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Pathophysiology of X-linked adrenoleukodystrophy.
[adrenomyeloneuropathy]
Currently
the
molecular
basis
for
the
clinical
heterogeneity
of
X-
linked
adrenoleukodystrophy
(
X-
ALD
)
is
poorly
understood
.
The
genetic
bases
for
all
different
phenotypic
variants
of
X-
ALD
are
mutations
in
the
gene
encoding
the
peroxisomal
ATP-binding
cassette
(
ABC
)
transporter
,
ABCD
1
(
formerly
adrenoleukodystrophy
protein
,
ALDP
)
.
ABCD
1
transports
CoA-activated
very
long
-chain
fatty
acids
from
the
cytosol
into
the
peroxisome
for
degradation
.
The
phenotypic
variability
is
remarkable
ranging
from
cerebral
inflammatory
demyelination
of
childhood
onset
,
leading
to
death
within
a
few
years
,
to
adults
remaining
pre-symptomatic
through
more
than
five
decades
.
There
is
no
general
genotype-phenotype
correlation
in
X-
ALD
.
The
default
manifestation
of
mutations
in
ABCD
1
is
adrenomyeloneuropathy
,
a
slowly
progressive
dying-back
axonopathy
affecting
both
ascending
and
descending
spinal
cord
tracts
as
well
as
in
some
cases
,
a
peripheral
neuropathy
.
In
about
60
%
of
male
X-
ALD
patients
,
either
in
childhood
(
35
-
40
%
)
or
in
adulthood
(
20
%
)
,
an
initial
,
clinically
silent
,
myelin
destabilization
results
in
conversion
to
a
devastating
,
rapidly
progressive
form
of
cerebral
inflammatory
demyelination
.
Here
,
ABCD
1
remains
a
susceptibility
gene
,
necessary
but
not
sufficient
for
inflammatory
demyelination
to
occur
.
Although
the
accumulation
of
very
long
-chain
fatty
acids
appears
to
be
essential
for
the
pathomechanism
of
all
phenotypes
,
the
molecular
mechanisms
underlying
these
phenotypes
are
fundamentally
different
.
Cell
autonomous
processes
such
as
oxidative
stress
and
energy
shortage
in
axons
as
well
as
non-cell
autonomous
processes
involving
axon-glial
interactions
seem
pertinent
to
the
dying-back
axonopathy
.
Various
dynamic
mechanisms
may
underlie
the
initiation
of
inflammation
,
the
altered
immune
reactivity
,
the
propagation
of
inflammation
,
as
well
as
the
mechanisms
leading
to
the
arrest
of
inflammation
after
hematopoietic
stem
cell
transplantation
.
An
improved
understanding
of
the
molecular
mechanisms
involved
in
these
events
is
required
for
the
development
of
urgently
needed
therapeutics
.
Diseases
Validation
Diseases presenting
"peripheral neuropathy"
symptom
adrenomyeloneuropathy
esophageal squamous cell carcinoma
hodgkin lymphoma, classical
homocystinuria without methylmalonic aciduria
kallmann syndrome
krabbe disease
neuralgic amyotrophy
oculocutaneous albinism
pyruvate dehydrogenase deficiency
sneddon syndrome
systemic capillary leak syndrome
thoracic outlet syndrome
triple a syndrome
waldenström macroglobulinemia
x-linked adrenoleukodystrophy
zellweger syndrome
This symptom has already been validated