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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 15 of 34

Differential diagnosis
Chloroquine and many other amphiphilic drugs that cause DIP can lead to glycolipid deposits
[98]
indistinguishable from Fabry disease .

FSGS may develop in Fabry disease and lead to a misdiagnosis when electron microscopy is not used to
reveal the lamellar bodies. This has the risk of the use of inappropriate immuno-suppressive therapy that is
ineffective with a possibility of adverse effects.

I-cell disease is a rare lipidosis caused by a lack of cellular mannose-6-phosphate needed to direct hydrolases
into the lysosome; it is characterized by distended podocytes with numerous intracytoplasmic clear vacuoles
containing lipids. On electron microscopy, there are no lamellar bodies; the lipid vacuoles stain positive for
[99]
colloidal iron, which is not seen in Fabry disease .
MANAGEMENT
Non-specific therapy
The principles of CKD management have been recently reviewed and will not be repeated here .
[100]

A multidisciplinary team is useful with a cardiologist, neurologist, gastroenterologist, ophthalmologist,
medical geneticist, pediatrician, social worker, and nurses, in addition to a nephrologist. Regular
assessments are required, particularly as patients age. As this is a rare disease, management is best done in a
medical center of excellence with experience in all aspects of Fabry disease.

In addition, a dietitian is helpful in counseling patients on a diet with low salt intake to minimize
proteinuria, and control hypertension and heart failure. A diet low in fermentable oligosaccharides,
disaccharides, monosaccharides, and polyols has been proposed to help reduce GI symptoms similar to
[101]
irritable bowel syndrome .
Fabry patients have an excess of psychiatric disease, which may be part of this disease spectrum and not just
[102]
the result of chronic pain . They may benefit from regular access to a mental health team.
Fabry patients should all receive genetic counseling to help with understanding of the X-linked pattern of
inheritance and reproductive choices. Additionally, a genetic counsellor can create a family pedigree which
is useful in screening family members at risk for Fabry disease. If there is any question as to the
pathogenicity of the GLA variant, then a medical geneticist should be consulted.

Limiting proteinuria
While ERT and pharmacologic chaperone therapy are valuable in stabilizing eGFR in Fabry nephropathy,
they have little impact on proteinuria. This mean that antiproteinuric therapy must be used in Fabry
nephropathy in conjunction with specific therapy. There have only been a few studies addressing CKD
therapies in Fabry disease to date.

Tahir et al. (2007) reported on the use of ACEinh and ARB as antiproteinuric therapy plus ERT in
11 patients with Fabry nephropathy . Sustained reductions in proteinuria with stabilization of kidney
[103]
function were achieved in six patients with stage III/IV CKD; the eGFR slope was -0.23 mL/min/1.73 m /yr
2
over 30 months of follow-up. Warnock et al. (2015) conducted a prospective study of the antiproteinuric
effect of ACEinh and ARB on 24 adult classical genotype patients with Fabry nephropathy receiving
recombinant agalsidase-beta therapy . A urine protein to creatinine ratio (uPCR) < 0.5 g/g or a 50%
[104]