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.

Healthcare transition from childhood to adulthood in pseudoxanthoma elasticum: Patient experience and recommendations for health practitioners.

PURPOSE: Health-care transition (HCT) is a necessary part of the care process for allsick adolescents, to allow their empowerment while limiting disruption to follow-up care. Pseudoxanthoma elasticum (PXE) runs the risk of losing patients to follow-up because young patients are predominantly asymptomatic. This can be detrimental as it can prevent primary prevention measures from being properly implemented. The purpose of this study was to assess satisfaction of PXE patients with their health-care transition and to identify the factors associated with its success, in order to improve care management in young PXE patients. METHODS: Patients aged 22 to 40 years diagnosed with PXE before the age of 16 years were included from the cohort of patients followed at Angers University Hospital. They were sent a questionnaire for the purposes of collecting data on medical management during adolescence, transition and adulthood. RESULTS: Eleven responses were obtained from the 21 patients surveyed. The median satisfaction score of PXE patients regarding their transition was 5/10. Three patients reported having discontinued follow-up after transition. In adulthood, the majority of the participants were followed up by 4 specialists as recommended. It was incumbent on 50% of the patients who changed doctors to provide details of their own medical history to the new practitioner. CONCLUSION: Better intra-practitioner communication and a chart summarizing the principles of primary prevention, optimal follow-up care and its frequency are simple to implement and in all likelihood result in better health-care transition for young PXE patients.

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.

Clinical practice guidelines for pseudoxanthoma elasticum (2017): Clinical Practice Guidelines for Pseudoxanthoma Elasticum Drafting Committee

Pseudoxanthoma elasticum (PXE) is a progressive hereditary disease that affects tissues such as the skin, retina, blood vessels, and gastrointestinal tracts. Therefore, comprehensive medical care across clinical departments specialized in specific organs is needed to provide the best clinical practices to PXE patients. The Japanese version of clinical guidelines developed by the Japanese Dermatological Association was published in 2017, and aimed to promote equal accessibility of PXE-related medical care. Here, the English version of Japanese guideline is reported, and is intended to be worldwide reference for medical care of PXE.

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.

[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.

PXE, a Mysterious Inborn Error Clarified.

Ever since Garrod deduced the existence of inborn errors in 1901, a vast array of metabolic diseases has been identified and characterized in molecular terms. In 2018 it is difficult to imagine that there is any uncharted backyard left in the metabolic disease landscape. Nevertheless, it took until 2013 to identify the cause of a relatively frequent inborn error, pseudoxanthoma elasticum (PXE), a disorder resulting in aberrant calcification. The mechanism found was not only biochemically interesting but also points to possible new treatments for PXE, a disease that has remained untreatable. In this review we sketch the tortuous road that led to the biochemical understanding of PXE and to new ideas for treatment. We also discuss some of the controversies still haunting the field.

Approach to the management of pregnancy in patients with pseudoxanthoma elasticum: a review.

Management of pregnancy in patients with rare diseases is often guided by incomplete knowledge because of a lack of high-quality case control studies or single-centre experience. Pseudoxanthoma elasticum (PXE) is an autosomal recessive metabolic disorder that results in calcification of elastic fibres of the skin, retina, and arteries, leading to skin lesions, eventual central visual loss, and potential arterial insufficiency in most patients. It is due to mutations in ABCC6, which encodes the eponymous membrane transport protein. We review the literature on pregnancy in PXE, including the effects of the diseases on pregnancy and its complications, the effect of PXE on the foetus, and the effects of pregnancy on PXE, and conclude that in the majority of pregnancies in women with PXE, the outcome for mother, baby, and the disease is uneventful. We also provide recommendations for managing pregnancy in PXE.

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.

Seudoxantoma elástico en el diagnóstico diferencial de las calcificaciones axilares en la mamografía / Pseudoxanthoma Elasticum in the Differential Diagnosis of Axillary Calcifications on Mammography

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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.