Biomarkers in Fabry Disease. Implications for Clinical Diagnosis and Follow-up

Abstract

Fabry disease (FD) is a lysosomal storage disorder caused by deficient alpha-galactosidase A activity in the lysosome due to mutations in the GLA gene, resulting in gradual accumulation of globotriaosylceramide and other derivatives in different tissues. Substrate accumulation promotes different pathogenic mechanisms in which several mediators could be implicated, inducing multiorgan lesions, mainly in the kidney, heart and nervous system, resulting in clinical manifestations of the disease. Enzyme replacement therapy was shown to delay disease progression, mainly if initiated early. However, a diagnosis in the early stages represents a clinical challenge, especially in patients with a non-classic phenotype, which prompts the search for biomarkers that help detect and predict the evolution of the disease. We have reviewed the mediators involved in different pathogenic mechanisms that were studied as potential biomarkers and can be easily incorporated into clinical practice. Some accumulation biomarkers seem to be useful to detect non-classic forms of the disease and could even improve diagnosis of female patients. The combination of such biomarkers with some response biomarkers, may be useful for early detection of organ injury. The incorporation of some biomarkers into clinical practice may increase the capacity of detection compared to that currently obtained with the established diagnostic markers and provide more information on the progression and prognosis of the disease.

Keywords: Gb3; biomarkers; cardiomyopathy; chronic kidney disease; classic phenotype; fabry disease; inflammatory response; late-onset phenotype; lyso-Gb3; vasculopathy.

Figure 1

Scheme of the main pathogenic pathways with biomarkers involved in Fabry disease. Pathogenic mechanisms described in the development of vascular involvement are initiated from Globotriaosylceramide (Gb3) and/or Globotriaosylsphingosine (lyso-Gb3) accumulation and/or chronic exposure to smooth muscle cells, endothelial cells or different blood immune cell types (solid red arrow), which in turn initiates different pathogenic cascades that contribute to the progression of vasculopathy (dashed red arrow). Inflammation derived from systemic vasculopathy may also be involved in the progression of disease related to cardiomyopathy and nephropathy (dashed black arrows). In addition, substrate can also accumulate or deposit on other cell types such us podocytes, other renal cells, or cardiomyocytes (solid red arrows), inducing different pathogenic mechanisms that may contribute to the development of renal and cardiac fibrosis. Gray boxes include different substrates related to the accumulation or exposure, as well as mediators involved in different pathways of response to the initial injury and progression towards fibrosis, which have been identified in clinical and experimental studies and that can be useful as diagnostic or follow-up biomarkers. α-SMA: α-smooth muscle actin; BNP: brain natriuretic peptide; C1Q/TNF: complement-c1q tumor necrosis factor-related protein; CICT: collagen type I carboxy-terminal telopeptide; CDH: ceramide dihexoside; FGF-2: fibroblast growth factor-2; Gb2: Galabiosylceramide; Gb3: Globotriaosylceramide; GSH: glutathione; GPx: glutathione peroxidase; hsTn: high sensitive Troponin; IL: interleukin; iNOS: inducible nitric oxide synthase; lyso-Gb3: Globotriaosylsphingosine; MCP-1: monocyte chemo-attractant protein; MDA: malondialdehyde; MMP-2: matrix metalloproteinase-2; MPO: myeloperoxidase; MR-proANP: midregional pro-atrial natriuretic peptide; NO: nitric oxide; NT: nitrotyrosine; 8-OHdG: 8-hydroxydeoxyguanosine; PIPP: procollagen type I carboxy-terminal propeptide; PIIINP: procollagen type III amino-terminal propeptide; sICAM-1: soluble intercellular adhesion molecule 1; sVCAM-1: soluble vascular cell adhesion molecule 1; S1P: sphingosine-1- phosphate; TBARS: thiobarbituric acid reactive species; TGFβ-1: transforming growth factor beta-1; Tn: troponin; TNF-α: tumor necrosis factor alpha; TNFR: tumor necrosis factor receptor; TSP-1: thrombospondin-1; Tyr: tyrosine; uPAR: urokinase-type plasminogen activator receptor; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor.

Figure 2

Scheme of potential pathogenic response pathways. Response pathways promoted from Gb3 and/or lyso-Gb3 accumulation and/or exposure that can develop in Fabry disease grouped by organ/tissue specificity, with some biomarkers involved. Dashed arrows indicate associations between systemic vasculopathy and renal and cardiac involvement. α-SMA: α-smooth muscle actin; BNP: brain natriuretic peptide; CICT: collagen type I carboxy-terminal telopeptide; FGF-2: fibroblast growth factor-2; Gb3: Globotriaosylceramide; GSH: glutathione; GPx: glutathione peroxidase; Tn: high sensitive Troponin; IL: interleukin; iNOS: inducible nitric oxide synthase; lyso-Gb3: Globotriaosylsphingosine; MCP-1: monocyte chemo-attractant protein; MDA: malondialdehyde; MMP-2: matrix metalloproteinase-2; MPO: myeloperoxidase; MR-proANP: midregional pro-atrial natriuretic peptide; NO: nitric oxide; NT: nitrotyrosine; 8-OHdG: 8-hydroxydeoxyguanosine; PIPP: procollagen type I carboxy-terminal propeptide; PIIINP: procollagen type III amino-terminal propeptide; sICAM-1: soluble intercellular adhesion molecule 1; sVCAM-1: soluble vascular cell adhesion molecule 1; S1P: Sphingosine-1- phosphate; TBARS: thiobarbituric acid reactive species; TGFβ-1: transforming growth factor beta-1; TNF-α: tumor necrosis factor alpha; TNFR: tumor necrosis factor receptor; Tyr: tyrosine; uPAR: urokinase-type plasminogen activator receptor; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor.