LC-MS lipidomics of renal biopsies for the diagnosis of Fabry disease

Hoda Safari Yazd; Sina Feizbakhsh Bazargani; Christine A Vanbeek; Kelli King-Morris; Coy Heldermon; Mark S Segal; William L Clapp; Timothy J Garrett

doi:10.1016/j.jmsacl.2021.11.004

LC-MS lipidomics of renal biopsies for the diagnosis of Fabry disease

J Mass Spectrom Adv Clin Lab. 2021 Nov 26:22:71-78. doi: 10.1016/j.jmsacl.2021.11.004. eCollection 2021 Nov.

Authors

Hoda Safari Yazd¹, Sina Feizbakhsh Bazargani¹, Christine A Vanbeek², Kelli King-Morris³, Coy Heldermon⁴, Mark S Segal⁵, William L Clapp⁶, Timothy J Garrett⁶

Affiliations

¹ Department of Chemistry, University of Florida, Gainesville, FL 32610, USA.
² AmeriPath, Renal Pathology, Oklahoma City, OK 73114, USA.
³ Department of Medicine, University of Central Florida, Orlando, FL 32827, USA.
⁴ Department of Neurology, University of Florida, Gainesville, FL 32610, USA.
⁵ Department of Medicine, Division of Nephrology, Hypertension & Renal Transplantation, University of Florida, Gainesville, FL 32610, USA.
⁶ Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA.

Abstract

Introduction: Lipidomics analysis or lipid profiling is a system-based analysis of all lipids in a sample to provide a comprehensive understanding of lipids within a biological system. In the last few years, lipidomics has made it possible to better understand the metabolic processes associated with several rare disorders and proved to be a powerful tool for their clinical investigation. Fabry disease is a rare X-linked lysosomal storage disorder (LSD) caused by a deficiency in α-galactosidase A (α-GAL A). This deficiency results in the progressive accumulation of glycosphingolipids, mostly globotriaosylceramide (Gb₃), globotriaosylsphingosine (lyso-Gb₃), as well as galabiosylceramide (Ga₂) and their isoforms/analogs in the vascular endothelium, nerves, cardiomyocytes, renal glomerular podocytes, and biological fluids.

Objectives: The primary objective of this study was to evaluate lipidomic signatures in renal biopsies to help understand variations in Fabry disease markers that could be used in future diagnostic tests.

Methods: Lipidomic analysis was performed by ultra-high pressure liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) on kidney biopsies that were left over after clinical pathology analysis to diagnose Fabry disease.

Results: We employed UHPLC-HRMS lipidomics analysis on the renal biopsy of a patient suspicious for Fabry disease. Our result confirmed α-GAL A enzyme activity declined in this patient since a Ga2-related lipid biomarker was substantially higher in the patient's renal tissue biopsy compared with two controls. This suggests this patient has a type of LSD that could be non-classical Fabry disease.

Conclusion: This study shows that lipidomics analysis is a valuable tool for rare disorder diagnosis, which can be conducted on leftover tissue samples without disrupting normal patient care.

Keywords: CAN, Acetonitrile; CDH, Cerebrodihexoside; Chcl3, Chloroform; Cnvs, Copy Number Variants; EIC, Extracted Ion Chromatogram; ERT, Enzyme Replacement Therapy; GLA, Glactosidase Alpha; Ga2, Galabiosylceramide; Gb3, Globotriaosylceramide; IPA, 2-Propanol; LC/MS, Liquid Chromatography-Mass Spectrometry; LSD, Lysosomal Storage Disorder; Lyso-Gb3, Globotriaosylsphingosine; MS/MS, Tandem Mass Spectrometry; Meoh, Methanol; ND, Not Detected; OCT, Optimal Cutting Temperature; SECIM, Southeast Center for Integrated Metabolomics; SRM, Selected Reaction Monitoring; UHPLC-HRMS, Ultra-High Pressure Liquid Chromatography-High-Resolution Mass Spectrometry; α-GAL A, α-Galactosidase A.