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Hemimegalencephaly: foetal tauopathy with mTOR hyperactivation and neuronal lipidosis.
[proteus syndrome]
Hemimegalencephaly
(
HME
)
is
a
hamartomatous
malformation
of
one
cerebral
hemisphere
.
As
this
is
a
disorder
of
cellular
growth
and
lineage
,
we
sought
evidence
of
an
early
ontogenetic
disturbance
of
microtubular
assembly
or
function
.
Three
male
infants
with
HME
had
brain
resections
for
refractory
epilepsy
.
One
died
postoperatively
at
2
.
5
months
and
an
autopsy
was
performed
.
Two
were
isolated
cases
and
one
has
Proteus
syndrome
.
The
phosphorylated
form
of
the
microtubule-associated
protein
tau
was
studied
,
transmission
electron
microscopy
(
EM
)
was
performed
,
and
activation
of
the
mTOR
pathway
was
defined
.
The
hippocampus
and
neocortex
of
HME
exhibited
cytoarchitectural
abnormalities
and
intense
tau
immunoreactivity
.
The
post-mortem
non-
HME
hemisphere
exhibited
sparse
dysmorphic
tau-reactive
cortical
neurones
,
intense
only
in
the
cingulate
gyrus
,
a
few
isolated
dysmorphic
white
matter
neurons
and
none
in
subcortical
structures
.
Numerous
enlarged
and
dysmorphic
cells
exhibited
P-
4
E
-
BP
1
and
phosphoribosomal
P-S
6
immunoreactivity
,
indicating
mTOR
activation
.
Control
brains
were
negative
for
tau
expression
and
mTOR
activation
.
EM
in
each
case
showed
abundant
lipid
in
neurones
and
astrocytic
end-feet
on
capillaries
,
and
well-preserved
mitochondria
;
oil
red
O
in
frozen
sections
and
semi-
thin
sections
also
showed
lipid
storage
by
light
microscopy
.
Because
HME
tissue
exhibited
enhanced
levels
of
phosphorylated
tau
protein
and
evidence
of
mTOR
hyperactivation
,
we
propose
that
the
pathogenesis
of
HME
may
involve
an
early
defect
in
microtubules
,
likely
related
to
the
AKT
3
gene
.
Lipidosis
of
neurones
and
glia
suggests
metabolic
impairment
of
yet
undetermined
type
and
relation
to
tauopathy
in
HME
.
Perinatal
treatment
of
HME
with
everolimus
theoretically
is
plausible
.
Diseases
Validation
Diseases presenting
"early ontogenetic disturbance"
symptom
proteus syndrome
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