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Canavan disease, a rare early-onset human spongiform leukodystrophy: insights into its genesis and possible clinical interventions.
[canavan disease]
The
brain
contains
high
concentrations
of
the
amino
acid
N-
acetyl-l-aspartate
(
NAA
)
and
its
'
glutamate
adduct
N-
acetyl-l-aspartylglutamate
(
NAAG
)
,
both
synthesized
primarily
by
and
stored
in
neurons
.
Upon
depolarization
both
are
exported
to
extracellular
fluid
(
ECF
)
with
NAA
targeted
to
oligodendrocytes
and
NAAG
targeted
to
astrocytes
where
they
are
hydrolyzed
by
specific
enzymes
.
While
the
functions
of
these
substances
are
incompletely
known
,
their
unique
tri
-cellular
metabolism
is
apparently
vital
to
normal
brain
function
.
Canavan
disease
(
CD
)
is
a
globally
occurring
but
rare
early
-onset
human
spongiform
leukodystrophy
associated
with
inborn
genetic
errors
affecting
the
activity
of
aspartoacylase
(
ASPA
)
,
the
enzyme
highly
expressed
in
oligodendrocytes
that
hydrolyzes
NAA
.
Several
hypotheses
attempt
to
explain
how
the
lack
of
ASPA
activity
results
in
the
inability
of
oligodendrocytes
to
build
or
maintain
axon-enveloping
myelin
sheaths
,
a
failure
reflected
in
the
CD
syndrome
by
profound
neurological
disturbances
.
Based
on
evidence
provided
by
recent
studies
,
as
well
as
on
descriptions
of
several
atypical
mild
cases
of
CD
and
of
a
singular
human
case
of
an
inborn
error
where
NAA
can
not
be
synthesized
,
we
provide
insights
into
the
possible
genesis
of
the
CD
syndrome
and
many
of
its
phenotypic
expressions
.
In
this
article
we
also
evaluate
current
hypotheses
,
and
discuss
possible
clinical
interventions
that
may
be
of
value
in
treatment
of
CD
.