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Are astrocytes the missing link between lack of brain aspartoacylase activity and the spongiform leukodystrophy in Canavan disease?
[canavan disease]
Canavan
disease
(
CD
)
is
a
genetic
degenerative
brain
disorder
associated
with
mutations
of
the
gene
encoding
aspartoacylase
(
ASPA
)
.
In
humans
,
the
CD
syndrome
is
marked
by
early
onset
,
hydrocephalus
,
macroencephaly
,
psychomotor
retardation
,
and
spongiform
myelin
sheath
vacuolization
with
progressive
leukodystrophy
.
Metabolic
hallmarks
of
the
disease
include
elevated
N-
acetylaspartate
(
NAA
)
levels
in
brain
,
plasma
and
CSF
,
along
with
daily
excretion
of
large
amounts
of
NAA
and
its
anabolic
metabolite
,
N-
acetylaspartylglutamate
(
NAAG
)
.
Of
the
observed
neuropathies
,
the
most
important
appears
to
be
the
extensive
demyelination
that
interferes
with
normal
neuronal
signaling
.
However
,
finding
the
links
between
the
lacks
of
ASPA
activity
in
oligodendrocytes
,
the
buildup
of
NAA
in
white
matter
(
WM
)
and
the
mechanisms
underlying
the
edematous
spongiform
leukodystrophy
have
remained
elusive
.
In
this
analytical
review
we
consider
what
those
links
might
be
and
propose
that
in
CD
,
the
pathological
buildup
of
NAA
in
limited
WM
extracellular
fluid
(
ECF
)
is
responsible
for
increased
ECF
osmotic-hydrostatic
pressure
and
initiation
of
the
demyelination
process
.
We
also
hypothesize
that
NAA
is
not
directly
liberated
by
neurons
in
WM
as
it
is
in
gray
matter
,
and
that
its
source
in
WM
ECF
is
solely
as
a
product
of
the
catabolism
of
axon-released
NAAG
at
nodes
of
Ranvier
by
astrocyte
NAAG
peptidase
after
it
has
docked
with
the
astrocyte
surface
metabotropic
glutamate
receptor
3
.
This
hypothesis
ascribes
for
the
first
time
a
possible
key
role
played
by
astrocytes
in
CD
,
linking
the
lack
of
ASPA
activity
in
myelinating
oligodendrocytes
,
the
pathological
buildup
of
NAA
in
WM
ECF
,
and
the
spongiform
demyelination
process
.
It
also
offers
new
perspectives
on
the
cause
of
the
leukodystrophy
in
CD
,
and
on
possible
treatment
strategies
for
this
inherited
metabolic
disease
.
Diseases
Validation
Diseases presenting
"mutations of the gene encoding aspartoacylase"
symptom
canavan disease
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