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Page 20 of 34 West et al. Rare Dis Orphan Drugs J 2024;3:22 https://dx.doi.org/10.20517/rdodj.2023.61

Nephrogenic diabetes insipidus (NDI) resolved with ERT and use of an ACEinh in a 7-year-old boy with
biopsy-proven Fabry nephropathy. It seems unlikely that the ACEinh would bring about a resolution of
[23]
NDI, leaving one to conclude that ERT was responsible .

Early manifestations of Fabry nephropathy and early renal biopsy sampling
Males with severe classical mutations in GLA, defined as a very low or undetectable leukocyte α-Gal
measurement and a disease-causing mutation, develop the classic phenotype with early and marked
accumulation of Gb3 and its metabolite, lyso-Gb3, in the plasma and in a variety of cell types, such as
vascular endothelial cells, smooth muscle cells, multiple kidney cell types, and cardiomyocytes.
Najafian et al., through quantitative renal electron-microscopic studies, have consistently shown that after
[145]
ERT or chaperone treatment , there is a proportional loss of Gb3 and podocyte shrinkage, resulting in
[144]
unchanged Gb3 density.
With the advent of intravenous ERT, there is now the capability to remove Gb3 from cells and, indeed,
endothelial cells are cleared of such deposits. Early ERT has also shown a tendency to clear some podocytes
[146]
of deposits in young children, as well as reducing foot process effacement . However, while the podocytes
show rarefication and a decrease in Gb3 deposits with ERT in adults, complete clearance is hindered [72,140] ,
partly because these cells bear a significantly greater burden of Gb3 due to aging and terminal
differentiation, rendering them unable to replicate. This situation is similar to that in the cardiomyocyte.

In the FIELD study, 31 male Fabry patients, 30 with classic variants, aged 5-18 years, were randomized to
receive agalsidase-beta at 0.5 mg/kg 2-weekly (n = 16) or 1.0 mg/kg 4-weekly (n = 15) for 5 years. Extensive
podocyte Gb3 deposits were observed, despite normal eGFR and no proteinuria . Fabry arteriopathy
[147]
worsened after 5 years in 5 of 6 patients. Podocyte Gb3 content and foot process width showed variable
responses. eGFR and proteinuria remained normal. Plasma and urine Gb3 levels normalized rapidly.
Plasma lyso-Gb3 levels substantially decreased but fluctuated after year 2. Angiokeratomas worsened in 5 of
16. These findings suggested that boys should be treated with agalsidase-beta at a dose of 1.0 mg/kg every
2 weeks. Important and irreversible renal pathologic changes (arteriopathy) antedated any clinical signs of
nephropathy in males with classic variant disease.

Treatment with pharmacologic chaperone
Hughes et al. reported that Fabry adults receiving migalastat show a similar eGFR over 18 months of
treatment to those randomized to ERT. Migalastat was well tolerated .
[148]
In patients bearing amenable mutations, migalastat resulted in stable renal function for up to 8.6 years
irrespective of treatment status (ERT-naïve and ERT-experienced), sex, or phenotype .
[149]

In a retrospective analysis of adult patients with Fabry disease amenable to migalastat treatment in
Switzerland, in males, the achieved leukocyte α-Gal enzyme activity differed from that in HEK cells after
incubation with migalastat, for example: 33% in leukocytes vs. 41% HEK cells for p.F113L variant; 43% in
leukocytes vs. 36% in HEK cells for p.N215S variant: 24%-30% in peripheral leukocytes vs. 96% in HEK cells
for S238N variant . These differences reflect the variations in these parameters rather than any
[150]
inaccuracies in the assays.

In a recent report, stable renal function was documented in adults on migalastat and it was suggested that
female patients should not be treated differently than males . In this study, 125 patients, comprising both
[151]
males and females, demonstrated generally stable renal function while receiving migalastat for 3.9 years. The