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Somatic mosaicism for a PDHA1 mutation in a female with pyruvate dehydrogenase deficiency.
[pyruvate dehydrogenase deficiency]
Somatic
mosaicism
for
a
mutation
in
the
X-
linked
PDHA
1
gene
was
found
in
a
girl
who
presented
with
manifestations
of
pyruvate
dehydrogenase
deficiency
.
Mutation
in
the
PDHA
1
gene
was
suggested
by
a
mosaic
pattern
of
E
1
alpha
subunit
immunostaining
;
however
,
initial
screening
of
cDNA
and
the
exons
and
intron-exon
boundaries
yielded
only
normal
sequence
,
apart
from
a
heterozygous
4
bp
insertion
in
intron
10
.
This
was
considered
to
be
a
polymorphism
as
it
is
also
present
in
her
unaffected
mother
who
has
normal
enzyme
activity
and
uniform
E
1
alpha
immunostaining
in
fibroblasts
.
Detailed
genetic
analysis
,
which
included
isolation
of
cloned
fibroblasts
expressing
the
mutant
X
chromosome
,
resulted
in
the
identification
of
a
base
substitution
in
the
acceptor
splice
site
of
intron
9
which
leads
to
activation
of
a
cryptic
upstream
splice
site
.
The
proportion
of
cells
expressing
the
mutation
was
then
determined
by
direct
analysis
of
the
X-
inactivation
pattern
.
Genetic
diagnosis
in
this
unique
case
of
PDHA
1
somatic
mosaicism
was
complicated
by
the
absence
of
an
abnormal
transcript
in
primary
fibroblasts
,
the
presence
of
three
different
alleles
and
an
X-
inactivation
pattern
favouring
expression
of
the
normal
,
paternal
,
X
chromosome
.
Although
the
mutation
was
only
present
in
a
proportion
of
cells
,
and
only
expressed
in
a
subset
of
these
due
to
random
X-
inactivation
,
the
resulting
enzyme
defect
was
sufficient
to
be
clinically
apparent
.
Diseases
Validation
Diseases presenting
"absence of an abnormal transcript in primary fibroblasts"
symptom
pyruvate dehydrogenase deficiency
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