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A novel PEX12 mutation identified as the cause of a peroxisomal biogenesis disorder with mild clinical phenotype, mild biochemical abnormalities in fibroblasts and a mosaic catalase immunofluorescence pattern, even at 40 degrees C.
[zellweger syndrome]
Mutations
in
12
different
PEX
genes
can
cause
a
generalized
peroxisomal
biogenesis
disorder
with
clinical
phenotypes
ranging
from
Zellweger
syndrome
to
infantile
Refsum
disease
.
To
identify
the
specific
PEX
gene
to
be
sequenced
,
complementation
analysis
is
first
performed
in
fibroblasts
using
catalase
immunofluorescence
.
A
patient
with
a
relatively
mild
phenotype
of
infantile
cholestasis
,
hypotonia
and
motor
delay
had
elevated
plasma
very
long
-chain
fatty
acids
and
bile
acid
precursors
,
but
fibroblast
studies
revealed
normal
or
only
mildly
abnormal
peroxisomal
parameters
and
mosaic
catalase
immunofluorescence
.
This
mosaicism
persisted
even
when
the
incubation
temperature
was
increased
from
37
degrees
C
to
40
degrees
C
,
a
maneuver
previously
shown
to
abolish
mosaicism
by
exacerbating
peroxisomal
dysfunction
.
As
mosaicism
precludes
complementation
analysis
,
a
candidate
gene
approach
was
employed
.
After
PEX
1
sequencing
was
unrewarding
,
PEX
12
sequencing
revealed
homozygosity
for
a
novel
c
.
102
A
>
T
(
p
.
R
34
S
)
missense
mutation
affecting
a
partially
conserved
residue
in
the
N-
terminal
region
important
for
localization
to
peroxisomes
.
Transfection
of
patient
fibroblasts
with
wild-
type
PEX
12
cDNA
confirmed
that
a
PEX
12
defect
was
the
basis
for
the
PBD
.
Homozygosity
for
c
.
102
A
>
T
was
identified
in
a
second
patient
of
similar
ethnic
origin
also
presenting
with
a
mild
phenotype
.
PEX
12
is
a
highly
probable
candidate
gene
for
direct
sequencing
in
the
context
of
a
mild
clinical
phenotype
with
mosaicism
and
minimally
abnormal
peroxisomal
parameters
in
fibroblasts
.
Diseases
Validation
Diseases presenting
"mild phenotype"
symptom
alpha-thalassemia
cowden syndrome
familial mediterranean fever
homocystinuria without methylmalonic aciduria
kabuki syndrome
monosomy 21
neonatal adrenoleukodystrophy
wolf-hirschhorn syndrome
zellweger syndrome
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