferative glomerulonephritis associated with pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE) is a multiorgan disorder affecting mainly the skin, the eyes, and the cardiovascular system. A 51-year-old woman was admitted to our clinic complaining of weakness and swelling of her legs for the past two years. She had a proteinuria of 7.29 g/24 h. Renal biopsy was performed, and the histological diagnosis was membranoproliferative glomerulonephritis. Four weeks later, she was admitted to the hospital due to pain in her left hand and necrosis in the fourth and fifth fingertips of the left hand. A skin biopsy was performed from the forearm and was reported as PXE. Herein, we present a case of membranoproliferative glomerulonephritis accompanying PXE.

Ectopic mineralization of connective tissue in Abcc6-/- mice: effects of dietary modifications and a phosphate binder--a preliminary study.

Pseudoxanthoma elasticum (PXE), a heritable multisystem disorder, is caused by mutations in the ABCC6 gene. We have developed a murine model for PXE by targeted inactivation of the corresponding mouse gene. A feature of this mouse model is ectopic mineralization of connective tissue capsule surrounding the bulb of vibrissae. This study was designed to investigate the effect of dietary sevelamer hydrochloride (Renagel), a phosphate binder, and specific mineral modifications on ectopic mineralization of connective tissue in Abcc6-/- mice. Three groups were fed a specific diet: (i) a standard rodent diet, (ii) a standard rodent diet supplemented with sevelamer hydrochloride, and (iii) a custom experimental diet with specific mineral modifications (high phosphorus, low calcium and low magnesium). The degree of mineralization was determined in hematoxylin-eosin-stained sections using computerized morphometric analysis and by chemical assays to measure the calcium and phosphorus content of the vibrissae. The results indicated increased mineralization in the Abcc6-/- mice fed a standard diet or a diet with mineral modifications as compared with control mice fed a standard diet. However, feeding Abcc6-/- mice with diet supplemented with sevelamer hydrochloride did not improve mineralization, in comparison to mice fed with normal diet. Collectively, these results suggest that the mineralization process in PXE may be exacerbated by changes in mineral intake. The role of dietary minerals, and phosphorus in particular, as well as that of phosphate binders, in ectopic mineralization of PXE, merits further investigation.

Pseudoxanthoma elasticum with cerebrovascular accident.

A 65-year-old male presented with right hemiparesis and skin lesions. On examination, the patient had multiple, discrete, skin-colored papules on the neck and upper chest with wrinkling of the skin. The lateral part of the trunk and medial aspect of both upper arms showed atrophic plaques. A computerized tomography scan of the head showed dilatation of the basilar artery with a frontoparietal infarct. Funduscopic examination showed characteristic angioid streaks. Skin biopsy of the papule and atrophic plaques showed epidermal atrophy, calcium deposits in the mid-dermis and basophilic clumped and fragmented elastic fibers in the mid- and lower dermis, all findings consistent with pseudoxanthoma elasticum. We are reporting here a case of pseudoxanthoma elasticum with cerebrovascular accident.

Descubriendo el pseudoxantoma elástico / Discovering the elasticum pseudoxanthoma

Enfermedad hereditaria rara, el pseudoxantoma elástico es un trastorno genético del tejido conectivo, que se caracteriza por fragmentación de las fibras elásticas y posterior calcificación de éstas afectando dermis, vasos sanguíneos y la membrana de Bruch de retina. El patrón de herencia es muy variable, lo que hace posible que esta enfermedad pueda estar subdiagnosticada. La escasa incidencia de esta patología justifica la presentación de dos casos que tuvieron solamente manifestaciones cutáneas.

Hereditary disease does not frequent pseudoxanthoma elastic; is a genetic upheaval of the conective weave, that characterizes by fragmentation of elastic fibers and later calcification of these, affecting dermis, blood vessels and membrane of Bruch of retina. The inheritance pattern is very variable which causes that disease; can be subdiagnosed. The litlle incidence of this pathology, causes that in our professional experience we have been able to diagnose two cases in which the manifestations were cutaneous.

Penicillamine induced pseudoxanthoma elasticum with elastosis perforans serpiginosa.

Long term D-penicillamine therapy, especially when used to treat Wilson's disease has been shown to cause elastosis perforans serpiginosa, pseudoxanthoma elasticum perforans and other degenerative dermatoses. We report a 23-year-old male patient who presented with multiple firm papules, nodules over the neck, axillae, front of elbows for five years. He was a known case of Wilson's disease on long-term treatment with penicillamine for the past 12 years. The papulonodular lesions were non-tender and some were discrete while others were arranged in a circinate pattern. There was central scarring of the skin within the circinate lesions. In addition, there were several small yellowish papules on both sides of the neck which eventually became confluent to form plaques. Histopathology confirmed the diagnosis of elastosis perforans serpiginosa and pseudoxanthoma elasticum. He was treated with cryotherapy (using liquid nitrogen through cryojet) for former lesions. The lesions showed remarkable improvement after five sittings. Now the patient is under trientine hydrochloride (750 mg twice daily) for Wilson's disease.

Pseudoxanthoma elasticum and its complications: two case reports.

We describe 2 patients with pseudoxanthoma elasticum (PXE) and angioid streaks. In one patient PXE was complicated by cardiovascular disease. The other patient presented with acute visual decline in one eye after a minor blunt injury. Information about PXE and its complications is given.

Juvenile pseudoxanthoma elasticum: recognition and management.

An 8-year-old girl had pseudoxanthoma elasticum (PXE) with the characteristic skin and ocular findings. She had no associated systemic symptoms and no family history of PXE. The disease was most likely inherited in an autosomal recessive fashion. It is reviewed with regard to etiology, inheritance, diagnosis, and, particularly, management.