Congenital Diseases Associated with Central Nervous System

Question 1

Explain the steps of morphogenesis

Answer 1

• Fusing of neural folds
• fusing starts between hindbrain and spinal cord and progresses up and down

Question 2

What are the possible deformities of neural tube closure

Answer 2

• Anencephaly (more cranial)
• Cranioarchischisis
• Spina bifida (more caudal)

Question 3

Where are the closure points in mouse

Answer 3

Closure 1 - Between the hindbrain and spinal cord
Closure 2 - On top of the head
Closure 3 - Near the face

Question 4

Where are the closure points in human

Answer 4

Closure 1 - Between the hindbrain and spinal cord
Closure 2 - On top of the head
Closure 3 - Near the face
Closure 4 - Just above number 1
Closure 5 - Most caudal end

Question 5

What are the 2 modes of neural tube closure

Answer 5

• 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

The primary and secondary neural tube become continuous
Somites 30-31 in human (2nd sacral)

Question 6

What are the steps in primary neuralation

Answer 6

Shaping of the neural plate occurs by convergence/extension

Tubing requires bending at hinge points

Cell wedging at hinge points: microtubules & actin filaments

Question 7

Describe the process of convergence-extension

Answer 7

A process of lengthening by narrowing, which requires cells to become polarized, in the plane of the cell layer

Question 8

What is the Wnt-PCP pathway

Answer 8

It is a network of proteins that lead to changes in the transcriptional state of the cell

Question 9

What are the steps in the Wnt-PCP signalling pathway

Answer 9

Wnts: secreted signalling molecules – the ligand

Frizzleds: Wnt receptor, transmembrane proteins

Vangl and Celsr: co-receptors necessary for signal transduction

Dvl1-3: cytoplasmic proteins, activated upon interaction between Wnts and Fzds

Question 10

What mutations in the Ant-PCP pathway can lead to neural tube defects

Answer 10

Mouse mutants in components of the Wnt-PCP pathway show neural tube defects:

celsr1-/- (crash)
vangl-/- (loop-tail)
scribble-/- (circletail)
dvl1/2
fzd3/6

The neural plate is abnormally broad with a non-bending region between neural folds - leading to chraniorachischisis

Question 11

Describe how cell wedging and apical constriction occurs

Answer 11

Actin myosin filament in the cell contract at the apical portion contracting the cell to a bottle shape.
The cytoskeleton is polarised and the actin-myosin filament the maintain the shape

Question 12

how does mutation lead to lack of neural tube closure

Answer 12

celsr1-/- (crash)
vangl-/- (loop-tail)
scribble-/- (circletail)
dvl1/2
fzd3/6
- these messengers mediate the constriction an when mutated it doesn’t take place
- therefore neural tube closure doesn’t occur

Question 13

what are the Environmental factors associated with NTDs

Answer 13

• Maternal diet
  Vitamin deficiency/malnutrition
  Folate
  Inositol
  High levels of sugar
• Maternal obesity
• Diabetes
• Hypertermia
• Teratogenic agents
  Valproic acid (VPA)
• Alcohol

Question 14

How is folic acid important in NTDs

Answer 14

• Clinical trials in humans in the 90’s showed a preventive effect of maternal folic acid supplementation prior to and during pregnancy
  4mg folate; >5x  recurrence risk; better with preconception start
• Supplementation dose:
  Current practice: 0.4 mg/day general; 5 mg/day recurrence
  …but supplementation does not reach everyone
• Fortification better than supplementation?
  e.g. mandatory cereal grain fortification in USA
  Fortification: ~ 70 - 200ug/day (USA, Canada)

Question 15

What are the uses of Folic acid

Answer 15

• Nucleotide synthesis
• Serine-glycine interconversion
• Mitochondrial tRNA modification
• Methyl group biogenesis
  proliferation
  respiration
  epigenetic modifications

Question 16

What are the mutations associated with folic acid

Answer 16

Mutations in folate related genes associated to NTDs:

• Transport molecules such as FOLR1, SLC46A1
• Metabolising enzymes such as MTHFD1, GLDC

Question 17

Why may folate deficiency not be the sole reason for NTDs

Answer 17

Usually there is a predisposing mutation
These can be in genes involved in folate transport/metabolism
But also in other unrelated genes important for NT closure
Examples: pax3, ciliogenesis genes
Folate mechanism of action in these cases is unclear

Question 18

What is Inositol and what is its functions

Answer 18

• Essential building block of phosphoinositides - structural components of the plasma membrane
• Involved in glucose metabolism and modulation of insulin levels

Question 19

How can Inositol prevent NTDs in folate-resistant experimental models

Answer 19

Spina bifida frequency in curly tail mouse mutants is reduced by inositol supplementation

Clinical trials still insufficient evidence for a protective effect in humans

Question 20

Can other factors cause NTDs

Answer 20

Environmental factors or nutrients deficiency can lead to NTDs in genetically predisposed animals