012 understanding and preventing neural tube defects Flashcards
what is a stillbirth?
death at the end of pregnancy (after 24 weeks, before that it is a miscarriage)
(the fetus is dead before birth)
what is a perinatal death?
- includes stillbirths and all neonatal deaths
how common are neural tube defects?
1 per 1000 pregnancies
what are the 4 main types of neural tube defects?
- anencephaly (40%)
- spina bifida (40%)
- craniorachischisis (10%)
- encephalocele (10%)
what is anencephaly?
- neural tube defect where the cranial/rostral part of the neural tube fails to close during development, so the fetus develops without parts of the skull and brain
what is spina bifida?
- open = myelomeningocele = spinal cord and meninges push through opening in back in sac of fluid
- meningocele = when the meninges push out through the spine into a fluid filled sac but the spinal cord is usually fine
- closed = occulta = a small gap in the spine due to vertebrate not forming properly, but the spinal cord is usually fine
what is craniorachischisis?
- a neural tube defect
- combination of anencephaly (absence of brain and skull) and also continuing to the cervical region of the spinal cord
- absence of brain, skull, skin covering and the spine is open
what is exencephaly?
- a neural tube defect
- a sac-like protrusion of the brain and meninges through a gap in the skull
what is primary neurulation?
- neural folding and closure of the neural tube up to the S2 level
what is secondary neurulation?
the closure of the caudal end of the neural tube (canalisation)
what are the 3 closures steps of the neural tube?
closure 1 = the main middle. neural tube section closes from the middle outwards
closure 2 = the rostral/cranial neuropore closes
closure 3 = the caudal neuropore closes
what are the 2 ways neural tube defects can occur?
- failure of neural tube closure
- re-opening of a closed neural tube
describe the generation of anencephaly
- failed cranial/rostral neurulation/closure –> exencephaly (neural tissue survives but no skull or meninges to surround it/protect it) –> anencephaly (neural tissue degenerates after exposure to amniotic fluid)
what is the pathway needed for neurulation/closure of the neural tube?
- planar cell polarity (PCP) pathway
- needed for closure 1 of the neural tube
- a knockout of any if the genes involved can lead to a neural tube defect
- the pathway is involved in the cytoskeleton
what happens if there is a defect in the planar cell polarity pathway (PCP)?
- embryo will have no midline extension - will remain short and wide
- wider midline gap to close
- failure of closure 1 –> craniorachischisis
- due to mutation in the Vangl2 gene
what happens if there is a loop tail mutation in embryos?
- the midline of the neural tube is wider as the cells do not migrate where they should be
- angle of bending is not correct and thus struggle to bend and fold to close the neural tube
what are the genetic risk factors of neural tube defects?
- folate metabolism genes mutations
- PCP signaling pathway genes mutations
what are the non-genetic risk factors of neural tube defects?
- anticonvulsant medications like valproic acid and carbamezepine
- folate antagonists like fumonisin and trimethoprim
- associated with diabetes, obesity, hyperthermia, fever, retinoids, alcohol?
- deficiency of folate, vitamin B12, inositol, zinc
is folic acid deficiency genetic or non-genetic?
- both
- there needs to be a Splotch (PAX3) gene mutation combined with a folate deficiency to cause NTDs
what are the current UK recommendations to prevent neural tube defects?
- folic acid supplements of 0.4mg daily when trying to conceive (or in first 2 weeks after missed period)
- for high risk NTD women = 4-5mg of folic acid
what are the USA recommendations/measures in place to prevent neural tube defects?
- additional 0.1mg for everyone via food fortification (putting it into bread, rice and milk…)
- however, it can lead to an increased prevalence of twins (not allowed in the UK)
what percentage of neural tube defects are resistant to folic acid?
30%
what NTD genetic mutations are folate responsive?
- splotch, cart1, cited2
what NTD genetic mutations are folate resistant?
- curly rail, axial defects, ephrinA5
what could possibly help with folate resistance in preventing NTDs?
- giving women folate and inositol supplements at the same time
- decreased NTD occurrence in trial
