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West et al. Rare Dis Orphan Drugs J 2024;3:22 https://dx.doi.org/10.20517/rdodj.2023.61 Page 9 of 34

A renal biopsy showing lamellar bodies is also insufficient for diagnosis as these are not specific to Fabry
disease. The most common mimic of Fabry nephropathy is a drug-induced phospholipidosis (DIP). There
are over 50 cationic amphiphilic drugs that inhibit lysosomal enzymes with resultant glycosphingolipid
[50]
[49]
accumulation in lysosomes . The renal pathology is indistinguishable from Fabry nephropathy . Patients
have CKD with proteinuria and occasionally low α-Gal activity. The only way to rule out DIP is through the
identification of a pathologic GLA variant. Choung et al. (2022) reported lamellar bodies in 32 [(0.73%) of
4,400 renal biopsies; only 6 (18.8%) had Fabry disease , and 26 (81.2%) had other renal pathology and/or
[50]
possible DIP] . This suggests that DIP might be more prevalent than Fabry nephropathy in some areas and
is an argument for GLA analysis in all Fabry disease patients.

When examining a patient with unexplained CKD, the presence of Maltese crosses in the urine sediment
under polarized light indicating lipiduria raises the possibility of Fabry nephropathy, especially if
proteinuria is sub-nephrotic or absent . Urine Mulberry cells will also show Maltese crosses and these are
[18]
[51]
said to be specific to Fabry disease .

Another renal clinical clue suggesting Fabry disease is the presence of parapelvic cysts on renal ultrasound.
Note that patients do not need to have a positive family history, as 5%-10% of variants are new mutations.

KIDNEY BIOPSY
Renal biopsy may be undertaken in patients with Fabry disease for various reasons. See Table 2. Electron
microscopy is essential for identifying the location, size, and number of glycosphingolipid deposits.
Advanced CKD in women with Fabry disease is uncommon relative to males with classic disease . A renal
[2]
biopsy should be considered to confirm the diagnosis and to rule out concomitant renal disease.

There are numerous case reports of patients with Fabry disease and a concurrent second renal disease,
usually a type of glomerulonephritis with IgA nephropathy as the most common . Clues to the presence of
[52]
a second glomerular disease would be the new onset of microhematuria, a sudden and marked increase in
proteinuria, or acute kidney injury superimposed on CKD in a previously stable patient.

While there are very rare reports of an immune complex membranous glomerulonephritis with anti-drug
antibodies during ERT in Pompe disease, another lysosomal disease, this has yet to be recognized in Fabry
disease [53,54] .

SCREENING FOR FABRY NEPHROPATHY
Screening for Fabry disease is usually done by a combination of GLA analysis, α-Gal activity, and plasma
lyso-Gb3. High-risk population screening studies for Fabry nephropathy have been carried out in patients
with CKD, focal segmental glomerulosclerosis (FSGS), those undergoing dialysis, or post renal
transplantation. In the largest meta-analysis to date, Linares (2023) included 55 studies with 84,062 screened
patients . Of these, 251 cases were positive for Fabry disease; 37.8% of the reported GLA variants were
[55]
non-disease causing, 31.7% had classical variants, 15.5% were late-onset, and 14.7% were VUS. The overall
prevalence was 0.10% in dialysis patients, 0.28% in kidney transplant patients, and 0.17% in those with
CKD . Thus, yields from screening for Fabry nephropathy are quite low, ranging from 1/1,000 to 1/357.
[55]
Despite recommendations in favour of screening CKD patients for Fabry disease, the cost-effectiveness of
such screening is questionable due to high costs . Conversely, family screening shows a much higher yield,
[56]
[57]
up to 50% or more, and may identify additional cases of Fabry kidney disease, making it a significantly
more cost-effective option.