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Page 2 of 11 Feriozzi et al. Rare Dis Orphan Drugs J 2024;3:11 https://dx.doi.org/10.20517/rdodj.2023.37

INTRODUCTION
Renal involvement is a significant factor in Fabry disease [FD], impacting patient outcomes considerably.
Prior to the availability of enzyme replacement therapy [ERT], it was the primary cause of death in Fabry
patients . The clinical course of Fabry nephropathy [FN] is variable. In males with the classical phenotype,
[1]
urinary concentration defects may manifest at a young age during the initial phase, often overlooked. Over
time, mild proteinuria develops, followed by arterial hypertension and progressive impairment of renal
function. The nephropathy follows a progressive, chronic course, with overt renal failure typically appearing
in the third or fourth decade of life, potentially necessitating dialysis treatment. For eligible patients, renal
transplant stands as a viable option, often yielding successful outcomes. Conversely, the renal clinical course
tends to be less aggressive in females and patients with late-onset variants, where nephropathy occurs later
in life. Typically, these phenotypes exhibit mild renal manifestations for a long time, with the diagnosis of
[2]
Fabry disease often delayed for many years or coincidentally made during a screening program .
Fabry disease is an X-linked monogenic disorder due to pathogenic variants in the GLA gene that encodes
for the lysosomal enzyme α-galactosidase A. The deficient activity of α-galactosidase A causes a progressive
lysosomal deposition of the glycosphingolipids: globotriaosylceramide [Gb3] and its derivative
globotriaosylsphingosine [Lyso-Gb3].

Even though only one gene is involved in the pathogenesis of the disease, clinical presentation among Fabry
patients is highly heterogeneous. Affected members from the same family, with the same GLA mutation,
[3]
classical or late onset, can present a broad spectrum of phenotypes . Consequently, over the years, it has
become more evident that the progressive deposition of Gb3 could not wholly explain the pathogenic
mechanisms that are taking place in tissues and organs. Thus, it has been hypothesized that additional
pathogenetic pathways could play a role in tissue damage .
[4]

Many studies have been initiated to understand these processes, and the pathogenetic molecular and cellular
mechanisms activated by GLA variant and lysosomal Gb3 deposition have captured significant attention
from researchers. Among the altered pathways, a subtle and chronic inflammation due to Gb3/Lyso-Gb3
[5,6]
exposure resulting in tissue fibrosis has been extensively described . This review will report these studies
with particular emphasis on the pathogenic development of FN.

EVIDENCE ON THE ROLE OF INFLAMMATION AND IMMUNE RESPONSE
Lysosomal deposits may act as damage-associated molecular patterns [DAMPs] or cause DAMP production
by injured cells. The presence of DAMPs is sensed by pattern recognition receptors in innate immune cells,
leading to pro-inflammatory activity resulting in cytokine secretion and apoptosis . The release of
[7]
cytokines interacts with leukocytes, resulting in perturbation in the proportion of leukocyte subsets in
peripheral blood from patients, and these cells display high surface expression of adhesion molecules . The
[8]
first pieces of evidence on the presence of chronic activation of inflammation associated with Fabry disease
came from studies on mononuclear cells from patients, showing a constitutive overproduction of IL1β and
[9,10]
TNFα . When exposed to high levels of Gb3, normal dendritic cells and macrophages produce pro-
inflammatory cytokines . This immune response was shown to be mediated by Toll-like receptor 4 (TLR4)
[9]
ligation.

Associated with this pro-inflammatory environment, mononuclear cells from naïve Fabry patients displayed
a higher apoptotic state, which is lower in patients undergoing ERT. Adding Gb3 to normal cells induces
[11]
apoptosis mediated by the intrinsic pathway in which altered mitochondria play a role . Furthermore,
neuronal apoptosis inhibitory protein and apoptosis-inducing factor were differentially expressed among