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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
"epilepsy"
symptom
22q11.2 deletion syndrome
adrenomyeloneuropathy
alexander disease
canavan disease
classical phenylketonuria
cohen syndrome
cowden syndrome
familial hypocalciuric hypercalcemia
gm1 gangliosidosis
hereditary cerebral hemorrhage with amyloidosis
hirschsprung disease
homocystinuria without methylmalonic aciduria
kabuki syndrome
locked-in syndrome
lymphangioleiomyomatosis
monosomy 21
neonatal adrenoleukodystrophy
pendred syndrome
phenylketonuria
proteus syndrome
pyruvate dehydrogenase deficiency
sneddon syndrome
wolf-hirschhorn syndrome
zellweger syndrome
This symptom has already been validated