neuronal migration disorders

1. DISORDERS OF
NEURONAL
MIGRATION
PRESENTER: Dr.SHASIDHAR REDDY

2. INTRODUCTION
Neuronal migration is a key feature of nervous system
development
-During development neurons migrate from the
subventricular area of the brain to the surface of the
brain under the influence of glia produced
-chemoattractants or
-chemorepellents
During embryogenesis neurons migrate approximately 2
cm (hundreds of cell body distances) to their final
destination.

3.  Neuronal migration occurs in three stages:
1. Leading Edge Extension
2. Nuclear Translocation (Nucleokinesis)
3. Retraction of Trailing Process

4. Leading edge extension is directed by actin polymerization and is
regulated by Rho type small GTPases.
In humans, mutations of filamin (an actin-associated protein), result
in heterotopic neurons, probably due to defective leading edge
extension.

5.  Nuclear translocation is composed of
two sub-phases:
-Centrosome Positioning
-Movement of the nucleus towards the
centrosome
 As the neuron migrates there are
major cytoskeletal alterations in the
actin and microtubule (MT) cytoskeletons.

6.  The end of migration requires the integrity of the Reelin
signaling pathway.
 Reelin is thought to trigger recognition-adhesion among
target neurons.
 Any defect in the initiator and mediator molecules of
cytoskeleton formation or signalling molecules like reelin
lead to defective neuronal migration

7. DEFINITION
A heterogenous group of disorders that share the same
etiopathological mechanism: a variable degree of
disruption in the migration of neuroblasts during
neurogenesis.
FOLLOWING ARE A FEW NEURONAL MIGRATION
DISORDERS
• LISSENCEPHALY
• SCHIZENCEPHALY
• NEURONAL HETEROTOPIAS
• POLYMICROGYRIAS
• FOCAL CORTICAL DYSPLASIAS
• PORENCEPHALY

8. LISSENCEPHALY
• It is a rare disorder characterized by absence of cerebral
convolutions and a poorly formed sylvian fissure
• MRI similar to a 3-4 months old fetal brain
• This condition is a result of faulty neuroblast migration
during early embryonic life
• Associated with enlarged lateral ventricles and
heterotopias in the white matter.

9. • Cytoarchitecture – 2 forms
• 4 layer cortex instead of normal 6 layers
• Disorganized neurons – no recognizable layers
• LIS1 gene or Reelin gene defect

10. Pathological types
 Agyria : Absence of gyri
 Pachygyria : Reduced number of broadened flat gyrus
with less folding.
(Both may be seen in the same brain.)

11.  Lissencephaly and band heterotopia are distinguished by
both pattern and severity of the malformation.
 Pattern or gradient may be
. Anterior more severe than posterior A>P.
. Posterior more severe than anterior P>A.
. Less often seen; anterior similar to posterior A=P.
 Patterns and grades are important to distinguish different
syndromes and gene association.

12. Infants with lissencephaly present clinically with following
features:
• Failure to thrive
• Microcephaly
• Marked developmental delay
• Severe seizure disorder
• Occular abnormalities-hypoplasia of optic nerve and
microphthalmia

13. AGYRIA
PACHYGYRIA

14. • Lissencephaly mostly occurs as an isolated finding but is associated
with miller-dieker syndrome in about 15% of cases.
 Miller-dieker syndrome:
 Classic Lissencephaly without gradient.
 Typical Facial appearance.
* Prominent forehead.
* Bi temporal hollowing.
* Short nose.
* Upturned nares.
* Prominent upper lip.
* Micrognathia(small jaw)
 Other important forms of lissencephaly include walker-warburg
variant and other cobblestone malformations.

16. SCHIZENCEPHALY
• Defined as presence of unilateral or bilateral clefts within
cerebral hemispheres
• Cleft may be fused or unfused differentiating it to be
open lipped (separated by CSF) or closed lipped
schizencephaly.

17. SCHIZENCEPHALY-CLOSED
LIPPED

18. SCHIZENCEPHALY-OPEN
LIPPED

19.  CLINICAL FEATURES
 Unilateral lesion- mild impairment and is a common cause
of congenital hemiparesis
• Bilateral lesion - severe MR.
seizures-difficult to control
microcephaly
spastic quadriparesis
 Closed lipped Schizencephaly - Hemiparesis/Motor delay
 Open lipped schizencephaly - Seizures / Hydrocephalus.

20. POLYMICROGYRIAS
 Characterized by excessive cortical in folding
resulting in many small gyri separated by shallow sulci,
associated with heterotopia.
MRI FINDINGS:
 Loss of normal gyral pattern, irregular or pebbled
brain surface.
 Increased number of small 2-5 mm wide gyri
separated by very shallow sulci.
 Irregular border between the cortex and underlying
thin white matter.

22. • CLINICAL FEATURES:
• Severe spasticity
• Epilepsy-including drug resistant forms
• Perisylvian area involvement results in psendobulbar palsy,
oromotor and speech apraxia.
• Developmental delay / MR.

23. NEURONAL HETEROTOPIAS
 Defined as group of neurons in an inappropriate
location – either below or above the cerebral cortex.
 Subtypes:
Periventricular nodular heterotopias
subcortical heterotopias

24. • Periventricular nodular heterotopias:
 Most common
 Islands of neurons and glial cells occur in subependymal
regions around the lateral ventricles
 Partial intractable seizures / 80-90% have epilepsy.
 Few present with chronic headache.

26.  Subcortical heterotopias:
 Band of gray matter heterotopia lies within the subcortical
white matter parallel to the overlying cerebral cortex but
separates from it by white matter.
 Generally unilateral.

27. Sub-cortical,symmetric,circumferentialbandsof graymatter,
separatedfromcortexbythinbandof whitematter. “Double cortex”
appearance.

28. PORENCEPHALY
• It is the presence of cysts or cavities within the brain that
result from developmental defects or acquired lesions,
including infarction of tissue.
• Porencephalic cysts are most commonly located in the region
of sylvian fissure and typically communicate with
subarachnoid space, ventricular system or both.
• Clinical features:
• Intellectual disability/mental retardation
• Spastic hemiparesis/quadriparesis
• Optic atrophy
• seizures

29. • Risk factors for porencephalic cyst formation include;
• Hemorrhagic venous infarctions
• Thrombophilias-Protein C def
-Factor-V leiden mutations
• Perinatal alloimmune thrombocytopenia
• Von willebrand disease
• Maternal warfarin use
• Maternal cocaine use
• Congenital infections
• Trauma during amniocentesis and maternal abdominal
trauma

31. FOCAL CORTICAL DYSPLASIAS
• These are abnormal cortical lamination in a discrete area
of cortex due to failure of neuronal migration in utero
• High resolution thin-section MRI can reveal these areas.
• Clinical features:
• Intractable seizures

33. LEARNING POINTS
Lissencephaly cause major developmental
problem and may shorten life.
 Some of less severe migrational and
organizational abnormalities may be clinically
silent but, associated with learning difficulties or
seizures or motor disability.
 Many of them are discovered in MRI,
some are microscopic and is relevant in
the assessment of refractory seizures.

34. REFERENCES
• NELSON TEXTBOOK OF PEDIATRICS-FIRST SOUTH ASIA
EDITION
• IAP TEXTBOOK OF PEDIATRICS
• SWAIMAN NEUROLOGY-5TH EDITION
• ROBINS TEXTBOOK OF PATHOLOGY-9TH EDITION

35. THANK YOU