18F-Flurodeoxyglucose and 18F-Sodium Fluoride Positron Emission Tomography/Computed Tomography Imaging of Arterial and Cutaneous Alterations in Pseudoxanthoma Elasticum

Mention, Pierre-Jean; Lacoeuille, Franck; Lefthériotis, Georges; Martin, Ludovic; Omarjee, Loukman

doi:10.1161/circimaging.117.007060

Cited by 13 publications

(14 citation statements)

References 4 publications

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“…The precise function of ABCC6 and its substrate is not yet fully understood. Low-grade inflammation [7], elastin degradation [8], and the primary deficiency in calcification inhibitors might all underlie the systemic calcification seen in PXE [6]. It has been shown, however, that PXE results in low systemic levels of inorganic pyrophosphate (PPi).…”

Section: Introductionmentioning

confidence: 99%

Genotype-phenotype correlation in pseudoxanthoma elasticum

et al. 2021

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Background and aims: Pseudoxanthoma elasticum (PXE) is caused by variants in the ABCC6 gene. It results in calcification in the skin, peripheral arteries and the eyes, but has considerable phenotypic variability. We investigated the association between the ABCC6 genotype and calcification and clinical phenotypes in these different organs. Methods: ABCC6 sequencing was performed in 289 PXE patients. Genotypes were grouped as two truncating, mixed, or two non-truncating variants. Arterial calcification mass was quantified on whole body, low dose CT scans; and peripheral arterial disease was measured with the ankle brachial index after treadmill test. The presence of pseudoxanthoma in the skin was systematically scored. Ophthalmological phenotypes were the length of angioid streaks as a measure of Bruchs membrane calcification, the presence of choroidal neovascularizations, severity of macular atrophy and visual acuity. Regression models were built to test the age and sex adjusted genotype-phenotype association. Results: 158 patients (median age 51 years) had two truncating variants, 96 (median age 54 years) a mixed genotype, 18 (median age 47 years) had two non-truncating variants. The mixed genotype was associated with lower peripheral (β: 0.39, 95%CI:-0.62;-0.17) and total (β: 0.28, 95%CI:-0.47;-0.10) arterial calcification mass scores, and lower prevalence of choroidal neovascularizations (OR: 0.41 95%CI:0.20; 0.83) compared to two truncating variants. No association with pseudoxanthomas was found. Conclusions: PXE patients with a mixed genotype have less severe arterial and ophthalmological phenotypes than patients with two truncating variants in the ABCC6 gene. Research into environmental and genetic modifiers might provide further insights into the unexplained phenotypic variability.

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Section: Introductionmentioning

confidence: 99%

Genotype-phenotype correlation in pseudoxanthoma elasticum

et al. 2021

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“…However, these trials did not yield positive conclusions and it is possible that the quantification methodology combined with the heterogeneity of the manifestations may have contributed to the inconclusive results. The capacity of 18 F-sodium fluoride ( 18 F-NaF) positron emission tomography/computed tomography (PET/CT) to identify and evaluate metabolically active osteogenesis in skin and arteries in PXE patients has been demonstrated [159,160]. This method was applied in the recent TEMP clinical trial and was able to discern some phenotypical changes within a year following etidronate administration (Cf.…”

Section: Treatment Outcome Conundrummentioning

confidence: 99%

“…ABCC6 deficiency causes a broad spectrum of manifestations beyond calcification that includes vascular malformation (rete mirabile, carotid hypoplasia) [ 164 ], dyslipidemia, and atherosclerosis [ 93 , 94 ], as well as ischemic stroke [ 165 ], inflammation [ 159 ], premature cellular senescence in hepatic cells and dermal fibroblasts [ 166 , 167 ], increased infarct size, and apoptosis [ 168 ]. ATP released by ABCC6 and the nucleotides/nucleosides generated downstream by the ectonucleotidases NPP1 and CD73 regulates cellular signaling towards P2 (nucleotides) and P1 (Ado) receptors, which have a wide range of physiological influences that could well explain these other manifestations [ 124 ].…”

Section: Rescue and Therapeutic Solutionsmentioning

confidence: 99%

ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions

Shimada

Pomozi

Zoll

et al. 2021

IJMS

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Pathological (ectopic) mineralization of soft tissues occurs during aging, in several common conditions such as diabetes, hypercholesterolemia, and renal failure and in certain genetic disorders. Pseudoxanthoma elasticum (PXE), a multi-organ disease affecting dermal, ocular, and cardiovascular tissues, is a model for ectopic mineralization disorders. ABCC6 dysfunction is the primary cause of PXE, but also some cases of generalized arterial calcification of infancy (GACI). ABCC6 deficiency in mice underlies an inducible dystrophic cardiac calcification phenotype (DCC). These calcification diseases are part of a spectrum of mineralization disorders that also includes Calcification of Joints and Arteries (CALJA). Since the identification of ABCC6 as the “PXE gene” and the development of several animal models (mice, rat, and zebrafish), there has been significant progress in our understanding of the molecular genetics, the clinical phenotypes, and pathogenesis of these diseases, which share similarities with more common conditions with abnormal calcification. ABCC6 facilitates the cellular efflux of ATP, which is rapidly converted into inorganic pyrophosphate (PPi) and adenosine by the ectonucleotidases NPP1 and CD73 (NT5E). PPi is a potent endogenous inhibitor of calcification, whereas adenosine indirectly contributes to calcification inhibition by suppressing the synthesis of tissue non-specific alkaline phosphatase (TNAP). At present, therapies only exist to alleviate symptoms for both PXE and GACI; however, extensive studies have resulted in several novel approaches to treating PXE and GACI. This review seeks to summarize the role of ABCC6 in ectopic calcification in PXE and other calcification disorders, and discuss therapeutic strategies targeting various proteins in the pathway (ABCC6, NPP1, and TNAP) and direct inhibition of calcification via supplementation by various compounds.

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“…TBR in the distal aorta, iliac, femoral and popliteal arteries was calculated by dividing the SUVmax by SUVmax derived from the inferior vena cava [21]. With respect to skin analysis, SUVmax and SUVmean were measured after a circular ROI had been drawn around three regions (spared lumbar/damaged neck/axillary folds) [22]. Mean linear SUV was calculated in the left and right axillary folds [22].…”

Section: Image Analysis: 18f-fdg/18f-naf-pet-ctmentioning

confidence: 99%

“…With respect to skin analysis, SUVmax and SUVmean were measured after a circular ROI had been drawn around three regions (spared lumbar/damaged neck/axillary folds) [22]. Mean linear SUV was calculated in the left and right axillary folds [22].…”

Section: Image Analysis: 18f-fdg/18f-naf-pet-ctmentioning

confidence: 99%

Assessment of Inflammation and Calcification in Pseudoxanthoma Elasticum Arteries and Skin with 18F-FluroDeoxyGlucose and 18F-Sodium Fluoride Positron Emission Tomography/Computed Tomography Imaging: The GOCAPXE Trial

Omarjee

Mention

Janin

et al. 2020

JCM

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Background: Pseudoxanthoma elasticum (PXE) is an inherited metabolic disease characterized by elastic fiber fragmentation and ectopic calcification. There is growing evidence that vascular calcification is associated with inflammatory status and is enhanced by inflammatory cytokines. Since PXE has never been considered as an inflammatory condition, no incidence of chronic inflammation leading to calcification in PXE has been reported and should be investigated. In atherosclerosis and aortic stenosis, positron emission tomography combined with computed tomographic (PET-CT) imaging has demonstrated a correlation between inflammation and calcification. The purpose of this study was to assess skin/artery inflammation and calcification in PXE patients. Methods: 18F-FluroDeoxyGlucose (18F-FDG) and 18F-Sodium Fluoride (18F-NaF) PET-CT, CT-imaging and Pulse wave velocity (PWV) were used to determine skin/vascular inflammation, tissue calcification, arterial calcium score (CS) and stiffness, respectively. In addition, inorganic pyrophosphate, high-sensitive C-reactive protein and cytokines plasma levels were monitored. Results: In 23 PXE patients, assessment of inflammation revealed significant 18F-FDG uptake in diseased skin areas contrary to normal regions, and exclusively in the proximal aorta contrary to the popliteal arteries. There was no correlation between 18F-FDG uptake and PWV in the aortic wall. Assessment of calcification demonstrated significant 18F-NaF uptake in diseased skin regions and in the proximal aorta and femoral arteries. 18F-NaF wall uptake correlated with CS in the femoral arteries, and aortic wall PWV. Multivariate analysis indicated that aortic wall 18F-NaF uptake is associated with diastolic blood pressure. There was no significant correlation between 18F-FDG and 18F-NaF uptake in any of the artery walls. Conclusion: In the present cross-sectional study, inflammation and calcification were not correlated. PXE would appear to more closely resemble a chronic disease model of ectopic calcification than an inflammatory condition. To assess early ectopic calcification in PXE patients, 18F-NaF-PET-CT may be more relevant than CT imaging. It potentially constitutes a biomarker for disease-modifying anti-calcifying drug assessment in PXE.

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18F-Flurodeoxyglucose and 18F-Sodium Fluoride Positron Emission Tomography/Computed Tomography Imaging of Arterial and Cutaneous Alterations in Pseudoxanthoma Elasticum

Abstract: International audienceno abstrac

Cited by 13 publications

References 4 publications

Genotype-phenotype correlation in pseudoxanthoma elasticum

Genotype-phenotype correlation in pseudoxanthoma elasticum

ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions

Assessment of Inflammation and Calcification in Pseudoxanthoma Elasticum Arteries and Skin with 18F-FluroDeoxyGlucose and 18F-Sodium Fluoride Positron Emission Tomography/Computed Tomography Imaging: The GOCAPXE Trial

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