1. CHELSEA A. IENNARELLA ANS 536 – PERINATOLOGY SPRING 2014 Central Nervous System Abnormalities

2. ANS 536 - Perinatology - CNS Development

3. Overview: Lecture 03/24/2014: Prenatal CNS Development Post-Natal CNS Development Male vs. Female Brain Congenital CNS Abnormalities Epigenetic Changes Species Differences in CNS Development and Physiology ANS 536 - Perinatology - CNS Development

4. DEFECTS IN CORTICAL DEVELOPMENT Congenital CNS Abnormalities

5. 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

6. 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

7. Microcephaly:

8. 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

9. Lissencephaly:

10. 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.

11. Lissencephaly:

12. NEURAL TUBE DEFECTS Congenital CNS Abnormalities

13. Neural Tube Defects: Neural tube fuses 18-26 days after ovulation. One of the most common congenital abnormalities. Complex interaction between genetics and environment.

14. 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

15. 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

16. Schalinske & Smazal 2012

17. Schalinske 2014 S G U T TS

18. Schalinske & Smazal 2012

19. 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 Types of NTDs:

20. Open NTDs

21. 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

22. 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

23. Spina Bifida: Occurs when caudal neuropore fails to close. backbone that protects the spinal cord does not form and close 3 sub-classifications

24. Closed NTDs

25. 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

26. Screening for Congenital CNS Abnormalities

27. 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

28. 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

29. 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

30. Epigenetics & the CNS

31. Epigenetics: Epigenetics: external modifications to DNA/RNA that regulate gene expression. Epigenetic Mechanisms:  DNA methylation  Modification of histone N-terminus  non-coding RNAs

32. Central Dogma of Molecular Biology:

33. DNA methylation: CH3 groups bind to CpG regions in the promoter region of genes to block transcription Results in silencing of that gene

34. Histone Modification: Addition of function groups to the N-terminus of histones results in a change in chromatin conformation. Acetylation Methylation Biotinylation Condensed ↔ Relaxed

35. microRNAs: large non-coding RNAs: Hybridize with mRNA to block translation. Hybridize with DNA template to block transcription. Non-Coding RNAs:

36. 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.)

37. Species Differences in CNS Development

38. 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

39. Morphological Differences:

40. 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.

42. Questions: ANS 536 - Perinatology - CNS Development