Pseudoxanthoma Elasticum, Kidney Stones and Pyrophosphate: From a Rare Disease to Urolithiasis and Vascular Calcifications

Pseudoxanthoma elasticum is a rare disease mainly due to ABCC6 gene mutations and characterized by ectopic biomineralization and fragmentation of elastic fibers resulting in skin, cardiovascular and retinal calcifications. It has been recently described that pyrophosphate (a calcification inhibitor) deficiency could be the main cause of ectopic calcifications in this disease and in other genetic disorders associated to mutations of ENPP1 or CD73. Patients affected by Pseudoxanthoma Elasticum seem also prone to develop kidney stones originating from papillary calcifications named Randall’s plaque, and to a lesser extent may be affected by nephrocalcinosis. In this narrative review, we summarize some recent discoveries relative to the pathophysiology of this mendelian disease responsible for both cardiovascular and renal papillary calcifications, and we discuss the potential implications of pyrophosphate deficiency as a promoter of vascular calcifications in kidney stone formers and in patients affected by chronic kidney disease.

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Role of Serum Fetuin-A, a Major Inhibitor of Systemic Calcification, in Pseudoxanthoma Elasticum

Clinical Chemistry ◽

10.1373/clinchem.2005.059253 ◽

2006 ◽

Vol 52 (2) ◽

pp. 227-234 ◽

Cited By ~ 60

Author(s):

Doris Hendig ◽

Veronika Schulz ◽

Marius Arndt ◽

Christiane Szliska ◽

Knut Kleesiek ◽

...

Keyword(s):

Blood Donors ◽

Family Members ◽

Gene Mutations ◽

Pseudoxanthoma Elasticum ◽

Elastic Fibers ◽

Fetuin A ◽

Cardiovascular Involvement ◽

Abcc6 Gene ◽

Sandwich Enzyme Immunoassay

Abstract Background: Pseudoxanthoma elasticum (PXE) is a hereditary disorder of the connective tissue affecting the skin, retina, and cardiovascular system and characterized by progressive calcification of abnormal and fragmented elastic fibers in the extracellular matrix. The aim of the present study was to investigate the association of fetuin-A, a major systemic inhibitor of calcification, with PXE. Methods: Fetuin-A was measured by quantitative sandwich enzyme immunoassay in sera from 110 German patients with PXE, 53 unaffected first-degree family members, and 80 healthy blood donors. We determined the distribution of the fetuin-A polymorphisms c.742C>T (p.T248M) and c.766C>G (p.T256S) in these same 3 groups. The occurrences of the frequent ABCC6 gene mutations c.3421C>T (p.R1141X) and c.EX23_EX29del were also assessed. Results: Serum fetuin-A concentrations in male and female PXE patients were lower than in unaffected first-degree relatives and controls [mean (SD) concentrations, 0.55 (0.11) g/L in patients; 0.70 (0.23) g/L in relatives; and 0.80 (0.23) g/L in controls (P <0.0001)]. Serum fetuin-A was higher in female PXE patients with cardiovascular involvement than in the corresponding male group (P <0.05). The fetuin-A polymorphism frequencies did not differ among PXE patients, family members, and blood donors. Conclusion: A deficiency of multidrug resistance-associated protein 6 leads to alteration of circulating substrates, e.g., inhibitors of calcification as fetuin-A, leading to progressive mineralization of elastic fibers in PXE.

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New ABCC6 gene mutations in German pseudoxanthoma elasticum patients

Journal of Molecular Medicine ◽

10.1007/s00109-004-0588-2 ◽

2004 ◽

Vol 83 (2) ◽

pp. 140-147 ◽

Cited By ~ 21

Author(s):

Doris Hendig ◽

Veronika Schulz ◽

Jutta Eichgr�n ◽

Christiane Szliska ◽

Christian G�tting ◽

...

Keyword(s):

Gene Mutations ◽

Pseudoxanthoma Elasticum ◽

Abcc6 Gene

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Identification of ABCC6 gene mutations in the Japanese patients with pseudoxanthoma elasticum (PXE)

Journal of Dermatological Science ◽

10.1016/j.jdermsci.2012.11.477 ◽

2013 ◽

Vol 69 (2) ◽

pp. e57-e58

Author(s):

Akira Iwanaga ◽

Mariko Yozaki ◽

Yosuke Yagi ◽

Koji Maemura ◽

Eiko Tsuiki ◽

...

Keyword(s):

Gene Mutations ◽

Pseudoxanthoma Elasticum ◽

Japanese Patients ◽

Abcc6 Gene

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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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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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Pseudoxanthoma Elasticum: Report of Two Cases

Case Reports in Dermatology ◽

10.1159/000513468 ◽

2021 ◽

pp. 230-237

Author(s):

Israel Antonio Esquivel-Pinto ◽

Maria Elisa Vega-Memije ◽

Araceli Alvarado-Delgadillo ◽

Andres Eduardo Campuzano-Garcia ◽

Amairani Manríquez-Robles

Keyword(s):

Early Diagnosis ◽

Rare Disease ◽

Autosomal Recessive ◽

Genetic Defect ◽

Autosomal Recessive Inheritance ◽

Pseudoxanthoma Elasticum ◽

Elastic Fibers ◽

Elastic Tissue ◽

Recessive Inheritance ◽

Therapeutic Approaches

Elastic pseudoxanthoma is a rare disease with autosomal recessive inheritance, also known as Grönblad-Strandberg syndrome, characterized by pathological mineralization of the elastic fibers in the connective tissue, affecting principally the dermis of skin, media, and intima of blood vessels and Bruch’s membrane of the eye. The genetic defect of the disorder is located on chromosome 16p13.1 and disease is caused by the lack of functional ABCC6 protein, which in turn causes extracellular accumulation and deposition of calcium and other minerals in the elastic tissue. In this article we present two cases of this rare disease. We emphasize, in the diagnostic criteria, the importance of its early diagnosis and the current therapeutic approaches.

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Clinical Phenotypes and ABCC6 Gene Mutations in Brazilian Families with Pseudoxanthoma Elasticum

Acta Dermato Venereologica ◽

10.2340/00015555-1570 ◽

2013 ◽

Vol 93 (6) ◽

pp. 739-740 ◽

Cited By ~ 1

Author(s):

C Faria ◽

Q Li ◽

H Guo ◽

J Uitto ◽

S Takeno ◽

...

Keyword(s):

Gene Mutations ◽

Pseudoxanthoma Elasticum ◽

Clinical Phenotypes ◽

Abcc6 Gene

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Dermal Alterations in Clinically Unaffected Skin of Pseudoxanthoma elasticum Patients

Journal of Clinical Medicine ◽

10.3390/jcm10030500 ◽

2021 ◽

Vol 10 (3) ◽

pp. 500

Author(s):

Federica Boraldi ◽

Francesco Demetrio Lofaro ◽

Lorena Losi ◽

Daniela Quaglino

Keyword(s):

Genetic Basis ◽

Pseudoxanthoma Elasticum ◽

Ultrastructural Level ◽

Matrix Composition ◽

Elastic Fibers ◽

Mechanical Forces ◽

Abcc6 Gene ◽

Systemic Disorder ◽

Skin Biopsies ◽

Unaffected Skin

Background: Pseudoxanthoma elasticum (PXE), due to rare sequence variants in the ABCC6 gene, is characterized by calcification of elastic fibers in several tissues/organs; however, the pathomechanisms have not been completely clarified. Although it is a systemic disorder on a genetic basis, it is not known why not all elastic fibers are calcified in the same patient and even in the same tissue. At present, data on soft connective tissue mineralization derive from studies performed on vascular tissues and/or on clinically affected skin, but there is no information on patients’ clinically unaffected skin. Methods: Skin biopsies from clinically unaffected and affected areas of the same PXE patient (n = 6) and from healthy subjects were investigated by electron microscopy. Immunohistochemistry was performed to evaluate p-SMAD 1/5/8 and p-SMAD 2/3 expression and localization. Results: In clinically unaffected skin, fragmented elastic fibers were prevalent, whereas calcified fibers were only rarely observed at the ultrastructural level. p-SMAD1/5/8 and p-SMAD2/3 were activated in both affected and unaffected skin. Conclusion: These findings further support the concept that fragmentation/degradation is necessary but not sufficient to cause calcification of elastic fibers and that additional local factors (e.g., matrix composition, mechanical forces and mesenchymal cells) contribute to create the pro-osteogenic environment.

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