012 understanding and preventing neural tube defects

Question 1

what is a stillbirth?

Answer 1

death at the end of pregnancy (after 24 weeks, before that it is a miscarriage)
(the fetus is dead before birth)

Question 2

what is a perinatal death?

Answer 2

• includes stillbirths and all neonatal deaths

Question 3

how common are neural tube defects?

Answer 3

1 per 1000 pregnancies

Question 4

what are the 4 main types of neural tube defects?

Answer 4

• anencephaly (40%)
• spina bifida (40%)
• craniorachischisis (10%)
• encephalocele (10%)

Question 5

what is anencephaly?

Answer 5

• 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

Question 6

what is spina bifida?

Answer 6

• 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

Question 7

what is craniorachischisis?

Answer 7

• 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

Question 8

what is exencephaly?

Answer 8

• a neural tube defect
• a sac-like protrusion of the brain and meninges through a gap in the skull

Question 9

what is primary neurulation?

Answer 9

• neural folding and closure of the neural tube up to the S2 level

Question 10

what is secondary neurulation?

Answer 10

the closure of the caudal end of the neural tube (canalisation)

Question 11

what are the 3 closures steps of the neural tube?

Answer 11

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

Question 12

what are the 2 ways neural tube defects can occur?

Answer 12

• failure of neural tube closure
• re-opening of a closed neural tube

Question 13

describe the generation of anencephaly

Answer 13

• 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)

Question 14

what is the pathway needed for neurulation/closure of the neural tube?

Answer 14

• 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

Question 15

what happens if there is a defect in the planar cell polarity pathway (PCP)?

Answer 15

• 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

Question 16

what happens if there is a loop tail mutation in embryos?

Answer 16

• 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

Question 17

what are the genetic risk factors of neural tube defects?

Answer 17

• folate metabolism genes mutations
• PCP signaling pathway genes mutations

Question 18

what are the non-genetic risk factors of neural tube defects?

Answer 18

• 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

Question 19

is folic acid deficiency genetic or non-genetic?

Answer 19

• both
• there needs to be a Splotch (PAX3) gene mutation combined with a folate deficiency to cause NTDs

Question 20

what are the current UK recommendations to prevent neural tube defects?

Answer 20

• 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

Question 21

what are the USA recommendations/measures in place to prevent neural tube defects?

Answer 21

• 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)

Question 22

what percentage of neural tube defects are resistant to folic acid?

Answer 22

30%

Question 23

what NTD genetic mutations are folate responsive?

Answer 23

• splotch, cart1, cited2

Question 24

what NTD genetic mutations are folate resistant?

Answer 24

• curly rail, axial defects, ephrinA5

Question 25

what could possibly help with folate resistance in preventing NTDs?

Answer 25

• giving women folate and inositol supplements at the same time
• decreased NTD occurrence in trial