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

(often irreversible lesions) or transcriptional profiles, whose detection depends on invasive procedures.
Consequently, the identification of non-invasive biomarkers of preclinical involvement of the organs may
have a profound impact on the treatment decisions, whether these biomarkers prove to have prognostic
[1]
value .

Finally, FD is a relatively slowly progressive disorder, with major events occurring mainly in adulthood.
This fact constitutes a major difficulty in the design of clinical trials [22-24] , because long follow-up periods are
required to demonstrate the benefits of any therapeutic intervention. Therefore, the identification of
surrogate biomarkers of response to treatment, with rigorous correlations with clinical outcomes, is
essential in the evaluation of the therapeutic strategies that are available or under development .
[1]

FABRY DISEASE BIOMARKERS USED IN THE CLINICAL PRACTICE
Currently, there are no proper or well established/validated plasma or urinary biomarkers for FD. However,
there are several biomarkers (imaging techniques and analytes [metabolites related to lipid abnormalities or
proteins]) that are used in clinical practice with some limitations. These biomarkers may reflect the systemic
disease burden or manifestations in a particular organ.

SYSTEMIC DISEASE BURDEN BIOMARKERS
Metabolites related to lipid abnormalities have been used as the main biomarkers of FD systemic burden,
namely globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3).

Research of potential protein biomarkers for FD showed a lack of prominent plasma protein abnormalities.
However, several biomarkers mainly related to inflammation and endothelial dysfunction have been
studied, but not widely validated and, consequently, are not currently used in clinical practice .
[1]

Globotriaosylceramide
FD is characterized by a disruption in glycosphingolipids metabolism, so lipid abnormalities have been
studied as potential biomarkers. For a long time, the primary accumulating substrate Gb3 has been
considered a surrogate marker for FD [Table 1], and its reduction in the endothelium has served as an
[1,22,25]
indicator for the development and registration of enzyme replacement therapy (ERT) with agalsidase β .
Role in diagnosis and phenotype evaluation
Gb3 is not only found inside the cells, but it has been recognized for a long time that its concentration is
increased in plasma and urine in FD male patients . Plasma and urine Gb3 values are more strikingly
[26]
elevated in FD males and plasma Gb3 is elevated in only a small percentage of female patients (15%-30%),
and urinary Gb3 may be within the normal range in 8%-13% and 12%-20% of male and female patients,
respectively [27,28] . There is a correlation between types of mutations and urinary Gb3 excretion, with patients
with missense mutations, mainly those associated with late-onset phenotypes, presenting lower values, most
of which within the normal range, even in male patients [29-31] . Thus, the added value of Gb3 for diagnostic
[1]
purposes is at least questionable .

Role in clinical monitoring and assessment of treatment response
The correlation between plasma or urinary Gb3 and clinical manifestations and its added value to monitor
progression of FD is also poor, without correlation with age, most of clinical parameters, and total disease
severity (measured by Mainz Severity Score Index [MSSI]) ; however, plasma Gb3 is significantly higher in
[32]
male patients with cerebral complications (compared with those without) and urinary Gb3 significantly
correlates with estimated glomerular filtration rate (GFR), urine protein-to-creatinine ratio, and albumin-