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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
"ichthyosis"
symptom
child syndrome
dystrophic epidermolysis bullosa
epidermolysis bullosa simplex
harlequin ichthyosis
hirschsprung disease
junctional epidermolysis bullosa
kallmann syndrome
lamellar ichthyosis
This symptom has already been validated