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PSEUDOXANTHOMA ELASTICUM: DIAGNOSTIC FEATURES, CLASSIFICATION, AND TREATMENT OPTIONS.

ABSTRACT: INTRODUCTION:Pseudoxanthoma elasticum (PXE), a multisystem orphan disease, clinically affects the skin, the eyes, and the cardiovascular system with considerable morbidity and mortality. The clinical manifestations reflect the underlying pathology consisting of ectopic mineralization of peripheral connective tissues. AREAS COVERED:The diagnostic criteria of PXE include characteristic clinical findings, together with histopathology of accumulation of pleiomorphic elastic structures in the dermis with progressive mineralization, and the presence of mutations in the ABCC6 gene. PXE-like cutaneous changes can also be encountered in other ectopic mineralization disorders, including generalized arterial calcification of infancy (GACI) caused by mutations in the ENPP1 gene. In some cases, overlapping clinical features of PXE/GACI, associated with mutations either in ABCC6 or ENPP1, have been noted. PXE demonstrates considerable inter- and intrafamilial heterogeneity, and consequently, accurate diagnosis is required for appropriate classification with prognostic implications. There is no effective and specific treatment for the systemic manifestations of PXE, but effective therapies to counteract the ocular complications are in current clinical use. EXPERT OPINION:A number of observations in the murine model, the Abcc6-/- mouse, have indicated that the mineral composition of diet, particularly the magnesium content, can influence the severity of the mineralization phenotype. These observations suggest that appropriate dietary interventions, coupled with lifestyle modifications, including smoking cessation, might alleviate the symptoms and improve the quality of life of individuals affected with this, currently intractable, orphan disease.

SUBMITTER: Uitto J

PROVIDER: S-EPMC4219573 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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PSEUDOXANTHOMA ELASTICUM: DIAGNOSTIC FEATURES, CLASSIFICATION, AND TREATMENT OPTIONS.

Uitto Jouni J Jiang Qiujie Q Váradi András A Bercovitch Lionel G LG Terry Sharon F SF

Expert opinion on orphan drugs 20140601 6

<h4>Introduction</h4>Pseudoxanthoma elasticum (PXE), a multisystem orphan disease, clinically affects the skin, the eyes, and the cardiovascular system with considerable morbidity and mortality. The clinical manifestations reflect the underlying pathology consisting of ectopic mineralization of peripheral connective tissues.<h4>Areas covered</h4>The diagnostic criteria of PXE include characteristic clinical findings, together with histopathology of accumulation of pleiomorphic elastic structures ...[more]

PMID: 25383264

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Project description:Pseudoxanthoma elasticum (PXE) is a genetic metabolic disease with autosomal recessive inheritance caused by mutations in the ABCC6 gene. The lack of functional ABCC6 protein leads to ectopic mineralization that is most apparent in the elastic tissues of the skin, eyes and blood vessels. The clinical prevalence of PXE has been estimated at between 1 per 100,000 and 1 per 25,000, with slight female predominance. The first clinical sign of PXE is almost always small yellow papules on the nape and sides of the neck and in flexural areas. The papules coalesce, and the skin becomes loose and wrinkled. The mid-dermal elastic fibers are short, fragmented, clumped and calcified. Dystrophic calcification of Bruch's membrane, revealed by angioid streaks, may trigger choroidal neovascularization and, ultimately, loss of central vision and blindness in late-stage disease. Lesions in small and medium-sized artery walls may result in intermittent claudication and peripheral artery disease. Cardiac complications (myocardial infarction, angina pectoris) are thought to be relatively rare but merit thorough investigation. Ischemic strokes have been reported. PXE is a metabolic disease in which circulating levels of an anti-mineralization factor are low. There is good evidence to suggest that the factor is inorganic pyrophosphate (PPi), and that the circulating low levels of PPi and decreased PPi/Pi ratio result from the lack of ATP release by hepatocytes harboring the mutant ABCC6 protein. However, the substrate(s) bound, transported or modulated by the ABCC6 protein remain unknown. More than 300 sequence variants of the ABCC6 gene have been identified. There is no cure for PXE; the main symptomatic treatments are vascular endothelial growth factor inhibitor therapy (for ophthalmic manifestations), lifestyle, lipid-lowering and dietary measures (for reducing vascular risk factors), and vascular surgery (for severe cardiovascular manifestations). Future treatment options may include gene therapy/editing and pharmacologic chaperone therapy.

Project description:ImportanceAcute retinopathy may partly explain variable disease manifestation and vision loss in patients with pseudoxanthoma elasticum (PXE). The diagnosis of this likely autoimmune process may inform patient counseling and treatment approaches.ObjectiveTo characterize acute retinopathy in patients with PXE as a disease manifestation that may be associated with profound visual impairment.Design, setting, and participantsThis single-center case series was conducted from May 2013 to October 2018. It used the patient database of the Department of Ophthalmology at the University of Bonn, a referral center for PXE in Germany. Patients at this center with genetically confirmed PXE and who met the inclusion criteria were included (n = 9). Patients underwent multimodal retinal imaging, including fundus photography, fundus autofluorescence (AF), optical coherence tomography (OCT), fluorescein angiography (FA), and indocyanine green angiography (ICGA); in select cases, electroretinography as well as antiretinal and anti-retinal pigment epithelium (RPE) antibody testing were also used.Main outcomes and measuresClinical presentation and disease course.ResultsNine patients (8 [89%] female; mean [range] age, 43 [19-55] years) with acute retinopathy were identified in a cohort of 167 consecutive patients with PXE (frequency of 5%). Symptoms ranged from light sensations or metamorphopsia to profound vision loss. Visual acuity was reduced in 6 patients (67%), ranging from a best-corrected visual acuity of 20/30 to perception of hand movements at manifestation. All patients revealed characteristic fundus features with temporary appearance of partly confluent outer retinal whitish dots at the posterior pole, which corresponded to areas of hyperautofluorescence on fundus AF, loss of the ellipsoid band on OCT, and associated scotomata. The FA and late-phase ICGA imaging showed associated hyperfluorescence and hypocyanescence. Electroretinography revealed a variable reduction of amplitudes. Changes were fully reversible within 1 month in 3 of 8 patients with available follow-up data. Of the remaining 5 patients, 3 had a prolonged and likely permanent vision loss (observation period, 1-64 months) mainly owing to central subretinal hyperreflective material originating from angioid streaks. In 4 (67%) of 6 tested, antiretinal and/or anti-RPE antibodies were detected.Conclusions and relevanceAcute retinopathy in patients with PXE may occur, with symptoms ranging from short-term, reversible alterations to irreversible vision loss; these findings contribute to understanding the variable ocular disease progression in PXE and provide insights into the autoimmune phenomena of the posterior pole.

Dataset Information

PSEUDOXANTHOMA ELASTICUM: DIAGNOSTIC FEATURES, CLASSIFICATION, AND TREATMENT OPTIONS.

Publications

PSEUDOXANTHOMA ELASTICUM: DIAGNOSTIC FEATURES, CLASSIFICATION, AND TREATMENT OPTIONS.

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