Bruch's Membrane Calcification in Pseudoxanthoma Elasticum

Sara Risseeuw, MD, PhD; Matthew G. Pilgrim, PhD; Sergio Bertazzo, PhD; Connor N. Brown, PhD; Lajos Csincsik, PhD; Sarah Fearn, PhD; Richard B. Thompson, PhD; Arthur A. Bergen, PhD; Jacoline B. ten Brink, BAS; Elod Kortvely, PhD; Wilko Spiering, MD, PhD; Jeannette Ossewaarde–van Norel, MD, PhD; Redmer van Leeuwen, MD, PhD; Imre Lengyel, PhD

Ophthalmology Science (Mar 2024)

Bruch's Membrane Calcification in Pseudoxanthoma Elasticum

Sara Risseeuw, MD, PhD,
Matthew G. Pilgrim, PhD,
Sergio Bertazzo, PhD,
Connor N. Brown, PhD,
Lajos Csincsik, PhD,
Sarah Fearn, PhD,
Richard B. Thompson, PhD,
Arthur A. Bergen, PhD,
Jacoline B. ten Brink, BAS,
Elod Kortvely, PhD,
Wilko Spiering, MD, PhD,
Jeannette Ossewaarde–van Norel, MD, PhD,
Redmer van Leeuwen, MD, PhD,
Imre Lengyel, PhD

Affiliations

Sara Risseeuw, MD, PhD: Department of Ophthalmology, University Medical Center Utrecht, Utrecht University, The Netherlands
Matthew G. Pilgrim, PhD: Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, Belfast, Northern Ireland, United Kingdom
Sergio Bertazzo, PhD: Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom
Connor N. Brown, PhD: Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, Belfast, Northern Ireland, United Kingdom
Lajos Csincsik, PhD: Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, Belfast, Northern Ireland, United Kingdom
Sarah Fearn, PhD: Department of Materials, Imperial College London, London, United Kingdom
Richard B. Thompson, PhD: Department of Ophthalmology, University Medical Center Utrecht, Utrecht University, The Netherlands; Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, Belfast, Northern Ireland, United Kingdom; Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom; Department of Materials, Imperial College London, London, United Kingdom; Departments of Human Genetics and Ophthalmology, Amsterdam UMC, location AMC Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Emma Center for Personalized Medicine, Amsterdam UMC, University of Amsterdam, The Netherlands; Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland; University of Maryland School of Medicine, Department of Biochemistry and Molecular Biology, Baltimore, Maryland; Department of Vascular Medicine, University Medical Center Utrecht, Utrecht University, The Netherlands
Arthur A. Bergen, PhD: Departments of Human Genetics and Ophthalmology, Amsterdam UMC, location AMC Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Emma Center for Personalized Medicine, Amsterdam UMC, University of Amsterdam, The Netherlands
Jacoline B. ten Brink, BAS: Departments of Human Genetics and Ophthalmology, Amsterdam UMC, location AMC Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Elod Kortvely, PhD: Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
Wilko Spiering, MD, PhD: Department of Ophthalmology, University Medical Center Utrecht, Utrecht University, The Netherlands; Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, Belfast, Northern Ireland, United Kingdom; Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom; Department of Materials, Imperial College London, London, United Kingdom; Departments of Human Genetics and Ophthalmology, Amsterdam UMC, location AMC Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Emma Center for Personalized Medicine, Amsterdam UMC, University of Amsterdam, The Netherlands; Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland; University of Maryland School of Medicine, Department of Biochemistry and Molecular Biology, Baltimore, Maryland; Department of Vascular Medicine, University Medical Center Utrecht, Utrecht University, The Netherlands
Jeannette Ossewaarde–van Norel, MD, PhD: Department of Ophthalmology, University Medical Center Utrecht, Utrecht University, The Netherlands
Redmer van Leeuwen, MD, PhD: Department of Ophthalmology, University Medical Center Utrecht, Utrecht University, The Netherlands
Imre Lengyel, PhD: Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, Belfast, Northern Ireland, United Kingdom; Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom; Correspondence: Imre Lengyel, The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK

Journal volume & issue: Vol. 4, no. 2
p. 100416

Abstract

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Purpose: To investigate the histology of Bruch’s membrane (BM) calcification in pseudoxanthoma elasticum (PXE) and correlate this to clinical retinal imaging. Design: Experimental study with clinicopathological correlation. Subjects and Controls: Six postmortem eyes from 4 PXE patients and 1 comparison eye from an anonymous donor without PXE. One of the eyes had a multimodal clinical image set for comparison. Methods: Calcification was labeled with OsteSense 680RD, a fluorescent dye specific for hydroxyapatite, and visualized with confocal microscopy. Scanning electron microscopy coupled with energy-dispersive x-ray spectroscopy (SEM-EDX) and time-of-flight secondary ion mass spectrometry (TOF-SIMs) were used to analyze the elemental and ionic composition of different anatomical locations. Findings on cadaver tissues were compared with clinical imaging of 1 PXE patient. Main Outcome Measures: The characteristics and topographical distribution of hydroxyapatite in BM in eyes with PXE were compared with the clinical manifestations of the disease. Results: Analyses of whole-mount and sectioned PXE eyes revealed an extensive, confluent OsteoSense labeling in the central and midperipheral BM, transitioning to a speckled labeling in the midperiphery. These areas corresponded to hyperreflective and isoreflective zones on clinical imaging. Scanning electron microscopy coupled with energy-dispersive x-ray spectroscopy and TOF-SIMs analyses identified these calcifications as hydroxyapatite in BM of PXE eyes. The confluent fluorescent appearance originates from heavily calcified fibrous structures of both the collagen and the elastic layers of BM. Calcification was also detected in an aged comparison eye, but this was markedly different from PXE eyes and presented as small snowflake-like deposits in the posterior pole. Conclusions: Pseudoxanthoma elasticum eyes show extensive hydroxyapatite deposition in the inner and outer collagenous and elastic BM layers in the macula with a gradual change toward the midperiphery, which seems to correlate with the clinical phenotype. The snowflake-like calcification in BM of an aged comparison eye differed markedly from the extensive calcification in PXE. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Published in Ophthalmology Science

ISSN: 2666-9145 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Ophthalmology
Website: https://www.journals.elsevier.com/ophthalmology-science/

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