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Atherosclerosis Jun 2022Pseudoxanthoma elasticum (PXE) is a genetic disorder characterized by systemic calcification of elastin fibers. Additionally, PXE is associated with an increased risk of...
BACKGROUND AND AIMS
Pseudoxanthoma elasticum (PXE) is a genetic disorder characterized by systemic calcification of elastin fibers. Additionally, PXE is associated with an increased risk of stroke. It has been hypothesized that this may be caused by accelerated (intracranial) atherogenesis, as a consequence of specific genetic mutations underlying PXE. Hence, we compared the distribution and burden of intracranial atherosclerosis between PXE patients and healthy controls.
METHODS
Fifty PXE patients and 40 age-and-sex-matched healthy controls (without previous ischemic cerebrovascular disease) underwent 3T MRI to visualize atherosclerotic intracranial vessel wall lesions (VWLs). We compared the presence and burden of VWLs (total and for the anterior cerebral, middle cerebral, intracranial internal carotid, posterior cerebral, and basilar arteries separately) between PXE patients and healthy controls using logistic (presence versus absence) and negative binomial regression models (VWL count) adjusted for relevant confounders. All regressions included group (PXE patients vs. healthy controls) as independent variable.
RESULTS
We found that 34 (68.0%) PXE patients and 28 (70.0%) healthy controls had a VWL (odds ratio for presence 1.06 [95%CI 0.38-2.91]). In addition, the total burden of VWLs was similar between PXE patients (68 VWLs) and healthy controls (73 VWLs, incidence rate ratio for count 0.81 [95%CI 0.55-1.20]). Findings were similar when analyses were stratified for artery.
CONCLUSIONS
The distribution and burden of intracranial atherosclerosis were similar between PXE patients and healthy controls. This implies PXE and its underlying mutations do not involve increased (intracranial) atherogenesis and that vascular calcification or other mechanisms explains the increased stroke risk in PXE.
Topics: Atherosclerosis; Case-Control Studies; Humans; Intracranial Arteriosclerosis; Pseudoxanthoma Elasticum; Stroke; Vascular Calcification
PubMed: 35468517
DOI: 10.1016/j.atherosclerosis.2022.04.014 -
Annals of Medicine and Surgery (2012) May 2022•PXE is an extremely rare autosomal recessive disease.•It involves major systems in the body like the cutaneous, ocular, cardiovascular, and gastrointestinal.•The...
•PXE is an extremely rare autosomal recessive disease.•It involves major systems in the body like the cutaneous, ocular, cardiovascular, and gastrointestinal.•The characteristic histopathological features are calcification and fragmentation of the elastic fibres.•Currently, specific or effective treatment is not available.
PubMed: 35432986
DOI: 10.1016/j.amsu.2022.103571 -
Dermatology and Therapy May 2022Non-dermatology medical specialties may refer patients for skin biopsies, searching for a particular diagnosis. However, the diagnostic impact of the skin biopsy is not... (Review)
Review
INTRODUCTION
Non-dermatology medical specialties may refer patients for skin biopsies, searching for a particular diagnosis. However, the diagnostic impact of the skin biopsy is not clearly established. This article aims to assess the indications for, and evaluate the clinical relevance of, skin biopsies in non-dermatology medical specialties.
METHODS
A questionnaire was sent to 23 non-dermatology specialty departments in a university medical center, requesting a list of indications for skin biopsies, as well as to 10 staff dermatologists to collect the indications of skin biopsies requested by non-dermatology specialties. Once the indications were collected, a literature search was performed to evaluate their clinical value and relevance.
RESULTS
Eleven non-dermatology specialties provided a list of skin biopsy indications, to which staff dermatologists added seven more indications. A literature search revealed evidence-based medicine data for six diseases, that is, amyloidosis, peripheral autonomic neuropathy, Sneddon's syndrome, intravascular lymphoma, sarcoidosis, and chronic graft-versus-host disease. Results were questionable concerning infectious endocarditis, acute graft-versus-host-disease, and the lupus band test. Skin biopsy were not evidenced as useful for the diagnosis of calciphylaxis, systemic scleroderma, Behçet's disease, or hypermobile Ehlers-Danlos syndrome. For the diagnosis of Alport's syndrome, pseudoxanthoma elasticum, and vascular Ehlers-Danlos syndrome, skin biopsy is currently outperformed by genetic analyses. For diagnoses such as Henoch-Schönlein purpura and Sjögren's syndrome, skin biopsy represents an additional item among other diagnostic criteria.
CONCLUSION
The usefulness of skin biopsy as requested by non-dermatology specialties is only evidenced for amyloidosis, peripheral autonomic neuropathy, Sneddon's syndrome, intravascular lymphoma, sarcoidosis, chronic graft-versus-host-disease, Henoch-Schönlein purpura, and Sjögren's syndrome.
PubMed: 35430724
DOI: 10.1007/s13555-022-00717-x -
Dermatologie (Heidelberg, Germany) Oct 2022Characteristic skin changes lead to diagnosis of pseudoxanthoma elasticum (PXE), an ectopic mineralization disorder, involving primarily the skin, eyesight, and arterial...
Characteristic skin changes lead to diagnosis of pseudoxanthoma elasticum (PXE), an ectopic mineralization disorder, involving primarily the skin, eyesight, and arterial vessels. Early recognition is crucial for timely treatment of extracutaneous complications. We hereby report a series of four cases of PXE with pathognomonic skin lesions and a broad spectrum of systemic complications.
Topics: Dermatologists; Humans; Multidrug Resistance-Associated Proteins; Pseudoxanthoma Elasticum; Skin
PubMed: 35428953
DOI: 10.1007/s00105-022-04987-6 -
Indian Journal of Dermatology,... 2022
Topics: Fibrosis; Gadolinium; Humans; Nephrogenic Fibrosing Dermopathy; Pseudoxanthoma Elasticum; Renal Insufficiency; Renal Insufficiency, Chronic; Skin Diseases
PubMed: 35389021
DOI: 10.25259/IJDVL_853_2021 -
The Journal of Investigative Dermatology Apr 2022Significant progress has been made in understanding pseudoxanthoma elasticum (PXE), which results from mutations in ABCC6. The low prevalence of PXE and its heterotypic...
Significant progress has been made in understanding pseudoxanthoma elasticum (PXE), which results from mutations in ABCC6. The low prevalence of PXE and its heterotypic presentation confound genotype-phenotype correlations and the characterization of many identified variants. Kowal et al. (2022) present an in vivo model to characterize and annotate ABCC6 variants, establishing a novel system for allele annotation in the patient population.
Topics: Alleles; Genetic Association Studies; Humans; Multidrug Resistance-Associated Proteins; Mutation; Mutation, Missense; Pseudoxanthoma Elasticum
PubMed: 35331386
DOI: 10.1016/j.jid.2022.02.008 -
The Journal of Dermatology Jul 2022
Topics: Humans; Mutation; Practice Guidelines as Topic; Pseudoxanthoma Elasticum
PubMed: 35318717
DOI: 10.1111/1346-8138.16354 -
The Abcc6a Knockout Zebrafish Model as a Novel Tool for Drug Screening for Pseudoxanthoma Elasticum.Frontiers in Pharmacology 2022Pseudoxanthoma elasticum (PXE) is a multisystem ectopic mineralization disorder caused by pathogenic variants in the ABCC6 gene. Though complications of the disease can...
Pseudoxanthoma elasticum (PXE) is a multisystem ectopic mineralization disorder caused by pathogenic variants in the ABCC6 gene. Though complications of the disease can be treated, PXE itself remains currently intractable. A strategy for rapid and cost-effective discovery of therapeutic drugs would be to perform chemical compound screening using zebrafish, but this approach remains to be validated for PXE. In this paper, we validate a stable CRISPR/Cas9 abcc6a knockout zebrafish model-which has spinal column hypermineralization as its primary phenotypic feature-as a model system for compound screening in ectopic mineralization. We evaluated the anti-mineralization potential of five compounds, which had (anecdotal) positive effects reported in Abcc6 knockout mice and/or PXE patients. Abcc6a knockout zebrafish larvae were treated from 3 to 10 days post-fertilization with vitamin K1, sodium thiosulfate, etidronate, alendronate or magnesium citrate and compared to matching controls. Following alizarin red S staining, alterations in notochord sheath mineralization were semiquantified and found to largely congrue with the originally reported outcomes. Our results demonstrate that the use of this abcc6a knockout zebrafish model is a validated and promising strategy for drug discovery against ectopic mineralization.
PubMed: 35317004
DOI: 10.3389/fphar.2022.822143 -
Intractable & Rare Diseases Research Feb 2022Pseudoxanthoma elasticum (PXE) is a rare, heritable disease caused by various, mainly recessively transmitted mutations in the gene. Due to calcification of soft...
Pseudoxanthoma elasticum (PXE) is a rare, heritable disease caused by various, mainly recessively transmitted mutations in the gene. Due to calcification of soft connective tissue phenotypic hallmarks are progressive loss of vision, alternation of the skin and early onset atherosclerosis. Beside these main features patients also suffer from impaired alveolar diffusion. The present study focused on impaired lung functioning based on a large cohort of patients with PXE, its long-term development, and genotype-phenotype correlation. Retrospectively, 98 patients and 45 controls were enrolled. All patients underwent body plethysmography and carbon monoxide diffusion testing. Of 35 patients three or more body plethysmographic records were available for long-term analysis. For genotype-phenotype analysis genotypes were grouped as two missense, mixed, or two nonsense mutations. Patients with PXE showed significantly reduced vital capacity ( < 0.05), diffusion capacity ( < 0.01), and diffusion transfer coefficient ( < 0.05). Over a mean period of 38 months diffusion capacity ( < 0.05) and diffusion transfer coefficient ( < 0.01) dropped significantly whereas lung volumes remained unchanged. Genotype-phenotype correlation revealed no connection between gene variants and lung functioning. In conclusion, PXE is accompanied by progressive reduction of alveolar diffusion indicating progressive alterations of lung tissue. Genotype-phenotype correlation with genotypes sorted as missense and nonsense mutations do not explain impaired lung functioning.
PubMed: 35261845
DOI: 10.5582/irdr.2021.01162 -
International Journal of Molecular... Feb 2022Arterial calcification is a common feature of pseudoxanthoma elasticum (PXE), a disease characterized by mutations, inducing a deficiency in pyrophosphate, a key...
UNLABELLED
Arterial calcification is a common feature of pseudoxanthoma elasticum (PXE), a disease characterized by mutations, inducing a deficiency in pyrophosphate, a key inhibitor of calcium phosphate crystallization in arteries.
METHODS
we analyzed whether long-term exposure of Abcc6 mice (a murine model of PXE) to a mild vitamin D supplementation, with or without calcium, would impact the development of vascular calcification. Eight groups of mice (including Abcc6 and wild-type) received vitamin D supplementation every 2 weeks, a calcium-enriched diet alone (calcium in drinking water), both vitamin D supplementation and calcium-enriched diet, or a standard diet (controls) for 6 months. Aorta and kidney artery calcification was assessed by 3D-micro-computed tomography, Optical PhotoThermal IR (OPTIR) spectroscopy, scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy (SEM-EDS) and Yasue staining.
RESULTS
at 6 months, although vitamin D and/or calcium did not significantly increase serum calcium levels, vitamin D and calcium supplementation significantly worsened aorta and renal artery calcification in Abcc6 mice.
CONCLUSIONS
vitamin D and/or calcium supplementation accelerate vascular calcification in a murine model of PXE. These results sound a warning regarding the use of these supplementations in PXE patients and, to a larger extent, patients with low systemic pyrophosphate levels.
Topics: Animals; Arteries; Calcification, Physiologic; Calcium; Calcium, Dietary; Dietary Supplements; Disease Models, Animal; Female; Mice; Multidrug Resistance-Associated Proteins; Pseudoxanthoma Elasticum; Vascular Calcification; Vitamin D
PubMed: 35216422
DOI: 10.3390/ijms23042302