congenital diseases associated with CNS Flashcards
how does neural tube form-morphogenesis and closure of neural tube?
- lateral edges of ectoderm fold and form neural fold at week 3.
- cranial end gives rise to brain
- caudal end gives rise to spinal cord
What are 3 defects of morphogenesis and closure of the neural tube?
- anencephaly = failure of neural tube to close at cranial side
- cranioarchischisis = combination of both anencephaly and spina bifida
- Spina bifida = failure to close at caudal side.
What are two modes of neural
- 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)
outline the steps of primary neurulation
- shaping and folding along Midline hinge point of neural plate
- elevation
- convergence
- closure
What are two main processes important for efficient folding of neural plate in primary neurulation?
- shaping of the neural plate which occurs by convergence/extension
- tubing requires bending at hinge points
- cell wedging at hinge points: microtubules and actin filaments.
Both these processes are controlled by Planar Cell polarity Pathway
What are convergence/extension and cell wedging controlled by?
-planar cell polarity pathway
What is the process of convergence- extension?
- a process of lengthening by narrowing, which requires cells to become polarized, in the plane of the cell layer.
convergence-extension is controlled by wnt-PCP pathway, outline the process.
- wnt -PCP pathway
- 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
What are mutation in Wnt-PCP pathway linked to?
- mutation can occur in Celsr, vangl, fizzle receptor
- mouse mutants in Wnt-PCP pathway cause craniorachischisis
- human mutations of same gene as mouse also associated with crabiorachischisis (failure of neural tube closure) and other NTD
what is cell wedging ?
- mechanism by which hinge point where neural plates are formed folds
- so cells in the neural change shape: apical side becomes very narrow
What are features of epithelium cell?
- epithelium cells have apico-basal polarity
- actin filaments maintain shape and are remodelled
- The wnt-PCP pathway localizes actomyosin to the apical surface, in a mediolateral polarized way.
What are environmental factors associated to NTDs?
1.maternal diet
-vitamin deficiency/malnutrition
(Folate and inositol)
-high levels of sugar
2. maternal obesity
3.diabetes
4. Hypertermia
5.teratogenic agents : valproic acid(VPA)
What is the association between folic acid and NTDs?
- clinical trials in humans in the 90s showed a preventive effect of maternal folic acid supplementation prior to and during pregnancy:
- 4mg folate ; >5x less recurrence risk: better with preconception start
- dose : 0.4mg/day for women, or 5mg for pregnant women
- fortification : artificially adding nutrients to food
What is the relationship between serum folate level and dose of supplement?
- linear relationship of serum folate level with dose of supplement and
What is the correlation between maternal folate plasma levels and incidence with NTD?
inverse log-log relationship of incidence of NTD with maternal plasma folate levels.
