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The gene expression profiles of induced pluripotent stem cells from individuals with childhood cerebral adrenoleukodystrophy are consistent with proposed mechanisms of pathogenesis.
[x-linked adrenoleukodystrophy]
X-
linked
adrenoleukodystrophy
(
X-
ALD
)
is
a
complex
disorder
with
variable
expressivity
that
affects
the
nervous
,
adrenocortical
and
male
reproductive
systems
.
Although
ABCD
1
mutations
are
known
to
provide
the
genetic
basis
for
X-
ALD
,
its
pathogenesis
is
not
fully
elucidated
.
While
elevated
very
long
chain
fatty
acid
(
VLCFA
)
levels
in
blood
and
reduced
VLCFA
catabolic
activity
in
cultured
fibroblasts
are
biomarkers
used
to
identify
ABCD
1
mutation
carriers
,
the
roles
peroxisomal
lipid
metabolism
play
in
disease
etiology
are
unknown
.
Primary
skin
fibroblasts
from
two
male
patients
with
the
childhood
cerebral
form
of
the
disease
(
CCALD
)
caused
by
ABCD
1
frameshift
or
missense
mutations
and
three
healthy
donors
were
transduced
with
retroviral
vectors
expressing
the
OCT
4
,
SOX
2
,
KLF
4
and
c-
MYC
factors
.
Candidate
induced
pluripotent
stem
cells
(
iPSCs
)
were
subject
to
global
gene
expression
,
DNA
methylation
,
DNA
copy
number
variation
,
and
genotyping
analysis
and
tested
for
pluripotency
through
in
vitro
differentiation
and
teratoma
formation
.
Saturated
VLCFA
(
sVLCFA
)
and
plasmalogen
levels
in
primary
fibroblasts
and
iPSCs
from
healthy
donors
as
well
as
CCALD
patients
were
determined
through
mass
spectroscopy
.
Skin
fibroblasts
from
CCALD
patients
and
healthy
donors
were
reprogrammed
into
validated
iPSCs
.
Unlike
fibroblasts
,
CCALD
patient
iPSCs
show
differentially
expressed
genes
(
DEGs
)
relevant
to
both
peroxisome
abundance
and
neuroinflammation
.
Also
,
in
contrast
to
fibroblasts
,
iPSCs
from
patients
showed
no
significant
difference
in
sVLCFA
levels
relative
to
those
from
controls
.
In
all
cell
types
,
the
plasmalogen
levels
tested
did
not
correlate
with
ABCD
1
mutation
status
.
Normal
ABCD
1
gene
function
is
not
required
for
reprogramming
skin
fibroblasts
into
iPSCs
or
maintaining
pluripotency
.
Relative
to
DEGs
found
in
fibroblasts
,
DEGs
uncovered
in
comparisons
of
CCALD
patient
and
control
iPSCs
are
more
consistent
with
major
hypotheses
regarding
disease
pathogenesis
.
These
DEGs
were
independent
of
differences
in
sVLCFA
levels
,
which
did
not
vary
according
to
ABCD
1
mutation
status
.
The
highlighted
genes
provide
new
leads
for
pathogenic
mechanisms
that
can
be
explored
in
animal
models
and
human
tissue
specimens
.
We
suggest
that
these
iPSC
resources
will
have
applications
that
include
assisting
efforts
to
identify
genetic
and
environmental
modifiers
and
screening
for
therapeutic
interventions
tailored
towards
affected
cell
populations
and
patient
genotypes
.
Diseases
Validation
Diseases presenting
"global gene expression"
symptom
canavan disease
x-linked adrenoleukodystrophy
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