Cardiovascular Histopathology of a 11-Year Old with Mucopolysaccharidosis VII Demonstrates Fibrosis, Macrophage Infiltration, and Arterial Luminal Stenosis

Abstract

Mucopolysaccharidosis type VII (MPS VII) is caused by β-glucuronidase deficiency, resulting in lysosomal accumulation of glycosaminoglycans (GAGs) and multisystemic disease. We present cardiovascular gross and histopathology findings from a 11-year-old MPS VII male, who expired after developing ventricular fibrillation following anesthesia induction. Gross anatomic observations were made at autopsy; postmortem formalin-fixed paraffin-embedded samples of the carotid artery, aorta, myocardium, and valves were sectioned and stained with hematoxylin-eosin, Verhoeff-Van Gieson, CD68, and trichrome stains. Gross heart findings include an enlarged, dilated heart, mitral valve prolapse with thick, shortened chordae tendinae, and thickened aortic valve cusps. The aorta contained raised intimal plaques mimicking conventional atherosclerosis. Cardiac myocytes included hypertrophic nuclei, subendocardial fibrosis, and increased interfascicular collagen. Coronary lumens were 40–70% stenosed by fibrointimal hyperplasia containing storage material-laden cells, CD68⁺ macrophages, and fragmented elastin laminae. Similar findings were visualized in aortic intimal plaques. We confirm that arterial plaques, elastin fragmentation, and activated CD68⁺ macrophage infiltration occur in human MPS VII, consistent with previously observed findings in murine and canine MPS VII. We also confirm ultrasonographically observed carotid intimal-medial thickening is an in vivo correlate of histopathologic vascular fibrointimal hyperplasia. MPS VII patients should be regularly monitored for cardiac disease, with methods such as Holter monitors and stress testing; MPS VII-directed treatments should effectively address cardiovascular disease.

Appendices

Synopsis

Significant cardiovascular disease (arterial fibrointimal stenosis, hypertrophic cardiomyopathy, valvular and myocardial fibrosis, and life-threatening dysrhythmias) was observed in a 11-year-old with mucopolysaccharidosis type VII; these findings indicate the importance of regular cardiology monitoring for MPS VII patients starting in early childhood.

Details of the Contributions of Individual Authors

• V.L. and R.Y.W. designed outline for manuscript as well as the figures

• L.P. performed postmortem

• L.P. and R.E. performed histopathology and interpretations

• V.L., L.P., R.E., and R.Y.W. wrote the manuscript

Name of the Corresponding Author

Raymond Y. Wang.

Competing Interest Statement

V.L., L.P., and R.E. have no conflicts of interest to declare. R.Y.W. is a study site principal investigator for a phase III study of recombinant human beta-glucuronidase for mucopolysaccharidosis type VII sponsored by Ultragenyx Pharmaceutical.

Details of Funding

This study was supported by CHOC Children’s Specialists (V.L. and R.Y.W.), The Brian and Caris Chan Family Foundation (R.Y.W.), and The University of California-Riverside School of Medicine (V.L.).

Details of Ethics Approval

This report was conducted under the auspices of Children’s Hospital of Orange County IRB #100109, approved 12 Apr 2010, renewed 17 Nov 2016.

A Patient Consent Statement

Consent for retrospective chart review and post mortem tissue donation was obtained from parents and is available for review upon request.

Documentation of Approval from the Institutional Committee for Care and Use of Laboratory Animals (or Comparable Committee)

Not applicable (no animal studies).