Zebrafish enpp1 mutants exhibit pathological mineralization, mimicking features of generalized arterial calcification of infancy (GACI) and pseudoxanthoma elasticum (PXE)

Pseudoxanthoma elasticum (PXE) is a rare, genetic, metabolic disease with an estimated prevalence of between 1 per 25,000 and 56,000. Its main hallmarks are characteristic skin lesions, development of choroidal neovascularization, and early-onset arterial calcification accompanied by a severe reduction in quality-of-life. Underlying the pathology are recessively transmitted pathogenic variants of the ABCC6 gene, which results in a deficiency of ABCC6 protein. This results in reduced levels of peripheral pyrophosphate, a strong inhibitor of peripheral calcification, but also dysregulation of blood lipids. Although various treatment options have emerged during the last 20 years, many are either already outdated or not yet ready to be applied generally. Clinical physicians often are left stranded while patients suffer from the consequences of outdated therapies, or feel unrecognized by their attending doctors who may feel uncertain about using new therapeutic approaches or not even know about them. In this review, we summarize the broad spectrum of treatment options for PXE, focusing on currently available clinical options, the latest research and development, and future perspectives.

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Pseudoxanthoma elasticum with prominent arterial calcifications evoking CD73 deficiency

Vascular Medicine ◽

10.1177/1358863x19853360 ◽

2019 ◽

Vol 24 (5) ◽

pp. 461-464 ◽

Cited By ~ 4

Author(s):

Magali Devriese ◽

Anne Legrand ◽

Marie-Cécile Courtois ◽

Xavier Jeunemaitre ◽

Juliette Albuisson

Keyword(s):

Vascular Calcification ◽

Pseudoxanthoma Elasticum ◽

Arterial Calcification ◽

Elastic Fibers ◽

Connective Tissues ◽

Tibial Arteries ◽

Ectopic Mineralization ◽

Abcc6 Gene ◽

Next Generation Sequencing Ngs ◽

Eye Lesions

Pseudoxanthoma elasticum (PXE) is a rare disorder characterized by skin, eye, and cardiovascular lesions due to ectopic mineralization and fragmentation of elastic fibers of connective tissues. We present an atypical case of PXE with diffuse vascular calcification and negligible skin and eye lesions. The patient was a 37-year-old man suffering from severe bilateral arterial calcifications in superficial femoral and posterior tibial arteries. Eye fundoscopy and skin examination were first considered normal. This phenotype suggested first the diagnosis of Arterial Calcification due to Deficiency of CD73 (ACDC) characterized by mutations in NT5E gene. However, we found two variants in ABCC6 gene, and no variant in NT5E. Skin reexamination revealed few lateral skin papules confined to the scalp. Phenotypic overlap was described in vascular calcification disorders, between GACI and PXE phenotypes, and we discuss here expansion of this overlap, including ACDC phenotype. Identification of these expanding and overlapping phenotypes was enabled by genetic screening of the corresponding genes, in a systematic approach. We propose to create a calcification next generation sequencing (NGS) panel with NT5E, GGCX, ENPP1, and ABCC6 genes to improve the molecular diagnosis of vascular calcification.

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Increased Elastin Degradation in Pseudoxanthoma Elasticum Is Associated with Peripheral Arterial Disease Independent of Calcification

Journal of Clinical Medicine ◽

10.3390/jcm9092771 ◽

2020 ◽

Vol 9 (9) ◽

pp. 2771

Author(s):

Jonas W. Bartstra ◽

Wilko Spiering ◽

Jody M. W. van den Ouweland ◽

Willem P. T. M. Mali ◽

Rob Janssen ◽

...

Keyword(s):

Peripheral Arterial Disease ◽

Ankle Brachial Index ◽

Pseudoxanthoma Elasticum ◽

Arterial Disease ◽

Arterial Calcification ◽

Elastin Degradation ◽

Liquid Chromatography Tandem Mass ◽

Peripheral Arterial ◽

Fontaine Classification

Pseudoxanthoma elasticum (PXE) results in extensive fragmentation and calcification of elastin fibers in the peripheral arteries, which results in peripheral arterial disease (PAD). Current research focuses on the role of calcifications in the pathogenesis of PXE. Elastin degradation and calcification are shown to interact and may amplify each other. This study aims to compare plasma desmosines, a measure of elastin degradation, between PXE patients and controls and to investigate the association between desmosines and (1) arterial calcification, (2) PAD, and (3) PAD independent of arterial calcification in PXE. Plasma desmosines were quantified with liquid chromatography-tandem mass spectrometry in 93 PXE patients and 72 controls. In PXE patients, arterial calcification mass was quantified on CT scans. The ankle brachial index (ABI) after treadmill test was used to analyze PAD, defined as ABI < 0.9, and the Fontaine classification was used to distinguish symptomatic and asymptomatic PAD. Regression models were built to test the association between desmosines and arterial calcification and arterial functioning in PXE. PXE patients had higher desmosines than controls (350 (290–410) ng/L vs. 320 (280–360) ng/L, p = 0.02). After adjustment for age, sex, body mass index, smoking, type 2 diabetes mellitus, and pulmonary abnormalities, desmosines were associated with worse ABI (β (95%CI): −68 (−132; −3) ng/L), more PAD (β (95%CI): 40 (7; 73) ng/L), and higher Fontaine classification (β (95%CI): 30 (6; 53) ng/L), but not with arterial calcification mass. Lower ABI was associated with higher desmosines, independent from arterial calcification mass (β (95%CI): −0.71(−1.39; −0.01)). Elastin degradation is accelerated in PXE patients compared to controls. The association between desmosines and ABI emphasizes the role of elastin degradation in PAD in PXE. Our results suggest that both elastin degradation and arterial calcification independently contribute to PAD in PXE.

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Dysregulation of gene expression in ABCC6 knockdown HepG2 cells

Cellular & Molecular Biology Letters ◽

10.2478/s11658-014-0208-2 ◽

2014 ◽

Vol 19 (4) ◽

Cited By ~ 17

Author(s):

Rocchina Miglionico ◽

Maria Armentano ◽

Monica Carmosino ◽

Antonella Salvia ◽

Flavia Cuviello ◽

...

Keyword(s):

Hepg2 Cells ◽

Autosomal Recessive ◽

Pseudoxanthoma Elasticum ◽

Arterial Calcification ◽

Elastic Fibers ◽

Ectopic Calcification ◽

Ectopic Mineralization ◽

Abcc6 Gene ◽

Basolateral Plasma Membrane

AbstractABCC6 protein is an ATP-dependent transporter that is mainly found in the basolateral plasma membrane of hepatocytes. ABCC6 deficiency is the primary cause of several forms of ectopic mineralization syndrome. Mutations in the human ABCC6 gene cause pseudoxanthoma elasticum (PXE), an autosomal recessive disease characterized by ectopic calcification of the elastic fibers in dermal, ocular and vascular tissues. Mutations in the mouse ABCC6 gene were also associated with dystrophic cardiac calcification. Reduced levels of ABCC6 protein were found in a β-thalassemic mouse model. Moreover, some cases of generalized arterial calcification in infancy are due to ABCC6 mutations. In order to study the role of ABCC6 in the pathogenesis of ectopic mineralization, the expressions of genes involved in this process were evaluated in HepG2 cells upon stable knockdown of ABCC6 by small hairpin RNA (shRNA) technology. ABCC6 knockdown in HepG2 cells causes a significant upregulation of the genes promoting mineralization, such as TNAP, and a parallel downregulation of genes with anti-mineralization activity, such as NT5E, Fetuin A and Osteopontin. Although the absence of ABCC6 has been already associated with ectopic mineralization syndromes, this study is the first to show a direct relationship between reduced ABCC6 levels and the expression of pro-mineralization genes in hepatocytes.

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Disseminated Arterial Calcification and Enhanced Myogenic Response Are Associated With Abcc6 Deficiency in a Mouse Model of Pseudoxanthoma Elasticum

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.113.302943 ◽

2014 ◽

Vol 34 (5) ◽

pp. 1045-1056 ◽

Cited By ~ 15

Author(s):

Gilles Kauffenstein ◽

A. Pizard ◽

Y. Le Corre ◽

E. Vessières ◽

L. Grimaud ◽

...

Keyword(s):

Mouse Model ◽

Pseudoxanthoma Elasticum ◽

Arterial Calcification ◽

Myogenic Response

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Cutaneous features of pseudoxanthoma elasticum in a patient with generalized arterial calcification of infancy due to a homozygous missense mutation in the ENPP1 gene

British Journal of Dermatology ◽

10.1111/j.1365-2133.2012.10811.x ◽

2012 ◽

Vol 166 (5) ◽

pp. 1107-1111 ◽

Cited By ~ 33

Author(s):

Q. Li ◽

W. Schumacher ◽

D. Jablonski ◽

D. Siegel ◽

J. Uitto

Keyword(s):

Missense Mutation ◽

Pseudoxanthoma Elasticum ◽

Arterial Calcification ◽

Homozygous Missense Mutation ◽

Enpp1 Gene

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Therapeutics Development for Pseudoxanthoma Elasticum and Related Ectopic Mineralization Disorders: Update 2020

Journal of Clinical Medicine ◽

10.3390/jcm10010114 ◽

2020 ◽

Vol 10 (1) ◽

pp. 114

Author(s):

Hongbin Luo ◽

Qiaoli Li ◽

Yi Cao ◽

Jouni Uitto

Keyword(s):

Plasma Levels ◽

Autosomal Recessive Disorder ◽

Pseudoxanthoma Elasticum ◽

Calcium Hydroxyapatite ◽

The Elderly ◽

Arterial Calcification ◽

Inorganic Pyrophosphate ◽

Treatment Development ◽

Arterial Blood ◽

Ectopic Mineralization

Pseudoxanthoma elasticum (PXE), the prototype of heritable ectopic mineralization disorders, manifests with deposition of calcium hydroxyapatite crystals in the skin, eyes and arterial blood vessels. This autosomal recessive disorder, due to mutations in ABCC6, is usually diagnosed around the second decade of life. In the spectrum of heritable ectopic mineralization disorders are also generalized arterial calcification of infancy (GACI), with extremely severe arterial calcification diagnosed by prenatal ultrasound or perinatally, and arterial calcification due to CD73 deficiency (ACDC) manifesting with arterial and juxta-articular mineralization in the elderly; the latter disorders are caused by mutations in ENPP1 and NT5E, respectively. The unifying pathomechanistic feature in these three conditions is reduced plasma levels of inorganic pyrophosphate (PPi), a powerful endogenous inhibitor of ectopic mineralization. Several on-going attempts to develop treatments for these conditions, either with the goal to normalize PPi plasma levels or by means of preventing calcium hydroxyapatite deposition independent of PPi, are in advanced preclinical levels or in early clinical trials. This overview summarizes the prospects of treatment development for ectopic mineralization disorders, with PXE, GACI and ACDC as the target diseases, from the 2020 vantage point.

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