congenital diseases associated with CNS

Question 1

two modes of neural tube closure

Answer 1

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

• primary and secondary neural tube become continuous
• sometimes 30-31 in humans (2nd sacral)

Question 2

primary neurulation: cellular and molecular mechanisms

Answer 2

• shaping of neural plate occurs by convergence/extension
• tubing requires bending at hinge points
• cell wedging at hinge points: microtubules and actin filaments

controlled by planar cell polarity pathway

Question 3

the process of convergence extension

Answer 3

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

Question 4

the Wnt-PCP pathways

Answer 4

wnt = 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 5

the Wnt-PCP pathway

Answer 5

mouse mutants in components of the wnt-PCP pathway show neural tube defects:

celsr1- crash 
vangl = loop tail
scribble = circle tail
dvl1/2 
fzd3/6

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

Question 6

what does the Wnt-PCP pathway do

Answer 6

localises actomyosin to the apical surface, in mediolateral polarised way

Question 7

primary neurulation: cellular and molecular mechanisms

Answer 7

Shaping of the neural plate occurs by convergence/extension
Tubing requires bending at hinge points
Cell wedging at hinge points: microtubules & actin filaments
Defective convergence/extension and cell wedging leads to chraniorachischisis

Question 8

neural tube defects in humans

Answer 8

Anencephaly: cranial neuropore failure
perinatal lethal (also craniorachischisis)
Spina Bifida: caudal neuropore failure
Occulta (unfused vertebral arches)
Meningocoele
Meningomyelocoele
Myeloschisis aperta
Most common CNS malformation (was ~10/10,000 births, now ~2/10,000)

Question 9

environmental factors associated NTDs

Answer 9

high levels of sugar

maternal obesity /diet
vitamin deficiency/malnutrition

diabetes
hypertermia
teratogenic agents
valproic acid

Question 10

folic acids and NTDs

Answer 10

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: 0.4mg/day or 5.0 for pregnant women
Current practice: 0.4 general; 5 recurrence
Fortification better than supplementation?
e.g. mandatory cereal grain fortification in USA
Fortification: ~ 70 - 200ug/day (USA, Canada)
Log relationship between dose & protection

Question 11

NTD and folates

Answer 11

Folic acid supplementation/fortification is the only known intervention preventive for any congenital anomaly

Probably no adverse effects
Suggested problems: B12 deficiency (reduce detection by masking anaemia, allowing neurotoxic complications); promotion of colon polyps to cancer - both not confirmed
Also reduces palate & heart defects

Up to ~70% (?) of NTD can be prevented by folate

But there are still NTDs that cannot be prevented by folate (“folate resistant NTD”)

Inositol
Can prevent NTDs in experimental models
Current clinical trials, still insufficient evidence for a protective effect in humans