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Abnormal barrier function in the pathogenesis of ichthyosis: therapeutic implications for lipid metabolic disorders.
[child syndrome]
Ichthyoses
,
including
inherited
disorders
of
lipid
metabolism
,
display
a
permeability
barrier
abnormality
in
which
the
severity
of
the
clinical
phenotype
parallels
the
prominence
of
the
barrier
defect
.
The
pathogenesis
of
the
cutaneous
phenotype
represents
the
consequences
of
the
mutation
for
epidermal
function
,
coupled
with
a
"
best
attempt
"
by
affected
epidermis
to
generate
a
competent
barrier
in
a
terrestrial
environment
.
A
compromised
barrier
in
normal
epidermis
triggers
a
vigorous
set
of
metabolic
responses
that
rapidly
normalizes
function
,
but
ichthyotic
epidermis
,
which
is
inherently
compromised
,
only
partially
succeeds
in
this
effort
.
Unraveling
mechanisms
that
account
for
barrier
dysfunction
in
the
ichthyoses
has
identified
multiple
,
subcellular
,
and
biochemical
processes
that
contribute
to
the
clinical
phenotype
.
Current
treatment
of
the
ichthyoses
remains
largely
symptomatic
:
directed
toward
reducing
scale
or
corrective
gene
therapy
.
Reducing
scale
is
often
minimally
effective
.
Gene
therapy
is
impeded
by
multiple
pitfalls
,
including
difficulties
in
transcutaneous
drug
delivery
,
high
costs
,
and
discomfort
of
injections
.
We
have
begun
to
use
information
about
disease
pathogenesis
to
identify
novel
,
pathogenesis-based
therapeutic
strategies
for
the
ichthyoses
.
The
clinical
phenotype
often
reflects
not
only
a
deficiency
of
pathway
end
product
due
to
reduced-function
mutations
in
key
synthetic
enzymes
but
often
also
accumulation
of
proximal
,
potentially
toxic
metabolites
.
As
a
result
,
depending
upon
the
identified
pathomechanism
(
s
)
for
each
disorder
,
the
accompanying
ichthyosis
can
be
treated
by
topical
provision
of
pathway
product
(
eg
,
cholesterol
)
,
with
or
without
a
proximal
enzyme
inhibitor
(
eg
,
simvastatin
)
,
to
block
metabolite
production
.
Among
the
disorders
of
distal
cholesterol
metabolism
,
the
cutaneous
phenotype
in
Congenital
Hemidysplasia
with
Ichthyosiform
Erythroderma
and
Limb
Defects
(
CHILD
syndrome
)
and
X-
linked
ichthyosis
reflect
metabolite
accumulation
and
deficiency
of
pathway
product
(
ie
,
cholesterol
)
.
We
validated
this
therapeutic
approach
in
two
CHILD
syndrome
patients
who
failed
to
improve
with
topical
cholesterol
alone
,
but
cleared
with
dual
treatment
with
cholesterol
plus
lovastatin
.
In
theory
,
the
ichthyoses
in
other
inherited
lipid
metabolic
disorders
could
be
treated
analogously
.
This
pathogenesis
(
pathway
)
-
driven
approach
possesses
several
inherent
advantages
:
(
1
)
it
is
mechanism-
specific
for
each
disorder
;
(
2
)
it
is
inherently
safe
,
because
natural
lipids
and
/
or
approved
drugs
often
are
utilized
;
and
(
3
)
it
should
be
inexpensive
,
and
therefore
it
could
be
used
widely
in
the
developing
world
.
Diseases
Validation
Diseases presenting
"pathogenesis-based therapeutic strategies for the ichthyoses"
symptom
child syndrome
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