Congenital Diseases Associated with Central Nervous System

Question 1

What does the neural tube differentiate into?

Answer 1

• The brain
• Spinal cord
• Cranial and spinal nerves
• Eyes and other sensory organs
• Neural crest

Question 2

When does neurulation occur and what do defects result in?

Answer 2

• 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.

Question 3

What is the neural plate?

Answer 3

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.

Question 4

What stimulates the neurulation process?

Answer 4

The notochord

Question 5

What happens when the neural tube closes?

Answer 5

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.

Question 6

What are the derivatives of the neural tube along the cranio-caudal axis?

Answer 6

Question 7

What congenital defects can arise from perturbation of different steps during CNS formation?

Answer 7

• Defects of early patterning of the CNS: holoprosencephaly
• Defects of neural tube closure: chraniorachischisis, exencephaly/anencephaly, spina bifida.
• Regional brain defects: rostro-caudal defects.

Question 8

What is Holoprosencephaly (HPE)?

Answer 8

• 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.

Question 9

What are the types of HPE’s?

Answer 9

• Alobar HPE
• Semilobar HPE
• Lobar HPE
• Microforms of HPE

Question 10

What is Alobar HPE?

Answer 10

• 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.

Question 11

What is Semilobar HPE?

Answer 11

Shows partial cortical separation, rudimentary hemispheres and a single ventricle.

Question 12

What is Lobar HPE?

Answer 12

Shows separate ventricles, but there is still incomplete frontal cortical separation.

Question 13

What are microforms of HPE?

Answer 13

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

Question 14

What do different conditions of defects in neural tube closure depend on?

Answer 14

Depending on the extent of the closure defect, or the region along the cranio-caudal axis where non-closure occurs.

Question 15

What is Craniorachischisis?

Answer 15

• 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.

Question 16

What is Exencephaly and Anencephaly?

Answer 16

• These conditions refer to the lack of closure in the brain region. Lack of closure results in exencephaly (“brain exposed”).
• In this condition, the brain tissue remains exposed to the amniotic cavity and eventually degenerates, resulting in anencephaly (“lack of brain”).

Question 17

What is Spina Bifida?

Answer 17

• This defect refers to the malformation of the spine and/or spinal cord, usually in the lumbar area.
• It can be due to the failure in the closing of the neural tube during neurulation. It can also be due to defective formation of the vertebrae, resulting in the spinal cord being exposed and unprotected.
• Spina bifida can be classified as occulta, meningocele and myelomeningocele

Question 18

What are the types of spina bifida?

Answer 18

Question 19

What are regional brain disorders?

Answer 19

Refers to diseases where whole elements of the CNS are missing or underdeveloped. They are often related to defective rostro-caudal CNS patterning.

Gene-phenotype correlations are not very clear.

Question 20

What is the Dandy-Walker Syndrome?

Answer 20

Deletion of ZIC1 and ZIC4 have been reported. In mouse models these genes, which encode for transcription factors, are expressed in the cerebellum and spinal cord and are essential for the formation of those structures.

Consistently, patients with Dandy-Walker syndrome show cerebellar hypoplasia, hydrocephalus and motor deficits.

Question 21

What is Joubert syndrome?

Answer 21

Another disorder associated to cerebellar hypoplasia/aplasia. The genetic basis of this syndrome is very heterogeneous and still poorly understood from a functional point of view.

Question 22

What is morphogenesis and closure of the neural tube?

Answer 22

• 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.

Question 23

What is the closure of the cranial and caudal neuropores?

Answer 23

• 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.

Question 24

What are the 2 modes of neural tube closure?

Answer 24

• Primary neurulation
  
  • Rolling-up of tube
  • Closure is by fold apposition then “zipping-up”
  • Finally, at cranial and caudal neuropores
• Secondary neurulation
  
  • Tunnelling or hollowing of tail bud – most caudal region of neural tube
• The primary and secondary neural tube becomes continuous
  
  • Located at level of somites 30-31 in humans (2^nd sacral)

Question 25

What is Primary Neurulation?

Answer 25

* **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.

Question 26

What are the cellular and molecular mechanisms in primary neurulation?

Answer 26

* Shaping of the neural plate occurs by **convergence/extension** * Tubing requires bending at specific hinge points * Formation of hinge points involves a transformation in the shape of a cell called **cell wedging** involves remodelling of microtubules and actin filaments. * Both processes are controlled by the **Planar Cell Polarity Pathway.** * Defective convergence/extension and cell wedging leads to craniorachischisis.

Question 27

What is the process of Convergence-Extension?

Answer 27

* **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.

Question 28

What is the Wnt-PCP (planar cell polarity pathway)?

Answer 28

* **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.

Question 29

What neural tube defects were found in components of the Wnt-PCP in mouse mutants?

Answer 29

* Celsr1 -/- (crash) * Vangl -/- (loop-tail) * Scribble -/- (circletail) * Dvl1/2 * Fzd3/6

Question 30

What is Craniorachischisis?

Answer 30

The neural plate is abnormally broad with a non-bending region between neural folds – leads to complete absence of neural tube closure

Question 31

Human mutations in PCP genes are associated with craniorachischisis what other neural tube defects (NTD's)?

Answer 31

* 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

Question 32

What is cell wedging and apical constriction?

Answer 32

* **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.

Question 33

How do cells in an epithelium have apico-basal polarity?

Answer 33

* 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.

Question 34

What are the neural tube defects in humans?

Answer 34

Question 35

What environmental factors are associated to NTD's?

Answer 35

* Maternal diet * Vitamin deficiency/malnutrition * Folate * Inositol * High levels of sugar * Maternal obesity * Diabetes * Hypertermia – mother undergone severe disease, high fevers during pregnancy * Teratogenic agents – an agent that can disturb the development of an embryo. They halt the pregnancy or produce a congenital malformation * Valproic acid (VPA)

Question 36

How do folic acid and NTD's link?

Answer 36

* 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

Question 37

What does folic acid fortification do?

Answer 37

* 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

Question 38

How are there NTD's that cannot be prevented by folate?

Answer 38

* "folate resistant NTD" * Inositol * Can prevent NTDs in experimental models * Current clinical trials, still insufficient evidence for a protective effect in humans