Acta Neuropathologica,
Journal Year:
2020,
Volume and Issue:
140(6), P. 881 - 891
Published: Sept. 26, 2020
Abstract
Polymicrogyria
(PMG)
is
a
developmental
cortical
malformation
characterized
by
an
excess
of
small
and
frustrane
gyration
abnormal
lamination.
PMG
frequently
associates
with
seizures.
The
molecular
pathomechanisms
underlying
development
are
not
yet
understood.
About
40
genes
have
been
associated
PMG,
copy
number
variations
also
described
in
selected
patients.
We
recently
provided
evidence
that
epilepsy-associated
structural
brain
lesions
can
be
classified
based
on
genomic
DNA
methylation
patterns.
Here,
we
analyzed
26
patients
employing
array-based
profiling
formalin-fixed
paraffin-embedded
material.
A
series
62
well-characterized
non-PMG
malformations
(focal
dysplasia
type
2a/b
hemimegalencephaly),
temporal
lobe
epilepsy,
non-epilepsy
autopsy
controls
was
used
as
reference
cohort.
Unsupervised
dimensionality
reduction
hierarchical
cluster
analysis
profiles
showed
formed
distinct
class.
Copy
from
data
identified
uniform
duplication
spanning
the
entire
long
arm
chromosome
1
7
out
patients,
which
verified
additional
fluorescence
situ
hybridization
analysis.
In
respective
cases,
about
50%
nuclei
center
lesion
were
1q
triploid.
No
chromosomal
imbalance
seen
adjacent,
architecturally
normal-appearing
tissue
indicating
mosaicism.
Clinically,
presented
unilateral
frontal
or
hemispheric
without
hemimegalencephaly,
severe
form
intractable
epilepsy
seizure
onset
first
months
life,
delay.
Our
results
show
among
other
according
to
their
profile.
One
subset
clinical
features
exhibits
1q.
Acta Neuropathologica Communications,
Journal Year:
2021,
Volume and Issue:
9(1)
Published: Jan. 6, 2021
Abstract
Focal
malformations
of
cortical
development
(MCD)
are
linked
to
somatic
brain
mutations
occurring
during
neurodevelopment.
Mild
malformation
with
oligodendroglial
hyperplasia
in
epilepsy
(MOGHE)
is
a
newly
recognized
clinico-pathological
entity
associated
pediatric
drug-resistant
focal
epilepsy,
and
amenable
neurosurgical
treatment.
MOGHE
histopathologically
characterized
by
clusters
increased
cell
densities,
patchy
zones
hypomyelination,
heterotopic
neurons
the
white
matter.
The
molecular
etiology
remained
unknown
so
far.
We
hypothesized
contribution
mosaic
variants
performed
deep
targeted
gene
sequencing
on
20
surgical
samples
from
single-center
cohort
patients.
identified
pathogenic
SLC35A2
9/20
(45%)
patients
rates
ranging
7
52%.
encodes
UDP-galactose
transporter,
previously
implicated
other
rare
type
congenital
disorder
glycosylation.
To
further
clarify
histological
features
-brain
tissues,
we
then
collected
17
multicenter
MCD
cases.
Histopathological
reassessment
including
anti-Olig2
staining
confirmed
diagnosis
all
Analysis
droplet
digital
PCR
pools
microdissected
cells
one
tissue
revealed
variant
enrichment
clustered
neurons.
Through
an
international
consortium,
assembled
unprecedented
series
26
-MOGHE
cases
providing
evidence
that
variants,
likely
occurred
neuroglial
progenitor
development,
genetic
marker
for
MOGHE.
Nature Reviews Neurology,
Journal Year:
2020,
Volume and Issue:
16(11), P. 618 - 635
Published: Sept. 7, 2020
Abstract
Malformations
of
cortical
development
(MCDs)
are
neurodevelopmental
disorders
that
result
from
abnormal
the
cerebral
cortex
in
utero.
MCDs
place
a
substantial
burden
on
affected
individuals,
their
families
and
societies
worldwide,
as
these
individuals
can
experience
lifelong
drug-resistant
epilepsy,
palsy,
feeding
difficulties,
intellectual
disability
other
neurological
behavioural
anomalies.
The
diagnostic
pathway
for
is
complex
owing
to
wide
variations
presentation
aetiology,
thereby
hampering
timely
adequate
management.
In
this
article,
international
MCD
network
Neuro-MIG
provides
consensus
recommendations
aid
both
expert
non-expert
clinicians
work-up
with
aim
improving
patient
management
worldwide.
We
reviewed
literature
clinical
presentation,
aetiology
approaches
main
subtypes
collected
data
current
practices
laboratories
within
Neuro-MIG.
reached
by
42
professionals
20
countries,
using
discussions
Delphi
process.
present
workflow
be
applied
any
individual
comprehensive
list
MCD-related
genes
associated
phenotypes.
designed
maximize
yield
increase
number
patients
receiving
personalized
care
counselling
prognosis
recurrence
risk.
Science,
Journal Year:
2021,
Volume and Issue:
371(6527)
Published: Jan. 21, 2021
The
cerebral
cortex
is
an
intricate
structure
that
controls
human
features
such
as
language
and
cognition.
Cortical
functions
rely
on
specialized
neurons
emerge
during
development
from
complex
molecular
cellular
interactions.
Neurodevelopmental
disorders
occur
when
one
or
several
of
these
steps
incorrectly
executed.
Although
a
number
causal
genes
disease
phenotypes
have
been
identified,
the
sequence
events
linking
disruption
to
clinical
expression
mostly
remains
obscure.
Here,
focusing
malformations
cortical
development,
we
illustrate
how
interactions
at
genetic,
cellular,
circuit
levels
together
contribute
diversity
variability
in
phenotypes.
Using
specific
examples
online
resource,
propose
multilevel
assessment
processes
key
identifying
points
vulnerability
developing
new
therapeutic
strategies.
Brain Communications,
Journal Year:
2021,
Volume and Issue:
3(4)
Published: Sept. 21, 2021
Abstract
The
mechanistic
target
of
rapamycin
signalling
pathway
serves
as
a
ubiquitous
regulator
cell
metabolism,
growth,
proliferation
and
survival.
main
cellular
activity
the
cascade
funnels
through
complex
1,
which
is
inhibited
by
rapamycin,
macrolide
compound
produced
bacterium
Streptomyces
hygroscopicus.
Pathogenic
variants
in
genes
encoding
upstream
regulators
1
cause
epilepsies
neurodevelopmental
disorders.
Tuberous
sclerosis
multisystem
disorder
caused
mutations
TSC1
or
TSC2,
with
prominent
neurological
manifestations
including
epilepsy,
focal
cortical
dysplasia
neuropsychiatric
Focal
type
II
results
from
somatic
brain
activators
MTOR,
AKT3,
PIK3CA
RHEB
major
drug-resistant
epilepsy.
DEPDC5,
NPRL2
NPRL3
code
for
subunits
GTPase-activating
protein
(GAP)
towards
Rags
(GATOR1),
principal
amino
acid-sensing
1.
Germline
pathogenic
GATOR1
non-lesional
associated
malformations
development.
Collectively,
mTORopathies
are
characterized
excessive
activation
In
first
large-scale
precision
medicine
trial
genetically
mediated
everolimus
(a
synthetic
analogue
rapamycin)
was
effective
at
reducing
seizure
frequency
people
tuberous
complex.
Rapamycin
reduced
seizures
rodent
models
DEPDC5-related
epilepsy
II.
This
review
outlines
personalized
approach
to
management
mTORopathies.
We
advocate
early
diagnostic
sequencing
identification
variant
may
point
an
occult
apparently
uncover
important
prognostic
information
including,
increased
risk
sudden
unexpected
death
GATORopathies
favourable
surgery
outcomes
due
mutations.
Lastly,
we
discuss
potential
therapeutic
application
inhibitors
GATOR1-related
Life,
Journal Year:
2022,
Volume and Issue:
12(6), P. 809 - 809
Published: May 29, 2022
This
paper
describes
the
contemporary
state
of
knowledge
regarding
processes
that
regulate
normal
development
embryonic–fetal
central
nervous
system
(CNS).
The
are
described
according
to
developmental
timetable:
dorsal
induction,
ventral
neurogenesis,
neuronal
migration,
post-migration
development,
and
cortical
organization.
We
review
current
literature
on
CNS
malformations
associated
with
these
regulating
processes.
specifically
address
neural
tube
defects,
holoprosencephaly,
(including
microcephaly,
megalencephaly,
lissencephaly,
cobblestone
malformations,
gray
matter
heterotopia,
polymicrogyria),
disorders
corpus
callosum,
posterior
fossa
malformations.
Fetal
ventriculomegaly,
which
frequently
accompanies
disorders,
is
also
reviewed.
Each
malformation
reference
etiology,
genetic
causes,
prenatal
sonographic
imaging,
anomalies,
differential
diagnosis,
complimentary
diagnostic
studies,
clinical
interventions,
neurodevelopmental
outcome,
life
quality.
Frontiers in Pediatrics,
Journal Year:
2022,
Volume and Issue:
9
Published: Jan. 14, 2022
Macrocephaly
affects
up
to
5%
of
the
pediatric
population
and
is
defined
as
an
abnormally
large
head
with
occipitofrontal
circumference
(OFC)
>2
standard
deviations
(SD)
above
mean
for
a
given
age
sex.
Taking
into
account
that
about
2–3%
healthy
has
OFC
between
2
3
SD,
macrocephaly
considered
“clinically
relevant”
when
SD.
This
implies
urgent
need
diagnostic
workflow
use
in
clinical
setting
dissect
several
causes
increased
OFC,
from
benign
form
familial
Benign
enlargement
subarachnoid
spaces
(BESS)
many
pathological
conditions,
including
genetic
disorders.
Moreover,
should
be
differentiated
by
megalencephaly
(MEG),
which
refers
exclusively
brain
overgrowth,
exceeding
twice
SD
(3SD—“clinically
megalencephaly).
While
can
isolated
or
may
first
indication
underlying
congenital,
genetic,
acquired
disorder,
most
likely
due
cause.
Apart
size
evaluation,
detailed
family
personal
history,
neuroimaging,
careful
evaluation
are
crucial
reach
correct
diagnosis.
In
this
review,
we
seek
underline
aspects
megalencephaly,
emphasizing
main
differential
diagnosis
major
focus
on
common
We
thus
provide
clinico-radiological
algorithm
guide
pediatricians
assessment
children
macrocephaly.
Expert Review of Neurotherapeutics,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Feb. 4, 2025
Introduction
Dysregulated
mechanistic
target
of
rapamycin
(mTOR)
activity
is
implicated
in
seizure
development
epilepsies
caused
by
variants
mTOR
pathway
genes.
Sirolimus
and
everolimus,
allosteric
inhibitors,
are
widely
used
transplant
medicine
oncology.
Everolimus
approved
for
treating
seizures
tuberous
sclerosis
complex
(TSC),
the
prototype
mTORopathy.
Emerging
evidence
suggests
that
inhibitors
could
also
be
effective
other
mTORopathies,
such
as
DEPDC5-related
epilepsy
focal
cortical
dysplasia
type
2
(FCD2).
