Biomarkers and Imaging Findings of Anderson–Fabry Disease—What We Know Now

Abstract

Anderson–Fabry disease (AFD) is an X-linked lysosomal storage disorder, caused by deficiency or absence of the alpha-galactosidase A activity, with a consequent glycosphingolipid accumulation. Biomarkers and imaging findings may be useful for diagnosis, identification of an organ involvement, therapy monitoring and prognosis. The aim of this article is to review the current available literature on biomarkers and imaging findings of AFD patients. An extensive bibliographic review from PubMed, Medline and Clinical Key databases was performed by a group of experts from nephrology, neurology, genetics, cardiology and internal medicine, aiming for consensus. Lyso-GB3 is a valuable biomarker to establish the diagnosis. Proteinuria and creatinine are the most valuable to detect renal damage. Troponin I and high-sensitivity assays for cardiac troponin T can identify patients with cardiac lesions, but new techniques of cardiac imaging are essential to detect incipient damage. Specific cerebrovascular imaging findings are present in AFD patients. Techniques as metabolomics and proteomics have been developed in order to find an AFD fingerprint. Lyso-GB3 is important for evaluating the pathogenic mutations and monitoring the response to treatment. Many biomarkers can detect renal, cardiac and cerebrovascular involvement, but none of these have proved to be important to monitoring the response to treatment. Imaging features are preferred in order to find cardiac and cerebrovascular compromise in AFD patients.

Improved Efficacy in a Fabry Disease Model Using a Systemic mRNA Liver Depot System as Compared to Enzyme Replacement Therapy

“…Two clinically relevant biomarkers present within this model are the glycosphingolipids known as Gb3 and lyso-Gb3, and they have been shown to accumulate within a variety of tissues among patients with Fabry disease. 4 , 5 , 6 , 7 , 8 , 9 Specifically, accumulation of these biomarkers due to a loss of function of the hGLA enzyme within the heart and kidneys results in symptoms such as diastolic dysfunction and exertional anginal pectoris as well as severely impaired glomerular filtration rates, ultimately leading to cardiomyopathies and end-stage renal disease, respectively. Due to the greatly increased exposure and accumulation of hGLA protein with hGLA mRNA treatment as compared to hGLA ERT, we hypothesized that such favorable pharmacokinetic properties would result in enhanced efficacy.…”

“… 1 , 2 , 3 Loss of GLA enzyme activity results in improper metabolism of glycolipids containing α-D-galactosyl moieties, such as globotriaosylceramide (Gb3, also known as ceramide trihexoside) and its deacylated metabolite lyso-globotriaosylceramide (lyso-Gb3). 4 , 5 , 6 Accumulation of these fatty lipids is observed within the lysosomes of multiple tissues, including liver, spleen, kidney, and heart, as well as the vasculature and plasma. Progressive accumulation of such lipids leads to clinical disease, manifesting as angiokeratomas, congestive heart failure, stroke, myocardial infarction, and end-stage renal failure ultimately leading to fatality.…”

Hot topics in Fabry disease

“…Clinical variability of different mutations, variable disease severity and symptom onset make the disease notoriously difficult to diagnose. There is huge clinical variability even within the same family mutation7 8 as well as large intersex variability. Heterozygote females tend to have higher residual enzyme activity as they are mosaic due to variable X-chromosome inactivation 9.…”

One-step synthesis of carbon-13-labeled globotriaosylsphingosine (lyso-Gb3), an internal standard for biomarker analysis of Fabry disease

“…Deficiency of alpha-galactosidase A leads to a buildup of globotriaosylceramide and its hydrolysed form lacking the fatty acyl chain (globotriaosylsphigosine, lyso-Gb3). Lyso-Gb3 is measured by liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) in the presence of an internal standard [3]. Most assays use a lyso-Gb3 analog (lyso-Gb3 with a glycine acyl linked to the amino group) as an internal standard [4].…”