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Feriozzi et al. Rare Dis Orphan Drugs J 2024;3:11 https://dx.doi.org/10.20517/rdodj.2023.37 Page 7 of 11

[53]
associated with decreased enzymatic degradation and could mediate resistance to ERT .

The genetic and pharmacological [by β2 adrenergic receptor agonist] inhibition of SNCA significantly
improves lysosomal structure and dysfunction. Therefore, only with SNCA correction can ERT reach the
target to amend the GLA defect.

All these experimental-based experiences share common evidence. The deposition of Gb3 is followed by
dysregulation of pathogenetic pathways, resulting in severe cellular injury. The enzymatic therapy can clear
the cells of Gb3 deposition but has limited effects on the dysregulated pathways. Therefore, an early start of
treatment can halt or reduce the Gb3 deposition and the activation of pathological pathways such as
progressive inflammation. Late therapy has a reduced effect because these dysregulated mechanisms, from a
certain point onwards, become independent of Gb3 activation.

COMPREHENSIVE IDEA ABOUT GB3 DEPOSITION, INFLAMMATION, FIBROSIS, AND
PROGRESSION OF RENAL DAMAGE
The pathogenesis of tissue damage in FD and, in this case, FN is very complex and still unclear.
Undoubtedly, the deposition of Gb3 alone cannot explain the variability of clinical cases and the different
rates of disease progression. Over the past few years, we have gathered much evidence that provides exciting
and complex pathogenetic pathways.

We can suppose [Figure 1] that gene mutation can already determine changes in biological processes in the
physiological activity of the endoplasmic reticulum with over-expression of the UPR. This UPR is
subsequently associated with stimulating inflammation, as described in other diseases such as cancer,
diabetes, and so on . In this case, we could define this as a pathology of the gene, so-called Agalopathy. We
[22]
must consider the GLA-mutant Zebrafish experimental model to support this hypothesis. This model has
the same functional mitochondrial alterations and structural changes of FN, but it lacks the Gb3 synthetase,
[54]
so there is no Gb3 lysosomal deposition .

The lysosomes are the site of a severe engulfment due to Gb3 deposition interfering with normal lysosome
functions, and dysregulation of physiological processes, such as autophagy, occurs. In particular, engulfed
podocytes detach from the glomerular basement membrane, and glomerular segmental sclerosis appears in
light microscopy .
[28]
Moreover, Gb3 deposition causes activation of inflammation through the interaction with Notch 1 and
NFkB, resulting in the recruitment of leukocytes to the glomeruli, exacerbating the status. Inflammatory
activation causes a chronic insult to the cells and tissues that determines a cellular de-differentiation with
activation of extracellular matrix protein synthesis and release of cytokines with inflammatory (IL1β) or
profibrotic(TGFβ) role. In the kidney, the mesangial cells produce an excess extracellular matrix, and
metalloproteinases have reduced remotion activity. All these processes can eventually become independent
[30]
from the initial Gb3 deposition, resulting in progressive renal tissue inflammation and fibrosis . Kidney
fibrosis is an irreversible process resulting in progressive loss of renal function and scar tissue development.

CONCLUSIONS
In the literature, evidence demonstrates that the deposition of Gb3 is associated with alterations in immune
response and subtle, non-overt processes of inflammation primarily mediated by innate immune
mechanisms. All the evidence of activation of inflammatory mechanisms (Gb3 deposition, cytokines release,