scholarly journals Therapy of Pseudoxanthoma Elasticum: Current Knowledge and Future Perspectives

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1895
Author(s):  
Max Jonathan Stumpf ◽  
Nadjib Schahab ◽  
Georg Nickenig ◽  
Dirk Skowasch ◽  
Christian Alexander Schaefer
Keyword(s):  
Current Knowledge ◽  
Treatment Options ◽  
Pseudoxanthoma Elasticum ◽  
Skin Lesions ◽  
Arterial Calcification ◽  
Future Perspectives ◽  
Strong Inhibitor ◽  
New Therapeutic Approaches ◽  
Pathogenic Variants ◽  
Abcc6 Gene

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 Although various treatment options have emerged during the last 20 years, many are either already outdated or not yet ready to be applied generally. Clinical physicians often are left stranded while patients suffer from the consequences of outdated therapies, or feel unrecognized by their attending doctors who may feel uncertain about using new therapeutic approaches or not even know about them.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.

Pseudoxanthoma elasticum with prominent arterial calcifications evoking CD73 deficiency

2019 ◽  
Vol 24 (5) ◽  
pp. 461-464 ◽  
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.

scholarly journals Dysregulation of gene expression in ABCC6 knockdown HepG2 cells

2014 ◽  
Vol 19 (4) ◽  
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.

scholarly journals Generalized Arterial Calcification of Infancy Type 1 (GACI1): Identification of a Novel Pathogenic Variant (c.1715T>C (p.Leu572Ser))

Diagnostics ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 1034
Author(s):  
Gaetano Pietro Bulfamante ◽  
Laura Carpenito ◽  
Emma Bragantini ◽  
Silvia Graziani ◽  
Maria Bellizzi ◽  
...  
Keyword(s):  
Sequence Analysis ◽  
Clinical Manifestations ◽  
Pathogenic Variant ◽  
Arterial Calcification ◽  
Medium Size ◽  
Internal Elastic Lamina ◽  
Pathogenic Variants ◽  
Abcc6 Gene ◽  
Enpp1 Gene

Generalized Arterial Calcification of Infancy (GACI) is a rare disease inherited in a recessive manner, with severe and diffuse early onset of calcifications along the internal elastic lamina in large and medium size arteries. The diagnosis results are from clinical manifestations, imaging, histopathologic exams, and genetic tests. GACI is predominantly caused by biallelic pathogenic variant in the ENPP1 gene (GACI1, OMIM#208000) and, to a lesser extent, by pathogenic variants in the ABCC6 gene (GACI2, OMIM#614473). We present a novel variation in the ENPP1 gene identified in a patient clinically diagnosed with GACI and confirmed by genetic investigation and autopsy as GACI type 1. The sequence analysis of the patient’s ENPP1 gene detected two heterozygous variants c.1412A>G (p.Tyr471Cys) and c.1715T>C (p.Leu572Ser). The variant c.1715T>C (p.Leu572Ser) has not been described yet in the literature and in mutation databases. A genetic analysis was also carried out for the parents of the newborn; the heterozygous pathogenic variant c.1412A>G (p.Tyr471Cys) was detected in the mother’s ENPP1 gene, and a sequence analysis of the father’s ENPP1 gene revealed the novel heterozygous variant c.1715T>C (p.Leu572Ser). Our results showed that the variant c.1715T>C (p.Leu572Ser) may have a pathogenic role in the development of GACI type1 (GACI1, OMIM#208000), at least when associated with the pathogenic c.1412A>G (p.Tyr471Cys) variant. The identification of novel mutations potentially enabled genotype/phenotype associations that will ultimately have an impact on clinical management and prognosis for the disease.

scholarly journals Mutations in the ABCC6 Gene as a Cause of Generalized Arterial Calcification of Infancy: Genotypic Overlap with Pseudoxanthoma Elasticum

2014 ◽  
Vol 134 (3) ◽  
pp. 658-665 ◽  
Author(s):  
Qiaoli Li ◽  
Jill L. Brodsky ◽  
Laura K. Conlin ◽  
Bruce Pawel ◽  
Andrew C. Glatz ◽  
...  
Keyword(s):  
Pseudoxanthoma Elasticum ◽  
Arterial Calcification ◽  
Abcc6 Gene

scholarly journals Pseudoxanthoma Elasticum and Cardiorenal Disease: A Case Report

2019 ◽  
Author(s):  
Luis D'Marco ◽  
Carlos Soto ◽  
Fabiola Dapena
Keyword(s):  
Genetic Disorder ◽  
Renal Involvement ◽  
Vascular Complications ◽  
Pseudoxanthoma Elasticum ◽  
Skin Lesions ◽  
Arterial Calcification ◽  
Elastic Fibres ◽  
Phosphate Homeostasis ◽  
Calcification Inhibitors ◽  
The Impact

Pseudoxanthoma elasticum (PXE) is a rare genetic disorder characterized by calcification of elastic fibres, skin lesions, fundus lesions and systemic vascular complications. PXE affects approximately 1 in 160,000 people, typically appearing as a formation of yellow papules containing abnormally calcified elastic fibres. The renal involvement of PXE has been reported. Several factors are known to promote soft tissue and accelerated arterial calcification in chronic kidney disease, including systemic inflammation, altered calcium and phosphate homeostasis, hypertension and a deficiency of endogenous calcification inhibitors. Given the impact of this disease, nephrologists may seek additional supportive features to improve and avoid the risk of complications. Moreover, PXE per se represents an interesting model to evaluate vascular disease in the early stages of renal disease.

scholarly journals Neonatal Seizures: An Overview of Genetic Causes and Treatment Options

2021 ◽  
Vol 11 (10) ◽  
pp. 1295
Author(s):  
Giulia Spoto ◽  
Maria Concetta Saia ◽  
Greta Amore ◽  
Eloisa Gitto ◽  
Giuseppe Loddo ◽  
...  
Keyword(s):  
Neonatal Period ◽  
Clinical Symptoms ◽  
Current Knowledge ◽  
Treatment Options ◽  
Neonatal Seizures ◽  
Pathogenic Variants ◽  
Ohtahara Syndrome ◽  
The Central Nervous System ◽  
Myoclonic Encephalopathy

Seizures are the most frequent neurological clinical symptoms of the central nervous system (CNS) during the neonatal period. Neonatal seizures may be ascribed to an acute event or symptomatic conditions determined by genetic, metabolic or structural causes, outlining the so-called ‘Neonatal Epilepsies’. To date, three main groups of neonatal epilepsies are recognised during the neonatal period: benign familial neonatal epilepsy (BFNE), early myoclonic encephalopathy (EME) and ‘Ohtahara syndrome’ (OS). Recent advances showed the role of several genes in the pathogenesis of these conditions, such as KCNQ2, KCNQ3, ARX, STXBP1, SLC25A22, CDKL5, KCNT1, SCN2A and SCN8A. Herein, we reviewed the current knowledge regarding the pathogenic variants most frequently associated with neonatal seizures, which should be considered when approaching newborns affected by these disorders. In addition, we considered the new possible therapeutic strategies reported in these conditions.

Pulmonary Manifestations in Rheumatoid Arthritis, Psoriatic Arthritis and Peripheral Spondyloarthritis Prevalence, Diagnostic Approach and Treatment Options

2020 ◽  
Vol 16 ◽  
Author(s):  
Daniel Dejcman ◽  
Valentin Sebastian Schäfer ◽  
Dirk Skowasch ◽  
Carmen Pizarro ◽  
Andreas Krause ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Psoriatic Arthritis ◽  
Lung Disease ◽  
Current Knowledge ◽  
Treatment Options ◽  
Pulmonary Diseases ◽  
Chronic Obstructive ◽  
Pulmonary Manifestations ◽  
Major Cluster ◽  
Peripheral Spondyloarthritis

: Interstitial lung disease (ILD) is the most common form of pulmonary impairment in patients with rheumatoid arthritis (RA). However, patients with RA or other arthritic diseases such as psoriatic arthritis (PsA) or peripheral spondyloarthritis (pSpA) may develop several other pulmonary diseases such as chronic obstructive lung disease (COPD) with a higher risk than patients without arthritis. The article at hand aims at summarizing the current knowledge on the prevalence of pulmonary diseases in the above-mentioned forms of arthritis, the challenges for prevalence studies and detecting pulmonary diseases in patients with arthritis as well as possible treatment options. Dyspnea, cough or other pulmonary symptoms or findings in arthritis patients should prompt gradual diagnostic procedures considering pulmonary manifestations as a major cluster of differential diagnosis. Considering its poor prognosis and morbidity burden, RA-ILD needs to be ruled out. Treatment of manifestations often lacks solid evidencebased guidelines and referrals to specialized centers are often necessary.

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