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Page 305 Zhang et al. J Transl Genet Genom 2024;8:302-11 https://dx.doi.org/10.20517/jtgg.2024.39

in Fabry disease stems from the accumulation of glycolipids in nearly all types of cells within the
glomerulus, with particularly large accumulations in podocytes. These deposits are not confined to the
glomerular cells but are also found within the tubular cells and the endothelium of the peritubular
[16]
capillaries . The progression of kidney disease is primarily characterized by podocyte damage, persistent
proteinuria, and permanent damage to the small blood vessels within the kidneys, leading to progressive
glomerulosclerosis, capillary wall thickening, tubular atrophy, interstitial fibrosis, and arterial and arteriolar
sclerosis. Several studies showed glomerulosclerosis and segmental sclerosis levels are sensitive indicators
for the kidney progression of patients with FD [13,17] .

Gb3 deposits in podocytes have drawn particular attention from researchers. On light microscopy, vacuoles
were frequently observed in podocytes. Electron microscopy revealed that the Gb3 accumulations within
the cells manifested as distinctive osmiophilic inclusions in the podocytes’ cytoplasm, exhibiting a pattern of
alternating light and dark concentric rings. These osmiophilic myelin bodies had a diameter ranging from 1
to 3 nm and presented a "zebra-like" pattern [Figure 1]. Effacement of the segmental foot processes was also
found in the podocytes. Using quantitative morphometric electron microscopic studies, it was indicated that
the proportion of podocyte cytoplasm filled with Gb3 deposits rises with age but stabilizes after the age of
27. This implies that there exists a critical level of Gb3 accumulation beyond which podocytes may sustain
[18]
injury and loss . Indeed, podocyturia (loss of podocytes through the urine) in Fabry nephropathy has been
generally examined and is considered an indicator of early kidney involvement in FD .
[19]
The accumulation of Gb3 can lead to its conversion into globotriaosylsphingosine (lyso-Gb3), a process
likely facilitated by the non-specific action of lysosomal acid ceramidase that cleaves the fatty acid from
Gb3. Elevated lyso-Gb3 levels in the plasma of FD patients suggest that it is a more reliable biomarker for
[20]
tracking disease progression compared to plasma Gb3 levels . In cultured podocytes, Lyso-Gb3 triggered
the activation of Notch1, leading to an increase in the production of tumor growth factor β1 (TGF-β1),
which facilitates the development of fibrosis and sustained inflammation by the synthesis of extracellular
matrix in renal cells via epithelial-to-mesenchymal transition . Another study found that human
[21]
podocytes respond to lyso-Gb3 by initially increasing the expression of genes for the αvβ3 integrin and
uPAR. The αvβ3/UPAR system plays a pivotal role in the detachment of podocytes and the subsequent
release of these cells in the urine, a process known as podocyturia . Analyses utilizing transcriptome
[22]
connectivity mapping and SILAC quantitative proteomics showed the deposits of α-synuclein (SNCA) as a
critical factor in podocyte damage. Suppressing SNCA through genetic and pharmacological interventions
[23]
may enhance the lysosomal structure and functionality in Fabry podocytes .

CURRENT TREATMENT
Enzyme replacement therapy
[24]
Since 2001, ERT has been available as a specific treatment option to compensate forαGalA deficiency
[Table 2]. At present, three formulations of recombinant human αGalA are accessible: agalsidase α
(Replagal®), agalsidase β(Fabrazyme®), and a biosimilar of agalsidase β (JR-051). Agalsidase α is
manufactured using a human cell line and administered at a dosage of 0.2 mg/kg, with an infusion duration
of 40 min. Agalsidase β is derived from Chinese hamster ovary cells, with a suggested dosage of 1.0 mg/kg
and a standard infusion time of approximately 240 min. At present, there is no strong data showing the
superiority of either one for treating FD . ERT has been demonstrated to significantly mitigate the impact
[25]
of FD on the heart, kidneys, and nervous system . Initiating ERT as early as possible may be beneficial. For
[26]
classical male patients, ERT should be begun upon diagnosis; heterozygous females and atypical male
patients are recommended to initiate ERT at the onset of clinical manifestations of FD. However, the
[26]
efficacy of ERT is less satisfactory in patients with advanced kidney disease and severe cardiac fibrosis .