L2: Neural Tube Deficits Flashcards

1
Q

what causes perinatal death

A

stillbirth and neonatal deaths

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2
Q

what is the biggest cause of stillbirths

A

anencephaly

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3
Q

CNS malformation stats

A

1 per 1000 pregnancies
over 250000 cases per year

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4
Q

main types of NTDs

A

anencephaly (40%)
open spina bifida (40%)
craniorachischisis (<10%)
encephalocele (10%)

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5
Q

what are the 2 phases of neuralation

A

primary and secondary

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6
Q

what is primary neuralation

A

neural tube folding and closure (in the midline by the notochord)

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7
Q

what is secondary neuralation

A

canalisation (no closure in the lower body)

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8
Q

days of neural tube closing in mice and humans

A

8-10 days in mice
21-28 days post fertilisation in humans

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9
Q

how many neural tube closures

A

1,2,3
humans do not have closure 2

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10
Q

what does the failure of closure 1 lead to

A

craniorachischisis

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11
Q

what does failure of closure 3 lead to

A

anencephaly (failure of anterior neuropore to close)

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12
Q

what does the failure of the posterior neuropore closing lead to

A

closed spinal dysraphism and open spina bifida (myelomeningocele)

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13
Q

how is walking affected if lesion is above/below the lumbar and sacral

A

if lesion is above - no walking
if lesion is below - walking

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14
Q

what are the two hits in development of open NTDs

A

1)failed cranial neuralation - neural tube does not close
2) exencephaly - tissue is viable and undergoes apoptosis

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15
Q

how to stop 2nd hit in spina bifida

A

in utero surgery to cover lesion (stops infection in the foetus)

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16
Q

genes involved in the failure of neural tube closure

A

Vangl2, Scrb1, CelSr1

17
Q

planar cell polarity signalling pathway

A

wnt5a&11 (external) bind to frizzled receptors causing change in conformation, forms complex

18
Q

role of PCP

A

regulate cytoskeleton (actin and myosin)
regulates cell shape and movement

19
Q

what does the disturbance of PCP cause

A

misexpression of Dishevelled/strabismus leads to open neural tube phenotype and short and broad body axis (No convergent extension)

20
Q

what mutant leads to no convergent extension

A

Vangl2 lp/lp (mouse)

21
Q

what does the vangl2lp/lp mutant cause

A

disrupted midline bending
no convergent extension
too many cells in midline
mechanical issue
no cell fusion

22
Q

established causes of NTDs

A

valproic acid (spina bifida taken for epilepsy)
fumonisin (fungal toxin from maize crop)

23
Q

NTD associations

A

diabetes
obesity
hyperthermia
fever
retinoids
alcohol

24
Q

what deficiencies cause NTDs

A

folate
vitb12
inositol
zinc

25
Q

what does scrb1 mutant cause

A

stops protein entering membrane (craniorachischisis)

26
Q

what causes low levels of NTDs

A

high B12 and folate

27
Q

how can folate deficiencies cause NTD

A

interact with Splotch
does not alone cause NTDs

28
Q

types of prevention for NTDs

A

treat after birth
prenatal diagnosis and abortion
surgical repair in foetus (in utero surgery)
primary prevention via folic acid

29
Q

foetal surgery to repair spina bifida

A

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

30
Q

what does chiari II malformation cause

A

affects cerebellum and HB
causes breathing problems

31
Q

UK folic acid recommendation

A

400ug in perinatal period
4-5mg for high risk NTD

32
Q

USA folic acid recommendation

A

100ug for everyone via fortification

33
Q

methods of obtaining folic acid

A

supplements (do not reduce rate of NTDs)
mandatory fortification of bread flour (reduces rate of NTDs) 140ug/100g

34
Q

how many NTDs have been reduced by fortification

A

30%

35
Q

how many NTDs are resistant to folates

A

30%
curlytail
axial defects
ephrinA5

36
Q

folate responsive genes

A

splotch
cart
cited2

37
Q

how can spina bifida be reduced in curly tail (ct) mutants

A

by giving inositol

38
Q

PONTI trial (prevention of neural tube defects by inositol)

A

women planning for pregnancy with previous NTD:
only 3 recurrences of anencephaly (no inositol)