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X-linked adrenoleukodystrophy: very long-chain fatty acid metabolism is severely impaired in monocytes but not in lymphocytes.
[x-linked adrenoleukodystrophy]
X-
linked
adrenoleukodystrophy
(
X-
ALD
)
is
a
fatal
neurodegenerative
disease
caused
by
mutations
in
the
ABCD
1
gene
,
encoding
a
member
of
the
peroxisomal
ABC
transporter
family
.
The
ABCD
1
protein
transports
CoA-activated
very
long
-chain
fatty
acids
(
VLCFAs
)
into
peroxisomes
for
degradation
via
β-oxidation
.
In
the
severest
form
,
X-
ALD
patients
suffer
from
inflammatory
demyelination
of
the
brain
.
As
the
extent
of
the
metabolic
defect
in
the
main
immune
cells
is
unknown
,
we
explored
their
phenotypes
concerning
mRNA
expression
pattern
of
the
three
peroxisomal
ABC
transporters
,
VLCFA
accumulation
and
peroxisomal
β-oxidation
.
In
controls
,
ABCD
1
expression
was
high
in
monocytes
,
intermediate
in
B
cells
and
low
in
T
cells
;
ABCD
2
expression
was
extremely
low
in
monocytes
,
intermediate
in
B
cells
and
highest
in
T
cells
;
ABCD
3
mRNA
was
equally
distributed
.
In
X-
ALD
patients
,
the
expression
patterns
remained
unaltered
;
accordingly
,
monocytes
,
which
lack
compensatory
VLCFA
transport
by
ABCD
2
,
displayed
the
severest
biochemical
phenotype
with
a
6
-
fold
accumulation
of
C
2
6
:
0
and
a
striking
70
%
reduction
in
peroxisomal
β-oxidation
activity
.
In
contrast
,
VLCFA
metabolism
was
close
to
control
values
in
B
cells
and
T
cells
,
supporting
the
hypothesis
that
sufficient
ABCD
2
is
present
to
compensate
for
ABCD
1
deficiency
.
Thus
,
the
vulnerability
of
the
main
immune
cell
types
is
highly
variable
in
X-
ALD
.
Based
on
these
results
,
we
propose
that
in
X-
ALD
the
halt
of
inflammation
after
allogeneic
hematopoietic
stem
cell
transplantation
relies
particularly
on
the
replacement
of
the
monocyte
lineage
.
Additionally
,
these
findings
support
the
concept
that
ABCD
2
is
a
target
for
pharmacological
induction
as
an
alternative
therapeutic
strategy
.
Diseases
Validation
Diseases presenting
"very long-chain fatty acids"
symptom
adrenomyeloneuropathy
neonatal adrenoleukodystrophy
x-linked adrenoleukodystrophy
zellweger syndrome
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