Central Nervous System Abnormalities
CHELSEA A. IENNARELLA
ANS 536 – PERINATOLOGY
SPRING 2014
ANS 536 - Perinatology - CNS Development
Overview:
Lecture 03/24/2014:
 Prenatal CNS
Development
 Post-Natal CNS
Development
 Male vs. Female Brain
ANS 536 - Perinatology - CNS Development
 Congenital CNS
Abnormalities
 Epigenetic Changes
 Species Differences in
CNS Development and
Physiology
Congenital CNS Abnormalities
DEFECTS IN CORTICAL DEVELOPMENT
Normal Cortical Development:
 Proliferative neuroepithelium forms a thick layer
surrounding the ventricles in developing brain.


neural stem cells and neural progenitor cells
neurons and glial cells formed migrate to the cortex
 Cortical Development Defects
 abnormal neuronal-glial proliferation
 abnormal neuronal migration
 abnormal cortical organization
Abnormal Neuronal-Glial Proliferation:
Microcephaly:
 Defined as an abnormally small head circumference.

diagnosed at birth or during childhood
 Can result from over 450 disorders.
 Down Syndrome
 Autosomal microcephaly (dominant or recessive)
 X-linked microcephaly
Microcephaly:
Abnormal Neuronal Migration:
Lissencephaly:
 Defined as a lack of gyri and sulci.

diagnosed at birth or soon after
 Can result from many different environmental
and/or genetic causes.



uterine viral infection
insufficient uterine blood supply
gene mutations
Lissencephaly:
Abnormal Cortical Organization:
Polymicrogyria:
 Defined as an excessive number of undersized gyri.

diagnosed at birth or during childhood
 Several contributing factors but exact cause is poorly
understood.
Lissencephaly:
Congenital CNS Abnormalities
NEURAL TUBE DEFECTS
Neural Tube Defects:
 Neural tube fuses 18-26 days after ovulation.
 One of the most common congenital abnormalities.
 Complex interaction between genetics and
environment.
Risk Factors for NTDs:
Genetic Factors:
 Family history of specific NTD.
 Mutations in enzymes involved in 1-carbon
metabolism.
Environmental Factors:
 Maternal dietary folate deficiency.
 Maternal induced folate deficiency.


sodium valproate
folate antagonists
Folate & NTDs:
 Folate and B12 important in reducing occurrence.
 Required for production/maintenance of new cells.
 DNA synthesis – thymidine synthesis
 Generation of CH3 groups; gene silencing and PTM
Schalinske & Smazal 2012
S
G
U
TS
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Schalinske 2014
Schalinske & Smazal 2012
Types of NTDs:
Open NTDs:
Closed NTDs:
brain and/or spinal cord
are exposed at birth
 anencephaly
 encephalocele
 spina bifida
spinal defect is covered
by skin at birth
 lipomyelomeningocele
 lipomeningocele
 tethered cord
Open NTDs
Anencephaly:
Occurs when rostral
neuropore fails to close.
 brain lacks all or part of
the cerebrum
 parts of brain not
covered by skin or bone
Encephalocele:
Occurs when rostral
neuropore fails to close.
 sac-like protrusion or
projection of the brain
and covering membranes
through an opening in
the skull
Spina Bifida:
Occurs when caudal
neuropore fails to close.
 backbone that protects
the spinal cord does not
form and close
 3 sub-classifications
Closed NTDs
Closed NTDs:
lipomyelomeningocele:

lipoma covering the site of a myelomeningocele
lipomeningocele:

lipoma covering the site of a meningocele
tethered cord:

spinal cord is held taught at one end, unable to move freely as
it should; results in stretching of spinal cord as child grows
Screening for Congenital
CNS Abnormalities
Screening for NTDs:
 Performed between 16-18 weeks of gestation
 range 15-33 weeks of gestation
 Measures maternal serum alpha-fetoprotein (AFP)
concentrations

Produced in liver fetus; leaks into amniotic fluid and
ultimately gets into maternal blood
Screening for Other CNS Abnormalities:
Amniocentesis:
 Performed between 16-22 weeks of gestation

sample of amniotic fluid is obtained and submitted for testing
Chorionic Villus Sampling:
 Performed between 10-12 weeks of gestation

Sample of the chorionic villi (placental tissue) taken and
submitted for testing
Amniocentesis & Chorionic Villus Sampling:
Amniocentesis Video:
http://www.youtube.com/watch?v=GZoswKIa4ic
Chorionic Villus Sampling Video:
http://www.youtube.com/watch?v=sxEf_ddmpZk
Epigenetics & the CNS
Epigenetics:
Epigenetics: external modifications to DNA/RNA that
regulate gene expression.
Epigenetic Mechanisms:



DNA methylation
Modification of histone N-terminus
non-coding RNAs
Central Dogma of Molecular Biology:
DNA methylation:
CH3 groups bind to CpG
regions in the promoter
region of genes to block
transcription
 Results in silencing of
that gene
Histone Modification:
Addition of function
groups to the N-terminus
of histones results in a
change in chromatin
conformation.
 Acetylation
 Methylation
 Biotinylation
Condensed ↔ Relaxed
Non-Coding RNAs:
microRNAs:
large non-coding RNAs:
Hybridize with mRNA to
block translation.
Hybridize with DNA
template to block
transcription.
Epigenetics & the CNS:
 Earliest stages of CNS development are most
susceptible to epigenetic modification.

Effects may be evident at birth or may not occur until later
stages of adulthood
Epigenetic influences on brain development and plasticity. (Fagiolini et al.)
Species Differences in CNS Development
Precocial vs. Altricial Young:
Precocial young: animals that are capable of a high
degree of independent activity from birth

cattle, guinea pig, sheep
Altricial young: young that are hatched or born in a
very immature and helpless condition so as to
require care for some time

cats, dogs, humans
Morphological Differences:
Overview:
 Congenital CNS abnormalities can result from NTDs
of issues in cortical development.
 Epigenetic Changes can have profound and lasting
effects on CNS.
 CNS development and physiology varies between
species.
Questions:
ANS 536 - Perinatology - CNS Development