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JACC. Case Reports Jun 2023A 60-year-old woman with pseudoxanthoma elasticum (PXE) underwent thorough coronary artery disease assessments. Intravascular imaging tests suggested fragmented and...
A 60-year-old woman with pseudoxanthoma elasticum (PXE) underwent thorough coronary artery disease assessments. Intravascular imaging tests suggested fragmented and calcified elastic fibers in the internal elastic lamina, suggesting a possible pathophysiology of coronary artery disease in PXE. Our case report would allow clinicians to acknowledge the clinical picture of PXE. ().
PubMed: 37396331
DOI: 10.1016/j.jaccas.2023.101894 -
The Keio Journal of Medicine Jun 2023Our Research Group for Rare and Intractable Skin Diseases operates within the Project for Research on Intractable Diseases of the Ministry of Health, Labour, and Welfare...
Our Research Group for Rare and Intractable Skin Diseases operates within the Project for Research on Intractable Diseases of the Ministry of Health, Labour, and Welfare of Japan and is conducting research on eight rare intractable skin diseases. Five of these are monogenic disorders (epidermolysis bullosa, congenital ichthyoses, oculocutaneous albinism, pseudoxanthoma elasticum, and hereditary angioedema), and for a sixth [generalized pustular psoriasis (GPP)], genetic predisposing factors are important. This review introduces our activities for raising public awareness of these six intractable hereditary skin diseases and summarizes our recent achievements in clarifying the situation of medical treatments for these diseases in Japan. We note our current progress in elucidating the pathogeneses of these diseases and in developing new treatment methods, and we discuss our progress in establishing clinical practice guidelines. A nationwide survey on epidermolysis bullosa and a clinical survey on congenital ichthyoses are progressing. The Angioedema Activity Score and the Angioedema Quality-of-Life Questionnaire, the latter of which is a quality-of-life evaluation tool, have been established for hereditary angioedema. Registries of patients with oculocutaneous albinism and pseudoxanthoma elasticum have been created, and the registry for the latter has achieved its target of 170 cases. For GPP, the results of our survey on clinical practice were published in 2021. Information regarding all six of these hereditary skin diseases has been disseminated to academic societies, medical professionals, patients, and the general public.
PubMed: 37380461
DOI: 10.2302/kjm.2023-0008-IR -
Intractable & Rare Diseases Research May 2023Pseudoxanthoma elasticum (PXE) is a rare, genetic, metabolic disease characterized by dystrophic calcification of elastic fibres in the skin, retina and vascular wall....
Pseudoxanthoma elasticum (PXE) is a rare, genetic, metabolic disease characterized by dystrophic calcification of elastic fibres in the skin, retina and vascular wall. Data on cardiac involvement are inconsistent. Hence, we aimed to evaluate cardiorespiratory response to incremental cardiopulmonary exercise testing (CPET) in PXE. A total of 30 PXE patients (54.0 ± 11.2 years, 40.0% male) and 15 matched controls underwent symptom-limited incremental CPET. PXE patients presented an impaired peak work rate as compared to controls (84.2 ± 16.0% . 94.7 ± 10.4%, = 0.03) that was accompanied by a lower peak oxygen uptake (in % predicted and mL/min/kg), reduced increments in oxygen uptake per increments of work rate (Δ´O/ΔWR, 8.4 ± 3.0 mL/min/W . 11.3 ± 4.9 mL/ min/W, = 0.02), lower peak oxygen pulse (78.0 ± 12.3% . 90.6 ± 19.6%, = 0.01) and reduced minute ventilation at peak exercise (´E, 66.2 ± 16.8% . 82.9 ± 25.2%, = 0.02). To summarize, we presently observed impairment in mainly cardiocirculatory parameters, whilst no substantial ventilatory limitation was detected. The potential implications of this finding for PXE management warrant further study.
PubMed: 37287659
DOI: 10.5582/irdr.2023.01014 -
Biomolecules Apr 2023Ectopic calcification and dysregulated extracellular matrix remodeling are prominent hallmarks of the complex heterogenous pathobiochemistry of pseudoxanthoma elasticum...
Ectopic calcification and dysregulated extracellular matrix remodeling are prominent hallmarks of the complex heterogenous pathobiochemistry of pseudoxanthoma elasticum (PXE). The disease arises from mutations in , an ATP-binding cassette transporter expressed predominantly in the liver. Neither its substrate nor the mechanisms by which it contributes to PXE are completely understood. The fibroblasts isolated from PXE patients and mice were subjected to RNA sequencing. A group of matrix metalloproteinases (MMPs) clustering on human chromosome 11q21-23, respectively, murine chromosome 9, was found to be overexpressed. A real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay and immunofluorescent staining confirmed these findings. The induction of calcification by CaCl resulted in the elevated expression of selected MMPs. On this basis, the influence of the MMP inhibitor Marimastat (BB-2516) on calcification was assessed. PXE fibroblasts (PXEFs) exhibited a pro-calcification phenotype basally. PXEF and normal human dermal fibroblasts responded with calcium deposit accumulation and the induced expression of osteopontin to the addition of Marimastat to the calcifying medium. The raised MMP expression in PXEFs and during cultivation with calcium indicates a correlation of ECM remodeling and ectopic calcification in PXE pathobiochemistry. We assume that MMPs make elastic fibers accessible to controlled, potentially osteopontin-dependent calcium deposition under calcifying conditions.
Topics: Humans; Mice; Animals; Pseudoxanthoma Elasticum; Osteopontin; Calcium; Calcinosis; Phenotype; Matrix Metalloproteinases; Multidrug Resistance-Associated Proteins
PubMed: 37189419
DOI: 10.3390/biom13040672 -
Anais Brasileiros de Dermatologia 2023
Topics: Humans; Pseudoxanthoma Elasticum; Skin Diseases; Skin
PubMed: 37087383
DOI: 10.1016/j.abd.2021.07.012 -
Journal of Vitreoretinal Diseases 2023To describe a patient with concurrent pseudoxanthoma elasticum (PXE) and Cowden syndrome who developed choroidal neovascularization (CNV) secondary to angioid streaks....
PURPOSE
To describe a patient with concurrent pseudoxanthoma elasticum (PXE) and Cowden syndrome who developed choroidal neovascularization (CNV) secondary to angioid streaks. The CNV presented at a young age and was relatively refractory to intravitreal antivascular endothelial growth factor (anti-VEGF) therapy.
METHODS
A retrospective chart review was performed.
RESULTS
A 32-year-old man was treated for bilateral sequential CNV over 11 years. Good visual acuity was maintained with 53 anti-VEGF injections in the right eye and 82 injections in the left eye. On average, 1 injection was administered every 1.7 months in each eye to control the exudation. A skin biopsy and genetic testing confirmed a diagnosis of PXE. He was also found to harbor a mutation consistent with Cowden syndrome.
CONCLUSIONS
The concurrent mutation lends a possible explanation for the relative resistance of CNV to anti-VEGF therapy in this patient with PXE. Phosphatase and tensin homolog is a tumor suppressor that negatively regulates the VEGF pathway.
PubMed: 37008396
DOI: 10.1177/24741264221117013 -
Frontiers in Bioscience (Landmark... Mar 2023Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive disorder caused by mutations in the () gene. Patients with PXE show molecular and clinical characteristics...
BACKGROUND
Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive disorder caused by mutations in the () gene. Patients with PXE show molecular and clinical characteristics of known premature aging syndromes, such as Hutchinson-Gilford progeria syndrome (HGPS). Nevertheless, PXE has only barely been discussed against the background of premature aging, although a detailed characterization of aging processes in PXE could contribute to a better understanding of its pathogenesis. Thus, this study was performed to evaluate whether relevant factors which are known to play a role in accelerated aging processes in HGPS pathogenesis are also dysregulated in PXE.
METHODS
Primary human dermal fibroblasts from healthy donors (n = 3) and PXE patients (n = 3) and were cultivated under different culture conditions as our previous studies point towards effects of nutrient depletion on PXE phenotype. Gene expression of , , , and were determined by quantitative real-time polymerase chain reaction. Additionally, protein levels of lamin A, C and nucleolin were evaluated by immunofluorescence and the telomere length was analyzed.
RESULTS
We could show a significant decrease of and gene expression in PXE fibroblasts under nutrient depletion compared to controls. The gene expression of and showed a significant increase in PXE fibroblasts when cultivated in 10% fetal calf serum (FCS) compared to controls. Immunofluorescence microscopy of and and mRNA expression of and showed no significant changes in any case. The determination of the relative telomere length showed significantly longer telomeres for PXE fibroblasts compared to controls when cultivated in 10% FCS.
CONCLUSIONS
These data indicate that PXE fibroblasts possibly undergo a kind of senescence which is independent of telomere damage and not triggered by defects of the nuclear envelope or nucleoli deformation.
Topics: Humans; Progeria; Aging, Premature; Lamin Type A; Pseudoxanthoma Elasticum; Farnesyltranstransferase; Metalloproteases; Zinc; Fibroblasts
PubMed: 37005749
DOI: 10.31083/j.fbl2803055 -
Journal of Family Medicine and Primary... Dec 2022Increased laxity of the skin can be caused by aging, significant weight loss, or defects in the elastic tissue. A 38-year-old female presented with increased laxity of...
Increased laxity of the skin can be caused by aging, significant weight loss, or defects in the elastic tissue. A 38-year-old female presented with increased laxity of the skin over the neck, thighs, and abdomen for 6 years, associated with headache and blurring of vision for a week. On cutaneous examination, prominent skin folds, laxity, and wrinkles were noted over the neck, abdomen, thighs, and groin, with yellowish papules along the neck creases. Ocular examination revealed features suggestive of angioid streaks. Skin biopsy showed fragmented elastic fibers and intervening calcium deposits on Verhoeff Van Gieson and Von Kossa stains. Based on these findings, a diagnosis of pseudoxanthoma elasticum (PXE) was made. The patient was started on oral and topical sunscreens and eye protection and advised regular follow-up. Diagnosing the condition early based on skin findings can help prevent further multi-system manifestations by taking appropriate preventive measures as this condition is progressive and has no cure.
PubMed: 36994043
DOI: 10.4103/jfmpc.jfmpc_2337_21 -
Journal of Clinical Medicine Feb 2023Pseudoxanthoma elasticum (PXE) is a rare ectopic calcification disorder affecting soft connective tissues that is caused by biallelic mutations. While the underlying...
Pseudoxanthoma elasticum (PXE) is a rare ectopic calcification disorder affecting soft connective tissues that is caused by biallelic mutations. While the underlying pathomechanisms are incompletely understood, reduced circulatory levels of inorganic pyrophosphate (PPi)-a potent mineralization inhibitor-have been reported in PXE patients and were suggested to be useful as a disease biomarker. In this study, we explored the relation between PPi, the genotype and the PXE phenotype. For this, we optimized and validated a PPi measurement protocol with internal calibration that can be used in a clinical setting. An analysis of 78 PXE patients, 69 heterozygous carriers and 14 control samples revealed significant differences in the measured PPi levels between all three cohorts, although there was overlap between all groups. PXE patients had a ±50% reduction in PPi levels compared to controls. Similarly, we found a ±28% reduction in carriers. PPi levels were found to correlate with age in PXE patients and carriers, independent of the genotype. No correlations were found between PPi levels and the Phenodex scores. Our results suggest that other factors besides PPi are at play in ectopic mineralization, which limits the use of PPi as a predictive biomarker for severity and disease progression.
PubMed: 36902680
DOI: 10.3390/jcm12051893 -
International Journal of Molecular... Mar 2023Pseudoxanthoma elasticum (PXE) is characterized by low levels of inorganic pyrophosphate (PPi) and a high activity of tissue-nonspecific alkaline phosphatase (TNAP).... (Randomized Controlled Trial)
Randomized Controlled Trial
Pseudoxanthoma elasticum (PXE) is characterized by low levels of inorganic pyrophosphate (PPi) and a high activity of tissue-nonspecific alkaline phosphatase (TNAP). Lansoprazole is a partial inhibitor of TNAP. The aim was to investigate whether lansoprazole increases plasma PPi levels in subjects with PXE. We conducted a 2 × 2 randomized, double-blind, placebo-controlled crossover trial in patients with PXE. Patients were allocated 30 mg/day of lansoprazole or a placebo in two sequences of 8 weeks. The primary outcome was the differences in plasma PPi levels between the placebo and lansoprazole phases. 29 patients were included in the study. There were eight drop-outs due to the pandemic lockdown after the first visit and one due to gastric intolerance, so twenty patients completed the trial. A generalized linear mixed model was used to evaluate the effect of lansoprazole. Overall, lansoprazole increased plasma PPi levels from 0.34 ± 0.10 µM to 0.41 ± 0.16 µM ( = 0.0302), with no statistically significant changes in TNAP activity. There were no important adverse events. 30 mg/day of lansoprazole was able to significantly increase plasma PPi in patients with PXE; despite this, the study should be replicated with a large number of participants in a multicenter trial, with a clinical end point as the primary outcome.
Topics: Humans; Cross-Over Studies; Diphosphates; Double-Blind Method; Phosphoric Diester Hydrolases; Pseudoxanthoma Elasticum
PubMed: 36902331
DOI: 10.3390/ijms24054899