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Biomedicines Sep 2023Previous studies revealed a link between inflammation and overactivation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling in...
Previous studies revealed a link between inflammation and overactivation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling in syndromes associated with aging. Pseudoxanthoma elasticum (PXE), a rare autosomal-recessive disorder, arises from mutations in (). On a molecular level, PXE shares similarities with Hutchinson-Gilford progeria syndrome, such as increased activity of senescence-associated- beta-galactosidase or high expression of inflammatory factors. Thus, this study's aim was the evaluation of activated STAT3 and the influence of JAK1/2-inhibitor baricitinib (BA) on inflammatory processes such as the complement system in PXE. Analysis of activation of STAT3 was performed by immunofluorescence and Western blot, while inflammatory processes and complement system factors were determined based on mRNA expression and protein level. Our results assume overactivation of JAK/STAT3 signaling, increased expression levels of several complement factors and high C3 protein concentration in the sera of PXE patients. Supplementation with BA reduces JAK/STAT3 activation and partly reduces inflammation as well as the gene expression of complement factors belonging to the C1 complex and C3 convertase in PXE fibroblasts. Our results indicate a link between JAK/STAT3 signaling and complement activation contributing to the proinflammatory phenotype in PXE fibroblasts.
PubMed: 37893046
DOI: 10.3390/biomedicines11102673 -
Cureus Oct 2023Pseudoxanthoma elasticum (PXE) is a rare multisystem disease characterized by progressive calcification and disintegration of elastic fibers. The disorder is attributed...
Pseudoxanthoma elasticum (PXE) is a rare multisystem disease characterized by progressive calcification and disintegration of elastic fibers. The disorder is attributed to a genetic mutation occurring in the ABCC6 gene, which encodes for the ATP-binding cassette transporter C6. This gene is located on chromosome 16. Patients commonly present with cutaneous, ophthalmic, and cardiovascular manifestations. However, there is a significant degree of phenotypic diversity. The diagnosis is determined by clinical manifestations, histological analysis of the lesions, and genetic analysis. The present study includes a case report of a 12-year-old female patient who presented with a chief complaint of painless, mildly pruritic yellow papules located on her neck for a period of one year. These papules were accompanied by comedones.
PubMed: 38022106
DOI: 10.7759/cureus.47041 -
Journal of Personalized Medicine Dec 2023Generalized arterial calcification of infancy (GACI) is a rare autosomal-recessive disease characterized by extensive arterial calcification in infancy, with clinical...
Generalized arterial calcification of infancy (GACI) is a rare autosomal-recessive disease characterized by extensive arterial calcification in infancy, with clinical manifestations such as arterial stenoses and heart failure. The ENPP1 inactivation mutation has been identified as a potential defect in most of the cases of GACI, while mutations in are demonstrated in patients who are genotyped as pseudoxanthoma elasticum and only limited cases of GACI are reported. Whole-exome sequencing was applied for the detection of pathogenic variants. Copy-number variants of pathogenic genes were also evaluated through a bioinformatic process and were further validated by real-time quantitative PCR. In this report, we described the clinical information and treatment of a patient with extensive arterial calcification. We have identified the underlying cause as biallelic mutations in (NM_00117: exon30, c.4223_4227dupAGCTC p.(Leu1410Serfs*56)) and a unique exonic deletion that spans from the first to the fourth exons of (chr16:16313388-16330869)). This discovery was made by utilizing a combined genetic testing approach. With the review of previously reported GACI patients with mutation, our work contributed to enriching the mutation spectrum of GACI and providing further information on this rare form of inherited disorder.
PubMed: 38248755
DOI: 10.3390/jpm14010054 -
Atherosclerosis Plus Mar 2024- Pseudoxanthoma elasticum (PXE) is a rare genetic disease caused by pathogenic mutations in the ABCC6 gene, resulting in low values of inorganic pyrophosphate (PPi)....
BACKGROUND AND AIMS
- Pseudoxanthoma elasticum (PXE) is a rare genetic disease caused by pathogenic mutations in the ABCC6 gene, resulting in low values of inorganic pyrophosphate (PPi). While low PPi is thought to contribute to arterial calcification, it remains unclear whether this fully explains premature calcification in PXE. It has been hypothesized that the ABCC6 gene could be related to dyslipidemia, which could contribute to vascular calcification seen in PXE. The aim of this study is to evaluate the relation between PXE and plasma lipid concentrations in a large cohort of PXE patients compared with reference values for the general population and compared with non-PXE controls.
METHODS
- The plasma concentrations of total cholesterol, HDL-cholesterol, tiglycerides, and LDL-cholesterol of 312 PXE patients were compared to age- and sex-matched modeled data of the general Dutch population. Differences in median lipid levels were compared with Mann-Whitney-U test. Secondly, plasma lipid concentrations of 44 PXE patients were compared to 44 not-genetically related relatives (spouses or friends), with linear models adjusted for age, sex and BMI.
RESULTS
- Total cholesterol in PXE patients was 5.6 [IQR 4.6-6.4] mmol/L versus 5.3 [IQR 4.7-6.0] mmol/L (p < 0.01) in the general population; triglycerides were 1.1 [IQR 0.9-1.7] mmol/L versus 1.0 [0.7-1.4] mmol/L (p < 0.01); HDL-c was 1.4 [IQR 1.2-1.7] mmol/L versus 1.5 [IQR 1.2-1.8] mmol/L (p = 0.03) and LDL-c was 3.3 [IQR 2.7-4.1] mmol/L versus 3.2 [IQR 2.7-3.8] mmol/L (p = 0.01). In the patient control analysis with 44 pairs and age, sex and BMI adjusted, comparison with the non-PXE controls only triglycerides were significantly different (mean difference: 0.38 (0.13-0.63)).
CONCLUSION
-The lipid profiles of PXE patients are marginally different from the general population or compared to a matched control group, but the differences are unlikely to be clinically relevant It is therefore unlikely that plasma lipids contribute to the premature vascular calcifications in PXE patients.
PubMed: 38221909
DOI: 10.1016/j.athplu.2023.12.003 -
Clinical and Experimental Nephrology Jan 2024Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease characterized by diminished inorganic plasma pyrophosphate (PPi), a strong calcification inhibitor. In...
BACKGROUND
Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease characterized by diminished inorganic plasma pyrophosphate (PPi), a strong calcification inhibitor. In addition to more typical calcification of skin, retina and arterial wall a diminished plasma PPi could lead to other ectopic calcification, such as formation of kidney stones.
OBJECTIVE
To compare the prevalence of kidney stones between PXE patients and hospital controls on computed tomography (CT).
METHOD
Low-dose CT images of PXE patients and controls were assessed by one radiologist, who was blinded for the diagnosis PXE. The number of kidney stones, and the size of the largest stone was recorded. Odds ratios (ORs) for having kidney stone were calculated using multivariable adjusted logistic regression.
RESULTS
Our study comprised 273 PXE patients and 125 controls. The mean age of PXE patients was 51.5 ± 15.9 years compared to 54.9 ± 14.2 in the control group (p = 0.04) and PXE patients more often were women (63 vs. 50%, p = 0.013). The prevalence of kidney stones on CT was similar: 6.9% in PXE patients, compared to 5.6% in controls (p = 0.6). In the multivariate analysis adjusting for age and sex, there was no significantly higher odds for PXE patients on having stones, compared to controls: OR 1.48 (95% CI 0.62-3.96).
CONCLUSION
There is no significant difference in the prevalence of incidental kidney stones on CT in PXE patients versus controls.
Topics: Humans; Female; Adult; Middle Aged; Aged; Male; Pseudoxanthoma Elasticum; Prevalence; Skin; Tomography, X-Ray Computed; Kidney Calculi
PubMed: 37837579
DOI: 10.1007/s10157-023-02405-2 -
American Journal of Ophthalmology Apr 2024To assess the onset, treatment frequency, and visual outcome of anti-vascular endothelial growth factor (anti-VEGF) treatment due to secondary choroidal...
PURPOSE
To assess the onset, treatment frequency, and visual outcome of anti-vascular endothelial growth factor (anti-VEGF) treatment due to secondary choroidal neovascularization (CNV) in patients with pseudoxanthoma elasticum (PXE).
DESIGN
Retrospective cohort study METHODS: One-hundred six eyes of 53 patients with PXE were analyzed. The assessment of CNV activity relied on hemorrhage visible on funduscopy and intra- / subretinal fluid on optical coherence tomography (OCT), individually defining a shortening or extension of treatment interval. Best-corrected visual acuity (BCVA) at baseline, age at anti-VEGF therapy initiation, and BCVA-drop events at exudation onset (worsening of BCVA of 2 or more lines) were documented. Further, we assessed the number of injections during the first year and the total number of injections, the time to treatment initiation of the fellow eye, and BCVA over time.
RESULTS
During a median observation period of 77 months (IQR 49; 126) patients received a median number of 28.0 anti-VEGF-injections (IQR 9.8; 43.5). Eight patients received no injection (median age at baseline 38.1 years), 11 patients underwent anti-VEGF treatment in one eye (median age 47.2 years) and 34 patients in both eyes (median age 51.8 years). The median age at the first anti-VEGF treatment was 52.80 years (IQR 47.2-57.6). Applying Cox regression models, the median "survival" time of fellow eye until treatment initiation was 16.8 months. In the group of bilateral treated patients, the median time difference was 9.6 months (IQR 2.1- 32.4, range 0-122) The median number of injections was 5.5 per eye in the first year of treatment (IQR 3-7) and was associated with the total number of injections in the observation period (2.33, CI 1.22-3.44, P < .001). A better BCVA at the last follow-up visit was associated with a better baseline BCVA (P < .001, R = 0.318) and with the absence of a BCVA drop at the onset of exudation (P = 0.035, R = 0.339).
CONCLUSIONS
The results of this study indicate that anti-VEGF treatment is required for most PXE patients at a relatively young age. Once treatment in one eye is initiated, the time to fellow eye treatment is relatively short. A BCVA drop before treatment initiation is a risk factor for worse visual outcomes, suggesting that treatment is prudent before exudation affects the central retina. Given the young age of onset and intensive treatment needs, patients with PXE might particularly benefit from longer-acting anti-VEGF therapeutics.
PubMed: 38614195
DOI: 10.1016/j.ajo.2024.03.026 -
Translational Vision Science &... Apr 2024To describe the ocular findings of murine pseudoxanthoma elasticum (PXE) models with ATP-binding cassette subfamily C member 6 (Abcc6) gene knockout.
PURPOSE
To describe the ocular findings of murine pseudoxanthoma elasticum (PXE) models with ATP-binding cassette subfamily C member 6 (Abcc6) gene knockout.
METHODS
This experiment was conducted in four Abcc6-/- rats and compared with six wild-type Abcc6+/+ control rats. The animals underwent necropsy at 6 months of age. Histological examination of the eyes was performed.
RESULTS
Histological examination of eight eyes from four Abcc6-/- rats revealed multiple nodular foci of calcification in the uvea, sclera, and conjunctiva, focally in perivascular distribution, as well as linear and nodular calcification of Bruch's membrane. Calcific foci were not associated with inflammation in the knockout rats. There was no evidence of calcification in control eyes.
DISCUSSION
The Abcc6-/- rat model shows that PXE can affect multiple ocular tissues beyond the calcification in Bruch's membrane noted in human eyes. Nodular calcific foci probably correspond to comet lesions seen in patients with PXE. The presence of ectopic calcium without inflammation distinguishes it from inflammatory calcium deposition in atherosclerosis. Further studies are needed to determine why PXE does not cause inflammatory infiltration.
TRANSLATIONAL RELEVANCE
The Abcc6-/- murine model may be suitable for studying ocular PXE pathophysiology and ectopic calcification and developing effective therapies.
Topics: Animals; Male; Rats; Bruch Membrane; Calcinosis; Disease Models, Animal; Gene Knockout Techniques; Multidrug Resistance-Associated Proteins; Pseudoxanthoma Elasticum
PubMed: 38656313
DOI: 10.1167/tvst.13.4.29 -
Mediterranean Journal of Rheumatology Mar 2024Wilson disease is a rare genetic disorder, characterised by excessive deposition of copper in the liver, brain, and other tissues. Penicillamine, a copper-chelating...
INTRODUCTION
Wilson disease is a rare genetic disorder, characterised by excessive deposition of copper in the liver, brain, and other tissues. Penicillamine, a copper-chelating agent, is used in high doses in the treatment of Wilson disease leading to a variety of cutaneous reactions, including hyper-sensitivity reactions, pseudoxanthoma elasticum, elastosis perforans serpiginosa, anetoderma, and cutis laxa (CL). We present a rare case of localised CL induced by penicillamine for Wilson disease, in the absence of elastosis perforans serpiginosa.
CASE DESCRIPTION
A 41-year-old male with Wilson disease treated with long-term high-dose penicillamine was referred to us for a basal cell carcinoma on the scalp. On physical examination, diffusely flaccid and redundant skin on the right side of the neck were observed. Histopathology revealed findings consistent with CL.
CONCLUSION
Long-term treatment with penicillamine for Wilson disease may induce localized CL, possibly by direct inhibition of cross-linkage of collagen fibres.
PubMed: 38736957
DOI: 10.31138/mjr.280223.pil -
Actas Dermo-sifiliograficas Oct 2023
PubMed: 37506833
DOI: 10.1016/j.ad.2023.07.017 -
Actas Dermo-sifiliograficas Oct 2023
Topics: Humans; Granuloma Annulare; Pseudoxanthoma Elasticum; Skin Abnormalities
PubMed: 36740175
DOI: 10.1016/j.ad.2022.05.041