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A safety trial of high dose glyceryl triacetate for Canavan disease.
[canavan disease]
Canavan
disease
(
CD
MIM
#
271900
)
is
a
rare
autosomal
recessive
neurodegenerative
disorder
presenting
in
early
infancy
.
The
course
of
the
disease
is
variable
,
but
it
is
always
fatal
.
CD
is
caused
by
mutations
in
the
ASPA
gene
,
which
codes
for
the
enzyme
aspartoacylase
(
ASPA
)
,
which
breaks
down
N-
acetylaspartate
(
NAA
)
to
acetate
and
aspartic
acid
.
The
lack
of
NAA-degrading
enzyme
activity
leads
to
excess
accumulation
of
NAA
in
the
brain
and
deficiency
of
acetate
,
which
is
necessary
for
myelin
lipid
synthesis
.
Glyceryltriacetate
(
GTA
)
is
a
short
-chain
triglyceride
with
three
acetate
moieties
on
a
glycerol
backbone
and
has
proven
an
effective
acetate
precursor
.
Intragastric
administration
of
GTA
to
tremor
mice
results
in
greatly
increased
brain
acetate
levels
,
and
improved
motor
functions
.
GTA
given
to
infants
with
CD
at
a
low
dose
(
up
to
0
.
25
g
/
kg
/
d
)
resulted
in
no
improvement
in
their
clinical
status
,
but
also
no
detectable
toxicity
.
We
present
for
the
first
time
the
safety
profile
of
high
dose
GTA
(
4
.
5
g
/
kg
/
d
)
in
2
patients
with
CD
.
We
treated
2
infants
with
CD
at
ages
8
months
and
1
year
with
high
dose
GTA
,
for
4
.
5
and
6
months
respectively
.
No
significant
side
effects
and
no
toxicity
were
observed
.
Although
the
treatment
resulted
in
no
motor
improvement
,
it
was
well
tolerated
.
The
lack
of
clinical
improvement
might
be
explained
mainly
by
the
late
onset
of
treatment
,
when
significant
brain
damage
was
already
present
.
Further
larger
studies
of
CD
patients
below
age
3
months
are
required
in
order
to
test
the
long
-term
efficacy
of
this
drug
.