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Quantification of N-acetylaspartic acid in urine by LC-MS/MS for the diagnosis of Canavan disease.
[canavan disease]
Canavan
disease
is
an
autosomal
recessive
leukodystrophy
characterized
by
excessive
excretion
of
N-
acetylaspartic
acid
(
NAA
)
in
urine
.
The
disease
is
caused
by
deficiency
of
aspartoacylase
,
the
enzyme
responsible
for
the
hydrolysis
of
NAA
into
acetate
and
l-aspartate
.
Patients
,
who
are
often
asymptomatic
in
their
early
months
,
show
a
wide
spectrum
of
clinical
presentation
thereafter
that
includes
macrocephaly
,
poor
head
control
,
seizures
,
abnormal
muscle
tone
,
optic
atrophy
,
significant
developmental
delay
and
death
.
In
this
work
,
we
describe
a
simple
liquid
chromatography-tandem
mass
spectrometry
(
LC
-
MS
/
MS
)
method
for
the
determination
of
NAA
in
urine
.
The
internal
standard
d
3
-
NAA
was
added
to
untreated
urine
and
the
mixture
was
injected
into
the
LC
-
MS
/
MS
system
operated
in
the
negative
ion
mode
.
Detection
was
achieved
in
multiple
reaction
monitoring
(
MRM
)
mode
by
monitoring
m
/
z
174
-
-
>
88
,
174
-
-
>
130
and
174
-
-
>
58
for
NAA
and
177
-
-
>
89
for
the
internal
standard
.
Separation
was
carried
out
on
a
C
8
column
(
2
.
1
x
150
mm
)
using
a
mixture
of
acetonitrile
and
water
(
1
:
1
v
/
v
)
containing
0
.
05
%
formic
acid
at
a
flow
rate
of
0
.
25
ml
/
min
.
NAA
was
eluted
at
1
.
6
min
and
the
run
time
was
approximately
2
min
.
Using
spiked
urine
,
the
assay
was
linear
up
to
2
mmol
/
L
with
limit
of
quantification
at
1
micromol
/
L
(
S
/
N
=
12
)
.
NAA
in
patients
'
urine
(
n
=
17
)
ranged
between
366
and
21
,
235
mmol
/
mol
creatinine
compared
to
controls
of
<
39
mmol
/
mol
creatinine
(
n
=
159
)
.
This
LC
-
MS
/
MS
method
for
NAA
as
described
involved
no
extraction
and
no
derivatization
,
showed
no
interference
,
and
gave
excellent
recovery
with
low
variability
and
short
analytical
time
.
Diseases
Validation
Diseases presenting
"leukodystrophy"
symptom
achondroplasia
adrenomyeloneuropathy
alexander disease
cadasil
canavan disease
carcinoma of the gallbladder
classical phenylketonuria
coats disease
fabry disease
gm1 gangliosidosis
krabbe disease
neonatal adrenoleukodystrophy
phenylketonuria
pyruvate dehydrogenase deficiency
wiskott-aldrich syndrome
x-linked adrenoleukodystrophy
zellweger syndrome
This symptom has already been validated