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Depletion of globosides and isoglobosides fully reverts the morphologic phenotype of Fabry disease.
[fabry disease]
Fabry
disease
is
a
monogenic
X-
linked
lysosomal
storage
disease
caused
by
α-galactosidase
A
(
αGalA
)
deficiency
.
Enzyme
replacement
therapy
through
administration
of
the
missing
αGalA
is
currently
the
only
accepted
therapeutic
option
.
However
,
this
treatment
is
connected
to
high
costs
,
has
ill-defined
indication
criteria
and
its
efficacy
is
controversially
discussed
.
Our
aim
was
to
explore
the
possibility
of
a
novel
targeted
substrate
reduction
therapy
for
Fabry
disease
.
Owing
to
the
fact
that
αGalA-
deficient
humans
and
mice
accumulate
the
same
glycosphingolipids
(
i
.
e
.
globosides
,
galabiosylceramide
and
isoglobosides
)
,
αGalA-
deficient
mice
were
crossed
with
mice
deficient
in
enzymes
synthesizing
these
classes
of
glycosphingolipids
(
i
.
e
.
globotrihexosylceramide
and
isoglobotrihexosylceramide
synthase
,
respectively
)
.
Functional
heart
and
kidney
tests
were
performed
together
with
an
extensive
biochemical
analysis
of
urine
and
serum
in
aged
mice
.
Lysosomal
storage
was
assessed
by
thin
layer
chromatography
and
electron
microscopy
.
We
showed
that
depletion
of
globosides
was
sufficient
to
fully
abolish
the
storage
of
glycosphingolipids
in
heart
,
kidney
and
liver
and
was
paralleled
by
a
complete
restoration
of
lysosomal
morphology
in
these
organs
.
In
contrast
,
in
dorsal
root
ganglia
,
a
depletion
of
both
globosides
and
isoglobosides
was
necessary
to
fully
counteract
the
lysosomal
storage
.
The
deficiency
in
globosides
and
/
or
isoglobosides
did
not
cause
any
adverse
effects
.
We
conclude
that
substrate
reduction
therapy
through
inhibition
of
the
synthesis
of
globosides
and
isoglobosides
represents
a
valuable
therapeutic
option
for
Fabry
disease
,
all
the
more
as
globosides
and
isoglobosides
seem
to
be
dispensable
.
Diseases
Validation
Diseases presenting
"has ill-defined indication criteria and its efficacy is controversially discussed"
symptom
fabry disease
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