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Page 18 of 29 Aguiar. Rare Dis Orphan Drugs J 2024;3:13 https://dx.doi.org/10.20517/rdodj.2023.56

Table 5. Experimental biomarkers in Fabry disease
Biomarkers Comment References
Inflammatory C-reactive protein was studied with conflicting results; [232-235,236,
IL-6 increases in patients with FD cardiomyopathy and decreases during ERT; 237,238]
IL-18 increases even in early stages of FD cardiomyopathy and decreases with ERT;
Myeloperoxidase and chitotriosidase only increase in males
Coagulation and Conflicting results, with minimal and inconsistent abnormalities in markers of platelet and coagulation [239,234,240-
endothelial activation; 243]
dysfunction Homocysteine increases in FD and one study reported an increase in all the patients presenting
cerebrovascular disease;
Nitric oxide metabolism biomarkers seem altered in FD and correlate with cardiomyopathy severity
Vasculopathy Sphingosine-1-phosphate promotes vascular smooth muscle cell proliferation and correlates with carotid [244]
artery intima-media thickness and LV mass index
Myocardial fibrosis Few studies show an increase in biomarkers of collagen type 1 synthesis and a decrease in matrix [144,245-247]
metalloproteinases, correlating with LV mass and FD cardiomyopathy progression;
Galectin-3 presents a significant increase, even in patients without signs of cardiac involvement, with a
significant correlation with LV mass and GFR
Urinary microscopy May be a useful tool for the non-invasive assessment of disease progression; it presents some [248]
limitations: its diagnostic value is not well established in patients with late-onset phenotypes, most of the
findings are not pathognomonic of FD, and its prognostic value needs further evidence
Podocyturia Podocyte counting in urine sediments is time-consuming and technically challenging to obtain reliable [249-254]
data (reading is observer-dependent). Inconsistent correlations with albuminuria and GFR are found;
thus, added value against albuminuria, in terms of diagnostic accuracy, nephropathy prognosis, and
response to ERT, has not been established
Tubular injury N-acetyl-β-glucosaminidase presents an inverse correlation with estimated GFR stronger than the one [255-258]
between estimated GFR and albuminuria and is a good predictor of nephropathy progression.
Uromodulin and bikunin were studied in small cohorts, with conflicting results
Plasma Analogs/isoforms of Gb3 and lyso-Gb3 increase in plasma (to a lesser extent than plasma lyso-Gb3); all [47,221,222]
metabolomics of them are significantly more elevated in male patients (compared with female patients) and most of
them show a significant decrease during ERT
Urinary Increased excretion of lyso-Gb3, Gb3, and galabiosylceramide isoforms/analogs (all but one of the lyso- [47,223-225]
metabolomics Gb3 analogs has relative concentrations that are higher than lyso-Gb3), with a more prominent increase
in male patients and a significant decrease during ERT
Plasma proteomics Conflicting results, with different protein profiles found [259-261]
Urinary proteomics The most consistent alterations found are the up-regulation of prostaglandin H2 D-isomerase and [226-231]
prosaposin (the latter is also observed in pediatric, pre-symptomatic patients); both are known to play
roles in processes that might be involved in FD pathophysiology
MicroRNAs Few microRNAs present very good diagnostic accuracy in distinguishing between classical, late-onset [46,262,263]
phenotypes, and other forms of cardiomyopathy; some correlations with GFR are found
Circular RNAs Few circular RNAs are differentially expressed in FD patients and circulating levels are related to the [264]
phenotype and disease severity
IL: Interleukin; ERT: enzyme replacement therapy; FD: Fabry disease; LV: left ventricle; GFR: glomerular filtration rate.

Figure 3. Proposed study design to evaluate biomarkers. (A) biomarkers to assess patient prognosis; (B) biomarkers to assess response
to treatment.