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In ferrochelatase-deficient protoporphyria patients, ALAS2 expression is enhanced and erythrocytic protoporphyrin concentration correlates with iron availability.
[erythropoietic protoporphyria]
The
activity
of
the
erythroid-
specific
isoenzyme
of
5
-
aminolevulinic
acid
synthase
(
ALAS
2
)
,
the
first
and
rate-limiting
enzyme
in
heme
biosynthesis
,
is
down-regulated
during
iron
-
deficiency
.
Ferrochelatase
(
FECH
)
,
the
last
enzyme
of
this
pathway
,
inserts
iron
into
protoporphyrin
IX
(
PPIX
)
to
form
heme
.
Patients
with
erythropoietic
protoporphyria
(
EPP
)
,
an
inherited
deficiency
in
FECH
,
often
show
signs
of
iron
deficiency
in
addition
to
phototoxicity
which
is
caused
by
PPIX
accumulation
.
However
,
iron
supplementation
often
leads
to
exacerbation
of
phototoxicity
.
We
report
three
EPP
patients
who
had
reduced
erythrocytic
PPIX
concentrations
when
they
were
iron
-
deficient
and
their
microcytic
and
hypochromic
anemia
deteriorated
.
Additionally
,
we
found
a
significant
increase
in
the
amount
of
ALAS
2
mRNA
and
protein
among
EPP
patients
.
To
verify
the
connection
between
FECH
deficiency
and
ALAS
2
over-expression
,
we
inhibited
FECH
in
cultured
cells
and
found
a
subsequent
increase
in
ALAS
2
mRNA
.
We
conclude
that
the
primary
deficiency
in
ferrochelatase
leads
to
a
secondary
increase
in
ALAS
2
expression
.
The
combined
action
of
these
two
enzymes
within
the
heme
biosynthetic
pathway
contributes
to
the
accumulation
of
PPIX
.
Furthermore
,
we
hypothesize
that
EPP
patients
may
benefit
from
a
mild
iron
deficiency
since
it
would
limit
PPIX
production
by
restricting
ALAS
2
over-expression
.
Diseases
Validation
Diseases presenting
"combined action of these two enzymes within the heme"
symptom
erythropoietic protoporphyria
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