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Glyceryl triacetate for Canavan disease: a low-dose trial in infants and evaluation of a higher dose for toxicity in the tremor rat model.
[canavan disease]
Canavan
disease
(
CD
)
is
a
fatal
dysmyelinating
genetic
disorder
associated
with
aspartoacylase
deficiency
,
resulting
in
decreased
brain
acetate
levels
and
reduced
myelin
lipid
synthesis
in
the
developing
brain
.
Here
we
tested
tolerability
of
a
potent
acetate
precursor
,
glyceryl
triacetate
(
GTA
)
,
at
low
doses
in
two
infants
diagnosed
with
CD
,
aged
8
and
13
months
.
Much
higher
doses
of
GTA
were
evaluated
for
toxicity
in
the
tremor
rat
model
of
CD
.
GTA
was
given
orally
to
the
infants
for
up
to
4
.
5
and
6
months
,
starting
at
25
mg
/
kg
twice
daily
,
doubling
the
dose
weekly
until
a
maximum
of
250
mg
/
kg
reached
.
Wild-
type
and
tremor
rat
pups
were
given
GTA
orally
twice
daily
,
initially
at
a
dose
of
4
.
2
g
/
kg
from
postnatal
days
7
through
14
,
and
at
5
.
8
g
/
kg
from
day
15
through
23
,
and
thereafter
in
food
(
7
.
5
%
)
and
water
(
5
%
)
.
At
the
end
of
the
trial
(
approximately
90
to
120
days
)
sera
and
tissues
from
rats
were
analysed
for
changes
in
blood
chemistry
and
histopathology
.
GTA
treatment
caused
no
detectable
toxicity
and
the
patients
showed
no
deterioration
in
clinical
status
.
In
the
high
-dose
animal
studies
,
no
significant
differences
in
the
mean
blood
chemistry
values
occurred
between
treated
and
untreated
groups
,
and
no
lesions
indicating
toxicity
were
detectable
in
any
of
the
tissues
examined
.
Lack
of
GTA
toxicity
in
two
CD
patients
in
low
-dose
trials
,
as
well
as
in
high
-dose
animal
studies
,
suggests
that
higher
,
effective
dose
studies
in
human
CD
patients
are
warranted
.
Diseases
Validation
Diseases presenting
"aged 8 and 13 months"
symptom
canavan disease
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