SIDS

Question 1

name 8 risk factors of sudden infant death sydrome

Answer 1

1. low birth weight
2. premature birth
3. male
4. 2-4 months old
5. mild viral infection
6. overheating
7. prone position (sleeping on front)
8. ante-natal drug use

Question 2

highlight 4 possible causes of SIDS

Answer 2

1. immunological polymorphisms (leads to altered inflammatory response)
2. autonomic disorders (structural and neutoransmitter chanhes in the brain stem. such as higher concentrations of NA and DA in peripheral chemoreceptors, making them more sensitive to neurotransmitter release in response to hypoxia)
3. metabolic disorders (liver abnormalities, changes in growth velocity, and abnormalities in fatty acid oxidation)
4. cardiac ion channel mutations

Question 3

1. in a study involving taking ECGs of newborns up to one year old, how many deaths were there? How many deaths were categorised as SIDS?
2. what was the normal QTc measured as?
3. what was the non-SIDS death QTc measured as?
4. what was the SIDS death QTc measured as?
5. what was shown by looking at the spread of data?
6. what do these values indicate?

Answer 3

1. 36 deaths in total. 24 were SIDS
2. 400±200msecs
3. 393±24msecs (not sigificantly different from normal)
4. 435±45msecs (2 SDs away from mean (440) therefore this is significantly higher than normal
5. a high proportion of babies that died from SIDS had a long QTc. (12 of 24 had a QTc >440msecs)
6. SIDS may be an LQTS

Question 4

1. how were genetic defects in SIDS patients identified?
2. how many mutations found in SIDS babies were also found in controls?
3. how many rare genetic varients found in SIDS babies were also found in controls?
4. how many common genetic varients found in SIDS babies were also found in controls?
5. How many of these mutations and rare varients were found to be related to LQT?
6. Name 5 channels that these mutatins were found in.

Answer 4

1. blind molecular screening of cases of death (140 SIDS, 69 borderline and 45 non-SIDS)
2. none
3. <0.7%
4. 8%
5. 12.9%
6. SCN5A, KCNQ1, KCNH2, CAV3 and KCNE1

Question 5

1. where are mutations in SCN5A found?
2. what are the majority of mutations assocated with?
3. how were the effects of the mutations on channel function studied?
4. name 2 mutants that had increased currents
5. name 2 mutants that displayed slower fast inactivation
6. name 3 mutants that displayed faster fast inactivation but increased persistent currents. What other defect did these mutants display?
7. how do persistent currents produce LQT?
8. overall, how does delayed inactivation result in LQT?

Answer 5

1. throught the protein: in the S4 domain, IC and EC loops and c terminus
2. defective fast inactivation or increased persistent currents
3. by expressing WT or mutant SCN5A, and taking whole cell patch clamp recordings; analysed fast inactivation; measured TTX sensitive persistent currents as a percentage of peak Na current
4. delAL586-587 and V1951L
5. F1489L and F2004L
6. S126L, R608H and T1304. Also had shifts in Vdep of inactivation
7. because inactivation of the channels was faster but not 100%, channels produce persistent currents iuntil inactivation is complete. Because channels are open for longer, repolarisation is delayed
8. delayed inactivation = delayed repolarisation

Question 6

1. what type of channels does KCNJ8 encode?
2. name 2 mutations in these channels that were identified in SIDS cases
3. where do these mutations lie?
4. what is the effect of the mutations on channel function.

Answer 6

1. Kir6.1, an ATP sensitive channel that helps the heart cope with metabolic stress
2. delE332 and V346I
3. C terminus
4. smaller I_k (LOF)

Question 7

1. how is premature birth associated with hypoxia?
2. how is the prone position associated with hypoxia?
3. how are mild viral infections associated with hypoxia?
4. give a piece of evidence from newborn mice that is associated with LQT
5. how may hypoxia lead to SIDS?

Answer 7

1. premature babies don’t produce surfactant. Surfactant helps the lunfgs to inflate, and to keep some air in the dead space. premature babies therefore have difficulty inflating their lungs ad exhale all air, making hypoxia a common occurance
2. the position of the baby means that the lungs can’t be inflated to their full capacity
3. makes breathing harder
4. under conditions of hypoxia, newborn mice had lower heart rates and longer QTC
5. the combo of the ion channel mutation and hypoxia may increase QTc to such an extent that it causes SIDS