Dataset Information

From Clinical Diagnosis to the Discovery of Multigene Rare Sequence Variants in Pseudoxanthoma elasticum: A Case Report.

ABSTRACT: Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive disease clinically characterised by early cutaneous alterations, and by late clinically relevant ocular, and cardiovascular manifestations. ABCC6 genetic tests are used to confirm clinical PXE diagnosis, but this strategy may be rather challenging when only one ABCC6 pathogenic variant is found. A next-generation sequencing approach focusing on 362 genes related to the calcification process and/or to inherited retinal diseases was performed on a patient with clinical PXE diagnosis (skin papules and laxity, angioid streaks, and atrophy) who was carrier of only one ABCC6 rare sequence variant. Beside ABCC6, several rare sequence variants were detected which can contribute either to the occurrence of calcification (GGCX and SERPINF1 genes) and/or to ophthalmological manifestations (ABCA4, AGBL5, CLUAP1, and KCNV2 genes). This wide-spectrum analysis approach facilitates the identification of rare variants possibly involved in PXE, thus avoiding invasive skin biopsy as well as expensive and time-consuming diagnostic odyssey and allows to broaden and to deepen the knowledge on this complex rare disease and to improve patients' counselling, also with a future perspective of personalised medicine.

SUBMITTER: Lofaro FD

PROVIDER: S-EPMC8427021 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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From Clinical Diagnosis to the Discovery of Multigene Rare Sequence Variants in Pseudoxanthoma elasticum: A Case Report.

Lofaro Francesco Demetrio FD Mucciolo Dario Pasquale DP Murro Vittoria V Pavese Laura L Quaglino Daniela D Boraldi Federica F

Frontiers in medicine 20210826

Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive disease clinically characterised by early cutaneous alterations, and by late clinically relevant ocular, and cardiovascular manifestations. ABCC6 genetic tests are used to confirm clinical PXE diagnosis, but this strategy may be rather challenging when only one ABCC6 pathogenic variant is found. A next-generation sequencing approach focusing on 362 genes related to the calcification process and/or to inherited reti ...[more]

PMID: 34513887

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Project description: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.

Project description:ImportanceAcute retinopathy may partly explain variable disease manifestation and vision loss in patients with pseudoxanthoma elasticum (PXE). The diagnosis of this likely autoimmune process may inform patient counseling and treatment approaches.ObjectiveTo characterize acute retinopathy in patients with PXE as a disease manifestation that may be associated with profound visual impairment.Design, setting, and participantsThis single-center case series was conducted from May 2013 to October 2018. It used the patient database of the Department of Ophthalmology at the University of Bonn, a referral center for PXE in Germany. Patients at this center with genetically confirmed PXE and who met the inclusion criteria were included (n = 9). Patients underwent multimodal retinal imaging, including fundus photography, fundus autofluorescence (AF), optical coherence tomography (OCT), fluorescein angiography (FA), and indocyanine green angiography (ICGA); in select cases, electroretinography as well as antiretinal and anti-retinal pigment epithelium (RPE) antibody testing were also used.Main outcomes and measuresClinical presentation and disease course.ResultsNine patients (8 [89%] female; mean [range] age, 43 [19-55] years) with acute retinopathy were identified in a cohort of 167 consecutive patients with PXE (frequency of 5%). Symptoms ranged from light sensations or metamorphopsia to profound vision loss. Visual acuity was reduced in 6 patients (67%), ranging from a best-corrected visual acuity of 20/30 to perception of hand movements at manifestation. All patients revealed characteristic fundus features with temporary appearance of partly confluent outer retinal whitish dots at the posterior pole, which corresponded to areas of hyperautofluorescence on fundus AF, loss of the ellipsoid band on OCT, and associated scotomata. The FA and late-phase ICGA imaging showed associated hyperfluorescence and hypocyanescence. Electroretinography revealed a variable reduction of amplitudes. Changes were fully reversible within 1 month in 3 of 8 patients with available follow-up data. Of the remaining 5 patients, 3 had a prolonged and likely permanent vision loss (observation period, 1-64 months) mainly owing to central subretinal hyperreflective material originating from angioid streaks. In 4 (67%) of 6 tested, antiretinal and/or anti-RPE antibodies were detected.Conclusions and relevanceAcute retinopathy in patients with PXE may occur, with symptoms ranging from short-term, reversible alterations to irreversible vision loss; these findings contribute to understanding the variable ocular disease progression in PXE and provide insights into the autoimmune phenomena of the posterior pole.

Project description:PurposeTo determine the prevalence and spatial pattern of rod and cone dysfunction in patients with pseudoxanthoma elasticum (PXE) and to correlate these with Bruch's membrane (BrM) calcification. PXE is a rare genetic disorder that causes calcification of Bruch's membrane, which eventually leads to loss of central vision. Understanding the functional implications of BrM calcification is crucial for developing effective treatments.MethodsIn this prospective natural history study (PROPXE, ClinicalTrials.gov ID: NCT05662085), performed at a tertiary referral center, 26 patients with PXE (14 women, 12 men; median age, 55 years; interquartile range, 43-59 years), diagnosed according to the Plomp criteria, underwent comprehensive ophthalmic evaluations, including best-corrected visual acuity (BCVA), contrast sensitivity testing, and multimodal imaging. Dark adaptometry was tested following a 59% rhodopsin bleach at 8°, 15°, 30°, and 46° eccentricity from the fovea along the temporal retina. The eye without a history of exudative macular neovascularization (MNV) or the better-seeing eye was selected as the study eye.ResultsOf 26 participants, 12 had no history of exudative MNV in the study eye, while 14 had previous or current treatment for MNV with a median BCVA of -0.07 logMAR and 0.11 logMAR, respectively. In the macula at 8° eccentricity, rod intercept time (RIT) was prolonged in 83.3% of nonexudative and 92.9% of exudative eyes, while BCVA and cone thresholds at 8° eccentricity were affected in only 42.3% and 65.4% of eyes. The delay in RIT was most pronounced in regions at risk of calcification and increased markedly with age. In addition, prolonged cone recovery time constants were evident that correlated with RIT.ConclusionsPatients with PXE exhibit significant slowing of both cone- and rod-mediated dark adaptation, particularly in regions prone to BrM calcification. These findings suggest that dark adaptometry and assessment of BrM calcification can serve as clinical tools for evaluating disease severity and monitoring progression in PXE, enabling earlier interventions before the onset of exudative MNV or atrophy.

Dataset Information

From Clinical Diagnosis to the Discovery of Multigene Rare Sequence Variants in Pseudoxanthoma elasticum: A Case Report.

Publications

From Clinical Diagnosis to the Discovery of Multigene Rare Sequence Variants in <i>Pseudoxanthoma elasticum</i>: A Case Report.

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