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Page 2 of 11 Schiffmann. Rare Dis Orphan Drugs J 2024;3:4 https://dx.doi.org/10.20517/rdodj.2023.50

INTRODUCTION
The goal of this update is to highlight and comment on recent advances in the pathogenesis and treatment
of Fabry disease by either describing novel observations or emphasizing and re-interpreting previously
published data.

The most important predictor and modifier of the age of clinical disease onset and overall disease severity is
[1]
residual α-galactosidase A activity . Patients with the classic form have no residual enzyme activity as
measured in peripheral blood white cells, while those with so-called late-onset (sometimes referred to as
[2]
atypical) Fabry disease have real measurable residual enzyme activity . Although disease severity tends to
decrease with increased residual α-galactosidase A activity, there is no strict linear correlation between
residual enzymatic activity and severity of clinical features, probably because of the presence of various
modifiers. What is often not appreciated is that there is a “disease threshold” of about 35% of mean
normal . In other words, α-galactosidase A activity below normal but above 35% of mean normal is not
[2]
thought to be associated with increased risk of clinical Fabry disease-related complications. This has
important implications when evaluating a GLA variant of unknown significance (VUS) and deciding if a
person with a particular GLA variant should be considered for therapy such as ERT or pharmacological
chaperone . Patients with late-onset Fabry disease may have any of the same organ/system complications
[3,4]
(heart, kidney, cerebrovascular, peripheral nerve) as patients with the classic form but typically develop
those complications at a later age, with the possible exception of late-onset female heterozygotes who rarely
if ever develop renal insufficiency .
[1]
The main reason for delay in diagnosis is the non-specific nature of the complications of Fabry disease .
[5]
The characteristics of a cerebrovascular stroke, the nephropathy, the small-fiber neuropathy, and most
cardiac manifestations in patients with Fabry disease are like those that occur in patients who have other
[5]
disorders - for example, diabetes mellitus - and are in many ways a phenocopy of Fabry disease .

PHENOTYPIC CATEGORIZATION OF GLA VARIANTS
As mentioned above, GLA gene variants associated with low residual α-galactosidase A activity may be
pathogenic if enzyme activity is below the disease threshold and are presumed non-pathogenic if it is higher.
However, some such variants may have low enzyme activity in some individuals and high (not disease-
causing) in others. The best example is the common A143T variant. It is considered a benign variant in
some publications but has been shown to be pathogenic in others . The T419A variant was shown to be
[6-9]
associated with 32% of mean normal activity in one male and 0% activity in two of his grandsons. Therefore,
both late-onset and classic phenotype co-occurred within the same family . The D313Y variant may be
[10]
another such example . Therefore, it is important to measure α-galactosidase A activity in blood leukocytes
[11]
of males in the family before concluding whether a GLA gene variant is disease-causing or not. The
pathogenicity of the mutation may be uniform in a particular family, but determination in female
heterozygotes is difficult since measurements of enzyme activity in peripheral blood white cells are not
useful in females, and levels of plasma lyso-Gb3 are often not elevated in such patients [7,10,12] . Since the
A143T variant is often detected by newborn screening, follow-up enzyme activity testing in blood
leukocytes of newborn males (and expressed as percent of mean normal of the same laboratory) would help
decide if the child (and therefore possibly his relatives) may be at risk for Fabry disease-related
manifestations.

Unfortunately, this is often not done for subjects born with this variant [13-15] . The cause of the large
individual variability in residual enzyme activity of some GLA variants has not yet been established. It is
likely that the ability of the cell to promote adequate protein folding and chaperoning of mutated