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A zebrafish model for pyruvate dehydrogenase deficiency: rescue of neurological dysfunction and embryonic lethality using a ketogenic diet.
[pyruvate dehydrogenase deficiency]
Defects
in
the
pyruvate
dehydrogenase
(
PDH
)
complex
result
in
severe
neurological
dysfunction
,
congenital
lactic
acidosis
,
growth
retardation
,
and
early
death
.
Current
treatments
for
PDH
deficiency
are
administered
postnatally
and
are
generally
unsuccessful
.
Because
many
patients
with
this
disease
are
born
with
irreversible
defects
,
a
model
system
for
the
development
of
effective
pre-
and
postnatal
therapies
would
be
of
great
value
.
In
a
behavioral
genetic
screen
aimed
to
identify
zebrafish
with
visual
function
defects
,
we
previously
isolated
two
alleles
of
the
recessive
lethal
mutant
no
optokinetic
response
a
(
noa
)
.
Here
we
report
that
noa
is
deficient
for
dihydrolipoamide
S-
acetyltransferase
(
Dlat
)
,
the
PDH
E
2
subunit
,
and
exhibits
phenotypes
similar
to
human
patients
with
PDH
deficiency
.
To
rescue
the
deficiency
,
we
added
ketogenic
substrates
to
the
water
in
which
the
embryos
develop
.
This
treatment
successfully
restored
vision
,
promoted
feeding
behavior
,
reduced
lactic
acidosis
,
and
increased
survival
.
Our
study
demonstrates
an
approach
for
establishing
effective
therapies
for
PDH
deficiency
and
other
congenital
diseases
that
affect
early
embryonic
development
.
Diseases
Validation
Diseases presenting
"we previously isolated two alleles of the recessive lethal mutant no optokinetic response a"
symptom
pyruvate dehydrogenase deficiency
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