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Mutations of the E1beta subunit gene (PDHB) in four families with pyruvate dehydrogenase deficiency.
[pyruvate dehydrogenase deficiency]
Pyruvate
dehydrogenase
complex
(
PDC
)
deficiencies
are
a
major
cause
of
primary
lactic
acidosis
.
Most
cases
result
from
mutations
of
the
gene
for
the
pyruvate
dehydrogenase
E
1
alpha
subunit
(
PDHA
1
)
,
with
fewer
cases
resulting
from
mutations
in
genes
for
E
3
,
E
3
-
binding
protein
,
E
2
,
and
the
E
1
beta
subunit
(
PDHB
)
.
We
have
found
four
cases
of
PDHB
mutations
among
83
analyzed
cases
of
PDC
deficiency
.
In
this
series
,
PDHB
mutations
were
found
to
be
about
10
%
as
frequent
as
PDHA
1
mutations
.
All
cases
were
diagnosed
by
low
PDC
activity
,
with
normal
E
2
and
E
3
activities
.
These
included
a
6
.
5
-
year
-old
male
(
consanguineous
,
homozygous
R
36
C
)
;
a
neonatal
female
who
died
soon
after
birth
,
(
compound
heterozygous
C
3
06
R
/
D
319
V
)
,
a
26
-
year
-old
female
(
heterozygous
I
142
M
/
W
165
S
)
,
and
a
13
month
old
female
(
consanguineous
,
homozygous
Y
132
C
)
who
is
a
sibling
of
a
previously
published
case
.
Their
ethnic
background
is
diverse
(
Caucasian
,
Arab
,
and
African
American
descent
)
.
All
cases
had
lactic
acidosis
and
developmental
delay
.
Three
cases
had
agenesis
of
the
corpus
callosum
,
seizures
,
and
hypotonia
;
one
died
within
the
first
year
of
life
.
These
clinical
findings
are
similar
to
those
of
PDHA
1
deficiency
,
except
that
ataxia
was
more
frequent
in
PDHA
1
cases
and
consanguinity
was
found
only
in
PDHB
families
.
PDC
activity
in
lymphocytes
from
six
parents
is
normal
,
who
all
are
heterozygous
carriers
for
the
respective
mutations
.
Immunoreactivity
of
E
1
beta
was
markedly
reduced
in
one
case
and
showed
a
slightly
larger
form
of
E
1
beta
in
one
case
.
Computer
analysis
predicts
that
:
R
36
C
affects
the
interaction
of
several
amino
acids
resulting
in
conformational
change
,
C
3
06
R
affects
interaction
of
the
two
beta
subunits
,
D
319
is
in
the
interface
of
E
1
and
E
2
,
I
142
M
affects
conformation
around
a
K
ion
affecting
stability
of
the
beta
subunit
,
W
165
S
affects
hydrophobic
interaction
between
the
beta
subunits
,
and
Y
132
C
affects
interaction
between
the
beta
subunits
.
All
of
these
residues
are
conserved
in
E
1
beta
across
species
,
and
Y
132
is
also
conserved
in
other
TPP-requiring
enzymes
.
These
observations
support
the
conclusion
that
these
are
pathogenic
mutations
.
Diseases
Validation
Diseases presenting
"pdc deficiency"
symptom
pyruvate dehydrogenase deficiency
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