Review

Authors: Kristina Pfau, Imre Lengyel, Jeannette Ossewaarde-van Norel...

Pseudoxanthoma elasticum (PXE) is an autosomal-recessively inherited multisystem disease. Mutations in the ABCC6-gene are causative, coding for a transmembrane transporter mainly expressed in hepatocytes, which promotes the efflux of adenosine triphosphate (ATP). This results in low levels of plasma inorganic pyrophosphate (PPi), a critical anti-mineralization factor. The clinical phenotype of PXE is characterized by the effects of elastic fiber calcification in the skin, the cardiovascular system, and the eyes. In the eyes, calcification of Bruch's membrane results in clinically visible lesions, including peau d'orange, angioid streaks, and comet tail lesions. Frequently, patients must be treated for secondary macular neovascularization. No effective therapy is available for treating the cause of PXE, but several promising approaches are emerging. Finding appropriate outcome measures remains a significant challenge for clinical trials in this slowly progressive disease. This review article provides an in-depth summary of the current understanding of PXE and its multi-systemic manifestations. The article offers a detailed overview of the ocular manifestations, including their morphological and functional consequences, as well as potential complications. Lastly, previous and future clinical trials of causative treatments for PXE are discussed.

Topics: Pseudoxanthoma Elasticum; Humans; Multidrug Resistance-Associated Proteins; Mutation

PubMed: 38815804
DOI: 10.1016/j.preteyeres.2024.101274

Review

Authors: Dominique P Germain

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.

Topics: Animals; Choroidal Neovascularization; Diphosphates; Humans; Metabolic Diseases; Peripheral Arterial Disease; Pseudoxanthoma Elasticum; Skin

PubMed: 28486967
DOI: 10.1186/s13023-017-0639-8

Authors: Bruna Morassi Sasso, Maria Letícia Cintra, Elemir Macedo de Souza...

PubMed: 29259928
DOI: 10.4322/acr.2017.035

Authors: Amir Hossein Saeidian, Leila Youssefian, Jianhe Huang...

PURPOSE

Heritable ectopic mineralization disorders comprise a group of conditions with a broad range of clinical manifestations in nonskeletal connective tissues. We report the genetic findings from a large international cohort of 478 patients afflicted with ectopic mineralization.

METHODS

Sequence variations were identified using a next-generation sequencing panel consisting of 29 genes reported in association with ectopic mineralization. The pathogenicity of select splicing and missense variants was analyzed in experimental systems in vitro and in vivo.

RESULTS

A total of 872 variants of unknown significance as well as likely pathogenic and pathogenic variants were disclosed in 25 genes. A total of 159 distinct variants were identified in 425 patients in ABCC6, the gene responsible for pseudoxanthoma elasticum, a heritable multisystem ectopic mineralization disorder. The interpretation of variant pathogenicity relying on bioinformatic predictions did not provide a consensus. Our in vitro and in vivo functional assessment of 14 ABCC6 variants highlighted this dilemma and provided unambiguous interpretations to their pathogenicity.

CONCLUSION

The results expand the ABCC6 variant repertoire, shed new light on the genetic heterogeneity of heritable ectopic mineralization disorders, and provide evidence that functional characterization in appropriate experimental systems is necessary to determine the pathogenicity of genetic variants.

Topics: Cohort Studies; Connective Tissue; Genetic Heterogeneity; Humans; Mutation, Missense; Pseudoxanthoma Elasticum

PubMed: 34906475
DOI: 10.1016/j.gim.2021.08.011

Authors: Shana Verschuere, Nastassia Navassiolava, Ludovic Martin...

PURPOSE

Pseudoxanthoma elasticum (PXE) is a heritable disorder affecting elastic fibers in the skin, eyes, and cardiovascular system. It is caused by biallelic pathogenic variants in the ABCC6 gene. To date, over 300 ABCC6 variants are associated with PXE, more than half being missense variants. Correct variant interpretation is essential for establishing a direct link between the variant and the patient's phenotype and has important implications for diagnosis and treatment.

METHODS

We used a systematic approach for interpretation of 271 previously reported and 15 novel ABCC6 missense variants, based on the semiquantitative classification system Sherloc.

RESULTS

Only 35% of variants were very likely to contribute directly to disease, in contrast to reported interpretations in ClinVar, while 59% of variants are currently of uncertain significance (VUS). Subclasses were created to distinguish VUS that are leaning toward likely benign or pathogenic, increasing the number of (likely) pathogenic ABCC6 missense variants to 47%.

CONCLUSION

Besides highlighting discrepancies between the Sherloc, American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP), ClinVar, and Leiden Open Variation Database (LOVD) classification, our results emphasize the need for segregation analysis, functional assays, and detailed evidence sharing in variant databases to reach a confident interpretation of ABCC6 missense variants and subsequent appropriate genetic and preconceptual counseling.

Topics: Humans; Multidrug Resistance-Associated Proteins; Mutation; Mutation, Missense; Phenotype; Pseudoxanthoma Elasticum

PubMed: 32873932
DOI: 10.1038/s41436-020-00945-6

Review

Authors: Max Jonathan Stumpf, Nadjib Schahab, Georg Nickenig...

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 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.

PubMed: 34944710
DOI: 10.3390/biomedicines9121895

Review

Authors: S Laube, C Moss

Pseudoxanthoma elasticum (PXE) is a rare multisystem disorder characterised by progressive calcification and fragmentation of elastic fibres. Recent genetic advances have identified the underlying defect to the ABCC6 gene on chromosome 16p13.1. Patients typically develop cutaneous, ocular, and cardiovascular manifestations but there is considerable phenotypic variability. The skin changes are usually apparent in adulthood, and rarely observed in childhood. Since the prognosis of PXE largely depends on the extent of extracutaneous organ involvement early recognition, intervention and lifestyle adjustments are important to reduce morbidity. First-degree family members should be carefully examined for any cutaneous or ophthalmologic features of PXE.

Topics: Cardiovascular Diseases; Child; Chromosomes, Human, Pair 16; Eye Diseases; Humans; Multidrug Resistance-Associated Proteins; Pseudoxanthoma Elasticum; Skin Diseases

PubMed: 15970621
DOI: 10.1136/adc.2004.062075

Review

Authors: Emmanuel Letavernier, Elise Bouderlique, Jeremy Zaworski...

Pseudoxanthoma elasticum is a rare disease mainly due to 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 or . 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.

Topics: 5'-Nucleotidase; Diphosphates; GPI-Linked Proteins; Humans; Kidney Calculi; Multidrug Resistance-Associated Proteins; Mutation; Pseudoxanthoma Elasticum; Rare Diseases; Urolithiasis; Vascular Calcification

PubMed: 31861118
DOI: 10.3390/ijms20246353

Review

Authors: Karobi Moitra, Sonia Garcia, Michelle Jaldin...

Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder characterized by the mineralization of connective tissues in the body. Primary manifestation of PXE occurs in the tissues of the skin, eyes, and cardiovascular system. PXE is primarily caused by mutations in the gene. The gene encodes the trans-membrane protein ABCC6, which is highly expressed in the kidneys and liver. PXE has high phenotypic variability, which may possibly be affected by several modifier genes. Disease advocacy organizations have had a pivotal role in bringing rare disease research to the forefront and in helping to sustain research funding for rare genetic diseases in order to help find a treatment for these diseases, pseudoxanthoma elasticum included. Because of these initiatives, individuals affected by these conditions benefit by being scientifically informed about their condition, having an effective support mechanism, and also by contributing to scientific research efforts and banking of biological samples. This rapid progress would not have been possible without the aid of disease advocacy organizations such as PXE International.

Topics: High-Throughput Nucleotide Sequencing; Humans; Multidrug Resistance-Associated Proteins; Mutation; Pseudoxanthoma Elasticum; Rare Diseases

PubMed: 28696355
DOI: 10.3390/ijms18071488

Authors: Harald Seeger, Nilufar Mohebbi

Topics: Adult; Blood Gas Analysis; Diagnosis, Differential; Exons; Female; Humans; Kidney; Multidrug Resistance-Associated Proteins; Mutation; Nephrocalcinosis; Parathyroid Hormone; Pseudoxanthoma Elasticum; Retinoscopy; Ultrasonography; Vitamin D

PubMed: 27181788
DOI: 10.1016/j.kint.2015.12.055