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Page 303 Zhang et al. J Transl Genet Genom 2024;8:302-11 https://dx.doi.org/10.20517/jtgg.2024.39

gene. This gene is responsible for the production of α-galactosidase A (α-GalA) and leads to a potentially
fatal buildup of globotriaosylceramide (Gb3) and relevant glycosphingolipids in tissues that contain
[1]
lysosomes. The estimated prevalence of this condition ranges from 1 in 40,000 to 1 in 117,000 individuals .
[2]
In newborn screenings, the prevalence is underestimated, ranging from 1 in 8,882 to 1 in 12,500 . High-risk
and family screening studies have revealed a higher frequency of FD than previously expected. Therefore,
the estimated prevalence varies depending on the type of screening, such as family, newborn, non-dialysis-
dependent chronic kidney disease patients, dialysis patients, and kidney transplant recipients . FD can be
[3]
categorized into two phenotypes: the classic and the non-classic. Classic FD primarily occurs in males, with
almost complete deficiency of α-Gal A activity, and complications such as kidney, heart, and
cerebrovascular issues appear earlier, leading to a poor prognosis. In contrast, the late-onset FD retains
residual enzymatic activity, often manifesting as single-organ involvement, typically affecting the kidneys or
[4]
heart .
Kidney complications are a predominant factor of morbidity and mortality in individuals with FD. The
primary clinical presentations of renal involvement include proteinuria, hypertension, and progressive
chronic kidney disease (CKD). Given that FD is a progressive disorder, it is essential for patients to receive a
definitive diagnosis promptly, so that they gain early monitoring, supportive care, and suitable treatment
options, which can prevent the onset of irreversible and potentially fatal complications. Since 2001, enzyme
replacement therapy (ERT) has been the primary treatment for FD. This treatment aims to stabilize the
condition, prevent the progression of organ damage, and alleviate disease symptoms. In addition, a
chaperone therapy known as migalastat (Galafold®, Amicus) was approved for use in certain FD patients in
the European Union in 2016 and subsequently in the United States in 2018 .
[5]

Podocytes are primary targets in Fabry nephropathy [Figure 1]. The accumulation of Gb3 causes injury to
podocytes, which are essential components of glomerular cells, responsible for maintaining the integrity of
the glomerular filtration barrier. In pediatric renal biopsies, the deposition of Gb3 within renal cells and the
podocyte foot process effacement can be detected, preceding the clinical onset of pathological albuminuria.
Previous studies have demonstrated that podocytes in Fabry nephropathy accumulate the most Gb3, leading
[6,7]
to the early occurrence of (micro)albuminuria . Given the restricted ability to regenerate, podocyte
damage and loss are regarded as pivotal events in the pathophysiology of kidney disease, making them
prime targets for therapeutic intervention. Inflammation also plays a significant pathogenetic role in FD.
Accumulated Gb3 in lysosomes results in the accumulation of impaired organelles and protein aggregates,
which initiate inflammation and oxidative stress. This initiates the synthesis of extracellular matrix proteins
to facilitate tissue repair. However, if uncontrolled, this reparative response can evolve into a pathological
state, causing excessive protein accumulation and renal fibrosis . In this work, we offer a comprehensive
[8]
review of Fabry nephropathy, with a particular focus on kidney podocyte lesions and treatment options.

CLINICAL FEATURES OF FABRY NEPHROPATHY
Kidney involvement occurs in 55% of Fabry disease patients . Albuminuria and estimated glomerular
[9]
filtration rate (eGFR) are the definitive indicators for tracking kidney conditions associated with FD
[Table 1] Proteinuria is usually a manifestation of podocyte injury and urinary protein excretion is closely
linked to renal function progression. In males with classic FD, pathological albuminuria often appears
between the ages of 20 and 30 years and serves as an independent risk factor for the worsening of kidney
conditions . Wanner et al. demonstrated that individuals experiencing rapid kidney disease progression
[4]
had notably elevated average ratios of urinary protein to urinary creatinine compared to those with slower
progression (1.5 vs. 0.2 for men; 1.4 vs. 0.5 for women; P < 0.0001) . Kidney function normally declines
[10]
over time and can cause end-stage renal disease (ESRD) in almost all classic male patients and some female