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Page 401 Chandramohan et al. J Transl Genet Genom 2024;8:394-404 https://dx.doi.org/10.20517/jtgg.2024.38

The pathognomonic osmiophilic, lamellar inclusion bodies are typically present within podocytes on
electron microscopy. It has been found that increased amounts of GL-3 inclusions correlated with decreased
[18]
podocyte numbers and a higher degree of proteinuria . Podocytes in the female Fabry phenotype were
found to have increased foot process width, and these dysfunctional podocytes are lost with age. Segmental
flattening of the foot processes in young Fabry disease patients with classic disease has been described by
Tøndel et al. in their case series. The occurrence of foot process effacement prior to the development of
overt proteinuria is thought to be due to signaling pathways and local inflammatory processes in addition to
[19]
the accumulation of GL-3 .
Other non-electron microscopy findings are also of significance. Glomerular sclerosis occurs early in FD,
and it has been reported that the presence of segmental and global glomerular sclerosis accelerates the eGFR
decline [13,20] . As seen in other diseases, the presence of numerous glomerular sclerosis lesions portends a
poorer prognosis. In our series, three patients had evidence of global sclerosis, and one had focal glomerular
sclerosis. This again underscores that these findings occur before the onset of commonly identified signs of
renal involvement, such as proteinuria or elevated creatinine. Interstitial fibrosis has also been associated
with poorer prognosis in Fabry, similar to IgA nephropathy and other diseases. A small study FD study
involving nine children and adolescents, with an average age of 13.5 years and minimal albuminuria,
exhibited biopsy changes, including interstitial fibrosis and arteriopathy, indicating that these processes start
early . This was also seen in our study. Although IFTA was minimal among our patients, it was present in
[21]
the majority. There are no reported gender dissimilarities in biopsy findings, but males have been reported
to have larger and increased podocyte inclusion bodies involving > 50% of the glomerulus even in the early
stages of CKD. Generally, females may have fewer histopathological features than males, such as global
[13]
sclerosis, podocyte vacuolization, and vascular inclusions .

According to data from the Fabry registry, the most common initial heralding events are renal failure and
cardiac arrhythmias. Approximately 20% of females over the age of 40 years have stages 3-5 CKD. It must be
noted that renal disease can contribute to and result from cardiac disease. The mean ages of death per the
Fabry registry and the Fabry outcomes survey (FOS) are 64.4 and 60.9 years, respectively, which are lower
than those of the general population. Early diagnosis and early implementation of therapies can have a
positive impact by preventing organ damage and improving the overall quality of life .
[22]

Classic mutations in FD lead to a complete absence of GLA, which is associated with more severe
manifestations of the disease . While classic mutations typically cause a more aggressive disease course in
[23]
males, female patients with these mutations can also exhibit severe phenotypes due to skewed
X-inactivation . We show that females with these mutations have glomerular sclerosis, podocyte inclusions,
[7]
and other features on renal biopsy that may lead to worsening GFR and renal complications. This supports
the need for early diagnosis and early initiation of ERT or other therapies. In our series, ERT was initiated in
patients with significant histologic findings, including podocyte vacuolization, foot process effacement, and
glomerular sclerosis, despite normal creatinine and minimal proteinuria.

Endomyocardial biopsies also play a role in assessing the extent of tissue involvement in patients with FD,
as well as in cases with variants of uncertain significance (VUS). In regions such as Taiwan, where biopsies
are mandatory to verify the primary etiology of hypertrophic cardiomyopathy, endomyocardial biopsies are
performed more frequently. Hsu et al. have shown that endomyocardial biopsies among Taiwanese patients
with IVS4 + 919G > A, a late-onset mutation, showed GL-3 accumulation within cardiomyocytes but not in
the capillary endothelial cells. The median creatinine among females in the cohort was 0.8 mg/dL and the
mean eGFR calculated per the MDRD equation was 73.2 mL/min/1.73m . This suggests that the females
2[24]