Rare Diseases Symptoms Automatic Extraction
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Pathogenesis-based therapy reverses cutaneous abnormalities in an inherited disorder of distal cholesterol metabolism.
[child syndrome]
Identification
of
the
underlying
genetic
,
cellular
,
and
biochemical
basis
of
lipid
metabolic
disorders
provides
an
opportunity
to
deploy
corrective
,
mechanism-targeted
,
topical
therapy
.
We
assessed
this
therapeutic
approach
in
two
patients
with
Congenital
Hemidysplasia
with
Ichthyosiform
erythroderma
and
Limb
Defects
(
CHILD
)
syndrome
,
an
X-
linked
dominant
disorder
of
distal
cholesterol
metabolism
.
On
the
basis
of
the
putative
pathogenic
role
of
both
pathway-product
deficiency
of
cholesterol
and
accumulation
of
toxic
metabolic
intermediates
,
we
assessed
the
efficacy
of
combined
therapy
with
lovastatin
and
cholesterol
.
We
also
evaluated
the
basis
for
the
poorly
understood
,
unique
lateralization
of
the
cutaneous
and
bone
malformations
of
CHILD
syndrome
by
analyzing
gene
activation
in
abnormal
and
unaffected
skin
.
Ultrastructural
analysis
of
affected
skin
showed
evidence
of
both
cholesterol
depletion
and
toxic
metabolic
accumulation
.
Topical
treatment
with
lovastatin
/
cholesterol
(
but
not
cholesterol
alone
)
virtually
cleared
skin
lesions
by
3
months
,
accompanied
by
histological
and
ultrastructural
normalization
of
epidermal
structure
and
lipid
secretion
.
The
unusual
lateralization
of
abnormalities
in
CHILD
syndrome
reflects
selective
clearance
of
keratinocytes
and
fibroblasts
that
express
the
mutant
allele
from
the
unaffected
side
.
These
findings
validate
pathogenesis-based
therapy
that
provides
the
deficient
end
product
and
prevents
accumulation
of
toxic
metabolites
,
an
approach
of
potential
utility
for
other
syndromic
lipid
metabolic
disorders
.