L2: Neural Tube Deficits Flashcards
what causes perinatal death
stillbirth and neonatal deaths
what is the biggest cause of stillbirths
anencephaly
CNS malformation stats
1 per 1000 pregnancies
over 250000 cases per year
main types of NTDs
anencephaly (40%)
open spina bifida (40%)
craniorachischisis (<10%)
encephalocele (10%)
what are the 2 phases of neuralation
primary and secondary
what is primary neuralation
neural tube folding and closure (in the midline by the notochord)
what is secondary neuralation
canalisation (no closure in the lower body)
days of neural tube closing in mice and humans
8-10 days in mice
21-28 days post fertilisation in humans
how many neural tube closures
1,2,3
humans do not have closure 2
what does the failure of closure 1 lead to
craniorachischisis
what does failure of closure 3 lead to
anencephaly (failure of anterior neuropore to close)
what does the failure of the posterior neuropore closing lead to
closed spinal dysraphism and open spina bifida (myelomeningocele)
how is walking affected if lesion is above/below the lumbar and sacral
if lesion is above - no walking
if lesion is below - walking
what are the two hits in development of open NTDs
1)failed cranial neuralation - neural tube does not close
2) exencephaly - tissue is viable and undergoes apoptosis
how to stop 2nd hit in spina bifida
in utero surgery to cover lesion (stops infection in the foetus)
genes involved in the failure of neural tube closure
Vangl2, Scrb1, CelSr1
planar cell polarity signalling pathway
wnt5a&11 (external) bind to frizzled receptors causing change in conformation, forms complex
role of PCP
regulate cytoskeleton (actin and myosin)
regulates cell shape and movement
what does the disturbance of PCP cause
misexpression of Dishevelled/strabismus leads to open neural tube phenotype and short and broad body axis (No convergent extension)
what mutant leads to no convergent extension
Vangl2 lp/lp (mouse)
what does the vangl2lp/lp mutant cause
disrupted midline bending
no convergent extension
too many cells in midline
mechanical issue
no cell fusion
established causes of NTDs
valproic acid (spina bifida taken for epilepsy)
fumonisin (fungal toxin from maize crop)
NTD associations
diabetes
obesity
hyperthermia
fever
retinoids
alcohol
what deficiencies cause NTDs
folate
vitb12
inositol
zinc
what does scrb1 mutant cause
stops protein entering membrane (craniorachischisis)
what causes low levels of NTDs
high B12 and folate
how can folate deficiencies cause NTD
interact with Splotch
does not alone cause NTDs
types of prevention for NTDs
treat after birth
prenatal diagnosis and abortion
surgical repair in foetus (in utero surgery)
primary prevention via folic acid
foetal surgery to repair spina bifida
22-24 wks after gestation
SB lesion covered +/- stem cells (release factors then die)
slight improvement in motor function (walking)
hindbrain herniation (Chiari II malformation) improved 50%, less hydrocephalus
higher brain defects not improved - learning defects
what does chiari II malformation cause
affects cerebellum and HB
causes breathing problems
UK folic acid recommendation
400ug in perinatal period
4-5mg for high risk NTD
USA folic acid recommendation
100ug for everyone via fortification
methods of obtaining folic acid
supplements (do not reduce rate of NTDs)
mandatory fortification of bread flour (reduces rate of NTDs) 140ug/100g
how many NTDs have been reduced by fortification
30%
how many NTDs are resistant to folates
30%
curlytail
axial defects
ephrinA5
folate responsive genes
splotch
cart
cited2
how can spina bifida be reduced in curly tail (ct) mutants
by giving inositol
PONTI trial (prevention of neural tube defects by inositol)
women planning for pregnancy with previous NTD:
only 3 recurrences of anencephaly (no inositol)
