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

α-galactosidase A molecules varies from one person to another, which leads to a rather wide spectrum of
[16]
enzyme activity of certain GLA variants .
UNDERSTANDING SECONDARY BIOLOGICAL ABNORMALITIES
Despite a fairly large number of efforts in the past 30 years to understand the pathogenic mechanism of
Fabry disease, we still have a poor grasp of how an increase of certain glycosphingolipids leads to multi-
organ dysfunction. One approach has been to look for disruptions in the biology of the cell or organ
involved in the disease in comparison with healthy controls [17-19] . The tendency, in many cases, is to consider
any deviation from the norm of protein or gene expression as a biological abnormality caused by the disease
that needs to be corrected or negated in some way. That may be true if the biological dysfunction is
maladaptive. However, “correcting” an adaptive (or even a neutral) cellular response may aggravate the
disease process. For example, depending on the biological context, autophagy can be either adaptive or
[20]
maladaptive . Another example of the importance of determining the significance of a biochemical
a b e r r a t i o n i n v o l v e s t h e a n i o n i c l i p i d l y s o b i s p h o s p h a t i d i c a c i d ( L B P A ) , a l s o c a l l e d
bis[(monoacylglycerol)phosphate]. It was found to be increased in both rare and common
[21]
neurodegenerative disorders, including in lysosomal diseases . This lipid was initially thought to be part of
the harmful lysosomal dysfunction seen in these disorders. Indeed, decreasing LBPA was thought to be
beneficial based on studies in a macrophage cell line in Gaucher disease . However, it was later found that
[22]
its accumulation in certain diseases is an ameliorative response to lysosomal dysfunction, including
increased autophagy, suggesting that augmenting its synthesis may have a major therapeutic benefit in a
wide spectrum of human diseases [23-25] . Interestingly, it was recently discovered that LBPA deficiency is the
direct cause of CLN5 neuronal ceroid lipofuscinosis due to a deficiency of its synthetic enzyme .
[23]
The need to distinguish between adaptive and maladaptive responses is equally important in Fabry disease
research. Researchers have recently described an overexpression of α-synuclein in glomeruli of kidney
biopsies and in a podocyte cell line from patients with Fabry disease . The podocyte structure and function
[17]
did not completely normalize with ERT. This finding led the authors to develop a knockdown model of
[17]
podocyte damage in Fabry disease using a podocyte cell line . Increased numbers of lysosomes, their pH,
and increased oxidative stress via reactive oxygen species were defined as the Fabry phenotype of this
podocyte line. Adding exogenous α-galactosidase A, using substrate reduction or a pharmacological
chaperone, reversed the abnormal expression of most proteins in this cell line but not the over-expression of
α-synuclein. On the other hand, knocking down α-synuclein in the Fabry podocyte cell line was associated
with a reduction in lysosomal area, lysosomal pH, and reactive oxygen species accumulation, while its over-
expression enhanced this cellular phenotype. However, the phenotypic abnormalities defined in the cell line
in vitro do not model the filtering function of podocytes in renal glomeruli in situ. In addition, it is
impossible to determine whether the over-expression of α-synuclein, as well as the combination of increased
lysosomes, lysosomal pH, and reactive oxygen species, are adaptive or maladaptive cellular responses in the
podocyte line, especially in podocytes in the intact glomerulus. Reactive oxygen species signaling plays an
important role in both cellular physiology and pathophysiology , as its function in both the innate and
[26]
[27]
even in the adaptive immune response illustrates . Additional doubt about the putative pathogenic role of
renal α-synuclein is raised by its apparent protective function in renal proximal tubules in the pathogenesis
of kidney fibrosis and by the absence of kidney disease in patients with Parkinson’s disease due to
[28]
triplication of SNCA locus and the consequent two-fold α-synuclein overexpression [29,30] . Interestingly,
similar findings including α-synuclein overexpression were found in the brain of the Fabry knockout mouse
model, but with no apparent neurological dysfunction or neurodegeneration [31-33] .