Page 87 - Read Online

Page 2 of 34 West et al. Rare Dis Orphan Drugs J 2024;3:22 https://dx.doi.org/10.20517/rdodj.2023.61

INTRODUCTION
Most lysosomal diseases are characterized by the deficiency of lysosomal enzyme function. In the case of
Fabry disease (OMIM 301500), the deficiency is that of alpha-galactosidase A (α-Gal), which cleaves the
terminal galactose residue from the glycosphingolipid substrates, the main one being globotriaosylceramide
(Gb3). As a result of this deficient enzyme activity, Gb3 accumulates in lysosomes in virtually all cells and
tissues throughout the body, leading to organ dysfunction. This results in strokes, renal failure,
cardiomyopathy, sensory peripheral neuropathy, hearing loss, altered sweating, corneal dystrophy, and
[1]
angiokeratomas with disability and early death . It is the most common lysosomal disease that has a major
kidney phenotype with a high prevalence of end-stage kidney disease (ESRD).

Kidney involvement in Fabry disease becomes clinically apparent in childhood with microalbuminuria. It is
highly prevalent, with most adult patients having renal Gb3 deposits on biopsy and/or proteinuria.
However, classically affected male patients and those with renal variant disease are most likely to develop
chronic kidney disease (CKD) and progress to ESRD.

While females are twice as likely as males to be involved in this X-linked disorder, mosaicism exhibited in
heterozygotes results in milder disease. As a result, females with Fabry disease are far less likely to have
progressive CKD or end up needing renal replacement therapy .
[2]

[3]
Overall, Fabry nephropathy is a rare cause of both CKD and ESRD. However, it is important as a treatable
cause of CKD. Efforts to make an early diagnosis with genetic counseling and early therapy can be of great
benefit to patients.

The diagnosis of Fabry disease is difficult as this rare condition is hard for clinicians to recognize due to its
shared clinical features with many other common diseases. Like many genetic disorders, Fabry disease is
characterized by great heterogeneity of both genotype and phenotype. There are over 1,000 variants
described so far in the GLA gene that codes for α-Gal (HGMD, ClinVar). Knowledge of a patient’s genotype
is helpful as it will often predict the Fabry disease phenotype, either classic early-onset Fabry disease or
later-onset cardiac or renal-limited disease. Male hemizygotes with very low α-Gal activity (< 3%) will have a
[1]
more severe disease phenotype than the female heterozygotes .
Management of Fabry disease has advanced greatly since the introduction of the first treatment with
recombinant human enzyme replacement therapy (ERT) in 2001, but there remain many unmet patient
needs. There are now additional agents available such as pharmacologic chaperone and modified ERT.
Investigational approaches include substrate reduction therapy, gene therapy, T and B cell therapies, and
mRNA therapies.

We review Fabry nephropathy to provide an update on this challenging condition.

EPIDEMIOLOGY
Fabry disease is the second most common form of lysosomal disease, next to Gaucher disease. It is pan-
ethnic and worldwide in distribution. Its prevalence has been estimated to be between 1 in 50,000 to 100,000
people .
[4]
[5-7]
Newborn screening studies have reported higher frequencies of 1/1,600 males and 1/4,000 females , with a
preponderance of late-onset or attenuated variants and variants of unknown significance (VUS) compared