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Orphanet Journal of Rare Diseases May 2017Pseudoxanthoma elasticum (PXE) is a genetic metabolic disease with autosomal recessive inheritance caused by mutations in the ABCC6 gene. The lack of functional ABCC6... (Review)
Review
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 -
Genetic heterogeneity of heritable ectopic mineralization disorders in a large international cohort.Genetics in Medicine : Official Journal... Jan 2022Heritable ectopic mineralization disorders comprise a group of conditions with a broad range of clinical manifestations in nonskeletal connective tissues. We report the...
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 -
Autopsy & Case Reports 2017
PubMed: 29259928
DOI: 10.4322/acr.2017.035 -
Genetics in Medicine : Official Journal... Jan 2021Pseudoxanthoma elasticum (PXE) is a heritable disorder affecting elastic fibers in the skin, eyes, and cardiovascular system. It is caused by biallelic pathogenic...
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 -
ACG Case Reports Journal Jun 2020
PubMed: 33062784
DOI: 10.14309/crj.0000000000000410 -
Biomedicines Dec 2021Pseudoxanthoma 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... (Review)
Review
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 -
Archives of Disease in Childhood Jul 2005Pseudoxanthoma elasticum (PXE) is a rare multisystem disorder characterised by progressive calcification and fragmentation of elastic fibres. Recent genetic advances... (Review)
Review
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 -
FEBS Letters Dec 2020Researchers working on basic and translational clinical science related to ABC transporters are enthusiastic and dedicated investigators. As the field has grown, so has... (Review)
Review
Researchers working on basic and translational clinical science related to ABC transporters are enthusiastic and dedicated investigators. As the field has grown, so has its contribution to human disease. Pseudoxanthoma elasticum (PXE) International, an advocacy organization established by non-scientists, began supporting research and convenings on these transporters, specifically ABCC6, the gene associated with PXE, 20 years ago. As a patient advocacy organization, we have spent more than 25 years creating a large research consortium, initiating, funding and conducting research. Years of basic modelling and vigorous hypothesis testing have resulted in some important advances leading to clinical trials. The synergy of basic scientists, lay advocates, clinicians and translational scientists has dramatically accelerated research on PXE and progress towards better and more effective treatments for PXE patients.
Topics: Biomedical Research; Humans; International Cooperation; Multidrug Resistance-Associated Proteins; Patient Advocacy; Pseudoxanthoma Elasticum; Research Personnel; Stakeholder Participation
PubMed: 33211322
DOI: 10.1002/1873-3468.14002 -
Dermatologie (Heidelberg, Germany) Apr 2023Genodermatoses are a group of inherited skin diseases whose diagnosis is challenging due to their rarity as well as their clinical and genetic diversity. The majority... (Review)
Review
Genodermatoses are a group of inherited skin diseases whose diagnosis is challenging due to their rarity as well as their clinical and genetic diversity. The majority of genodermatoses are autosomal or X‑linked inherited, but mosaic forms are also observed. Genodermatoses comprise various phenotypes ranging from limited cutaneous disease to severe cutaneous and extracutaneous involvement and may also be early warning signs of a multisystemic disorder. Despite recent advances in genetic technology and skin imaging modalities, dermoscopy can be useful for screening, diagnosis, and treatment follow-up. In ectopic mineralization and lysosomal storage disorders (pseudoxanthoma elasticum and Fabry disease, respectively), cutaneous manifestations may indicate involvement of other organs. In keratinization diseases (e.g., ichthyoses) and acantholytic skin fragility disorders (e.g., Darier and Hailey-Hailey disease), dermoscopy may help to assess treatment response by visualizing background erythema, hyperkeratosis, and interkeratinocyte space prominence. Dermoscopy is a noninvasive, easily accessible, useful, in vivo assessment tool that is well established in dermatology to recognize characteristic features of genodermatoses.
Topics: Humans; Dermoscopy; Skin; Ichthyosis; Keratosis; Pemphigus, Benign Familial
PubMed: 36882583
DOI: 10.1007/s00105-023-05124-7