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Aguiar. Rare Dis Orphan Drugs J 2024;3:13 https://dx.doi.org/10.20517/rdodj.2023.56 Page 15 of 29

chronic nonspecific glomerular and tubulointerstitial lesions seen in kidney biopsies seem to correlate better
with the natural history and manifestations of FD nephropathy (GFR and proteinuria) [9,15,191,192] .

Role in the evaluation of treatment response
Histological biomarkers have also been used as surrogate endpoints to assess the response of FD to DST,
showing a significant increase in the percentage of normal glomeruli in the agalsidase α phase III clinical
[24]
trial ; a significant decrease in the inclusion score in the kidney microvascular capillary endothelial cells in
the agalsidase β phase III clinical trial, with a complete clearance of the endothelial, mesangial and distal
convoluted tubule/collecting duct cells after 54 months of the extension study [22,34] ; a significantly greater
reduction in the mean number of Gb3 inclusion per kidney interstitial capillary than in the placebo group in
[66]
the migalastat phase III clinical trial .

Nonetheless, clearance of inclusions in glomerular podocytes is much more difficult and time-dependent.
The largest published study showed that, after a mean of almost 10 years, there was a significant decrease in
the Gb3 inclusions in the podocytes both in the so-called “lower fixed dose group” (0.2 mg/Kg/EOW for the
entire follow-up) and in the “higher dose group” (doses higher than 0.2 mg/Kg/EOW for, at least, part of the
follow-up period), but with a significant correlation between the cumulative dose of ERT received and the
clearance of podocyte Gb3; however, GFR only had a significant decrease in the “higher dose group” and
[193]
remained stable in the “lower fixed dose group” .
Nevertheless, the importance of the finding of persistent podocyte Gb3 inclusions remains controversial,
because its role as a surrogate biomarker for the progression of renal dysfunction (GFR) in patients treated
with ERT is not well established. Notwithstanding the significant correlation between the decrease in
urinary albuminuria and the decrease in podocyte Gb3 inclusion score in a long-term evaluation of
histological outcomes, in the same cohort, GFR remained stable in all patients, regardless of the decrease in
podocyte Gb3 inclusions . Similarly, in the 54-month extension study of the agalsidase β phase III clinical
[18]
trial, despite persistent inclusion in podocytes in the six evaluated patients, only in one patient, there was a
progressive decline in GFR . Moreover, as mentioned above, even in untreated patients, there is no
[34]
correlation between semi-quantitative scoring systems for intracellular Gb3 inclusions and GFR [9,15,17,191] and
there is evidence of heavy podocyte inclusions in patients with late-onset variants, despite the small risk of
progressive nephropathy [194,195] .

CENTRAL NERVOUS SYSTEM BIOMARKERS
Research for biomarkers of central nervous system (CNS) in FD has been challenging due to the limited
knowledge about the physiopathology of CNS involvement in FD. No valuable serum biomarkers exist for
the early detection, risk stratification, or monitoring of cerebrovascular disease progression . There is a
[196]
weak correlation between serum cystatin-C and CNS pathology in males . In females, plasma lyso-GB3
[92]
correlates with WML severity .
[41]
Magnetic resonance imaging
Currently, brain MRI is the most useful tool for evaluating CNS in FD, with several sequences studied as
biomarkers of its involvement.

White matter lesions
WML in the form of single, multiple, or confluent hyperintensities in T2-weighted MRI are the most
commonly reported image markers of neurovascular involvement in FD patients (present in about 2/3 of
the patients, despite the absence of overt clinical signs of cerebral disease) [197,198] . The localization pattern is