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Thiamine-responsive pyruvate dehydrogenase deficiency in two patients caused by a point mutation (F205L and L216F) within the thiamine pyrophosphate binding region.
[pyruvate dehydrogenase deficiency]
The
human
pyruvate
dehydrogenase
complex
(
PDHC
)
catalyzes
the
thiamine-dependent
decarboxylation
of
pyruvate
.
Thiamine
treatment
is
very
effective
for
some
patients
with
PDHC
deficiency
.
Among
these
patients
,
five
mutations
of
the
pyruvate
dehydrogenase
(
E
1
)
alpha
subunit
have
been
reported
previously
:
H
44
R
,
R
88
S
,
G
8
9
S
,
R
263
G
,
and
V
389
fs
.
All
five
mutations
are
in
a
region
outside
the
thiamine
pyrophosphate
(
TPP
)
-
binding
region
of
the
E
1
alpha
subunit
.
We
report
the
biochemical
and
molecular
analysis
of
two
patients
with
clinically
thiamine-responsive
lactic
acidemia
.
The
PDHC
activity
was
assayed
using
two
different
concentrations
of
TPP
.
These
two
patients
displayed
very
low
PDHC
activity
in
the
presence
of
a
low
(
1
x
10
(
-
4
)
mM
)
TPP
concentration
,
but
their
PDHC
activity
significantly
increased
at
a
high
(
0
.
4
mM
)
TPP
concentration
.
Therefore
,
the
PDHC
deficiency
in
these
two
patients
was
due
to
a
decreased
affinity
of
PDHC
for
TPP
.
Treatment
of
both
patients
with
thiamine
resulted
in
a
reduction
in
the
serum
lactate
concentration
and
clinical
improvement
,
suggesting
that
these
two
patients
have
a
thiamine-responsive
PDHC
deficiency
.
The
DNA
sequence
of
these
two
male
patients
'
X-
linked
E
1
alpha
subunit
revealed
a
point
mutation
(
F
2
05
L
and
L
216
F
)
within
the
TPP-binding
region
in
exon
7
.
