Congenital Diseases Associated with Central Nervous System Flashcards
What does the neural tube differentiate into?
- The brain
- Spinal cord
- Cranial and spinal nerves
- Eyes and other sensory organs
- Neural crest
When does neurulation occur and what do defects result in?
- Defects in neural tube formation will affect the formation of some or all of these structures.
- In humans, neurulation occurs between weeks 3 and 4.
What is the neural plate?
It is initially a flat sheet of cells located along the dorsal portion of the developing embryo in direct continuation with the epidermis, and exposed to the extraembryonic medium. This sheet of cells will become a tube, and will end up being located inside the embryo.
What stimulates the neurulation process?
The notochord
What happens when the neural tube closes?
It becomes patterned along the dorso-ventral and the rostro-caudal axes. This process is driven by secreted signalling molecules, which promote the specification of different CNS structures along each axis.
What are the derivatives of the neural tube along the cranio-caudal axis?
What congenital defects can arise from perturbation of different steps during CNS formation?
- Defects of early patterning of the CNS: holoprosencephaly
- Defects of neural tube closure: chraniorachischisis, exencephaly/anencephaly, spina bifida.
- Regional brain defects: rostro-caudal defects.
What is Holoprosencephaly (HPE)?
- A defect of dorso-ventral forebrain patterning
- HPE is a structural malformation of the forebrain characterised by impaired midline cleavage of the brain.
- HPE can be classified as alobar, semilobar or lobar, depending on the degree of severity of the midline defect.
What are the types of HPE’s?
- Alobar HPE
- Semilobar HPE
- Lobar HPE
- Microforms of HPE
What is Alobar HPE?
- Refers to the formation of a single ventricle, and the absence of interhemispheric fissure.
- Not only the brain, but also other CNS derivatives and face structures are affected in this from.
- For example, the separation of the eye field into two optic primordia does not occur, and the affected individuals also display cyclopia.
What is Semilobar HPE?
Shows partial cortical separation, rudimentary hemispheres and a single ventricle.
What is Lobar HPE?
Shows separate ventricles, but there is still incomplete frontal cortical separation.
What are microforms of HPE?
Some milder forms of HPE have been described, which show much milder midline defects, sometimes only identifiable by a single maxillary median incisor or hypotelorism (close set eyes), and no brain malformation
What do different conditions of defects in neural tube closure depend on?
Depending on the extent of the closure defect, or the region along the cranio-caudal axis where non-closure occurs.
What is Craniorachischisis?
- This is the most severe form of neural tube defect. The neural tube remains open along the whole body axis.
- Sometimes the forebrain closes normally, and the defect is then called rachischisis.
What are the types of spina bifida?
What is morphogenesis and closure of the neural tube?
- Closure of neural plate progresses both anteriorly and posteriorly.
- When opening remains in anterior portion its called encephaly, if it occurs at the caudal region, it is called spina bifida.
What is the closure of the cranial and caudal neuropores?
- Closure 1 – located at edge between hindbrain and spinal cord
- Closure 2 – located at edge between midbrain and forebrain
- Closure 3 – located in most rostral portion of forebrain and starts later than closure 2 and only progresses posteriorly.
- Closure 4 – More rostral to hindbrain and closure 1
- Closure 5 – located at very posterior portion of neural plate and progresses anteriorly.
What is Primary Neurulation?
- Neural plate has to be shaped
- Narrows down along mediolateral axis
- Extend along rostro-caudal axis
- Folding occurs by the formation of hinge points along different regions of the neural plate
- Midline hinge point – along middle of neural plate
- Midline hinge point allows edges of neural plate to become closer together
- Neural folds (edges of neural plate) become further opposed to each other by a process called convergence that involves formation of more hinge points.
- Eventually 2 folds fuse together and close to form neural tube.
What is the process of Convergence-Extension?
- A process of lengthening by narrowing, which requires cells to become polarised, in the plane of the cell layer and intercalate amongst each other.
- Elongates in anterior-posterior axis – happens during elongation of neural plate.
What is the Wnt-PCP (planar cell polarity pathway)?
- Wnts – secreted signaling molecules – the ligand
- Frizzleds – Wnt receptor, transmembrane proteins. 10 different Frizzleds in the human genome. All can bind to different combination of Wnt molecules.
- Vangl and Celsr – co-receptors necessary for signal transduction.
- Within the cell, the first molecule that is targeted after the activation of the first membrane complex is called Dvl1-3 – cytoplasmic proteins, activated upon interaction between Wnts and Fzds.
- Dvl1-3 together with other proteins regulates transcription and regulates the dynamics of the cytoskeleton.
Human mutations in PCP genes are associated with craniorachischisis what other neural tube defects (NTD’s)?
- Celsr-1 is a transmembrane protein, the boxes show places in the protein where mutations have been found in humans.
- Scribl protein is a cytoplasmic component and the mutations can be found
What is cell wedging and apical constriction?
- Cell wedging is the mechanism where the hinge points are formed. It involves the change of cells in the neural plate so their apical side becomes narrow.
- The tissue becomes folded along these regions
- Apical constriction of cell is due to remodelling of cytoskeleton along apical cortex of the cell.
How do cells in an epithelium have apico-basal polarity?
- The cytoskeleton is polarised within the cell.
- At the sub-apical region of cells, there are tight arrays of actin filaments that are important for the shape of the cell.
- Remodelled as the cell becomes bottle shaped.
- Remodelling driven by Wnt-PCP pathway
- The Wnt-PCP pathway localises actomyosin to the apical surface, in a mediolateral polarised way.
What are the neural tube defects in humans?
How do folic acid and NTD’s link?
- Clinical trials in humans in the 90s showed a preventative effect of maternal folic acid supplementation prior to and during pregnancy
- 4mg folate >5 x decreased recurrence risk, better with preconception start
- Supplementation dose 0.4mg/day or 5.0 for pregnant women
- Fortification better than supplementation?
- E.g mandatory cereal grain fortification in USA
- Fortification Z70-200 microgram/day
- Log relationship between dose and protection
What does folic acid fortification do?
- Need to take supplementation of folic acid for 20 weeks before pregnancy for enough folic acid to be present in the plasma – easier to fortify food.
- Folic acid supplementation/fortification is the only known intervention preventative for any congenital anomaly.
- Probably no adverse effects
- Suggested problems B12 deficiency (reduce detection my masking anaemia, allowing neurotoxic complications), promotion of colon polyps to cancer
- Reduces palate and heart defects
- Up to 70% of NTD can be prevented by folate
