SIDS

Question 1

Possible causes

Answer 1

1. Immunological polymorphisms > inflammatory response different to normal under infection can cause death (?)
2. Autonomic disorders > Structural and neurotransmitter changes in brain stem
3. Metabolic disorders > Abnormalities in liver, changes growth velocity, abnormalities in fatty acid oxidation pathways (all examples)
4. Cardiac ion channel mutations > 1st proposed in 1976

Question 2

Definition of SIDS

Answer 2

Sudden death that is unexpected by previous history. Postmortem examination of the infant fails to show an adequate cause of death. (First defined in 1969)

Happens in infants younger than 1 year during sleep. It accounts for around 2.5k deaths per year in the USA and is the 3rd most common cause of infant death.

Question 3

Risk factors of SIDS

Answer 3

• Male > Incidence in higher compared to female, unsure why
• 2-4 months old > when most occur
• Born prematurely
• Low birth weight
• Low socioeconomic status
• Low parental educational status
• Drug users as parents
• Winter > cold temperatures
• Smoke exposure > any smoke residue on clothes, smoking in presence etc
• Prone position > put to sleep on TUMMIES rather than BACKS
• Overheating
• Mild viral infection
  + More

Question 4

“Back to Sleep” Campaign

Answer 4

-Pattern observed when parents put infants to sleep in prone position > campaign to rectify
- Statement made in 1992, and then campaign in 1994
- 1.4 deaths per 1000 lives before campaign, to down to 0.55-0.56 per 1000
- Data extracted from lullaby trust

Question 5

Cardiac function with SIDS - A Norweigan Study on ECG and QTc

Answer 5

• Recorded ECGs in newborns up to a year old, 34442 were studied.
• 33,034 completed the study
• 34 of the infants died, and 24 of these were SIDS, occuring at 2nd to 3rd month of life.

Findings: ECGs gathered through the study and gathered QTc signal (QT interval of cardiac cycle)
NORMAL vs SIDS vs NON-SIDS
- Heart rate was similar throughout
- QTc differed. SIDS has 435 +-45 msec. The QTc for normal was 400+-20. 2 standard deviations away from WT (440) shows that SIDS infants have an average outside/ close to the maximum the WT range.
- Data from an infant that died of SIDS compared to one that died of known causes shows that QTc signal was significantly higher than 440 > a lot of them had long QT syndrome (50%, 12 of 24 deaths)

Question 6

SCN5A

Answer 6

From the 201 SIDS cases study into mutations, SCN5A was studied. 8 mutations were studied in SCN5A

• No specific pattern of where mutation is
• Overexpressed WT and mutants in cells to study currents
• No major difference/ CoF phenotypes, only subtle changes. Currents arent significantly different.
  HOWEVER they were SUBTLE so still there > realised that these were sufficient to impact cardiomyocytes hence function of the heart, leading to long QT syndrome.
• Inactivation was impacted slightly enough to impact heart function.

Question 7

Cardiac genetics and SIDS - A Norweigan study

Answer 7

• 201 SIDS studied compared to WT
• Looked at genetic profiles of those that died to see genetic variants > Mutations not in controls, rare variants found in less than 0.7% controls and common variants found in more than 8% controls. Common variants not to be thought of interest.

-Epidemiology also studied compared to SIDS death, mutants and those that didnt have mutations. Epidemiology is not different between the mutant versus non-mutant cases. > Risk factors are similar despite if they have the mutations for the cardiac system etc.

• 12.9% of the cases had mutations or rare variants. 9.5% (19/201) had a mutation which are known to have an impact on the ion channels in the heart. (ost common -13 individuals with Nav mutation)

Question 8

Mutations for time constant fast inactivation

Answer 8

FASTER INACTIVATION:
- S216L, delAL536-587, R680H, T1304M, V1951L
NORMAL:
- P2006A
SLOWER INACTIVATION:
- F1486L, F2004L

*How fast is inactivation? > is it the same rate, gathered from time constant data
* How much? > Is it complete? It might be fast, but it wont be as much as WT; faster inactivation mutations have LESS inactivation leading to prolonged QT > Persistent currents

Question 9

Persistent currents in scn5a

Answer 9

• Studying the end of the recording to see how much inactivation
• Amount of inactivation in all mutations vary BUT theyre all lower than WT. Sufficient to delay depolarisation leading to long QT
• Some able to get to steady state faster BUT amount of current is still higher than WT > membrane potential has to depolarise a little more to initiate same amount of inactivation hence the delay
• All hav a faster recovery from inactivation > activated to inactivated and reprime after inactivation much faster than WT, allowing for quicker timing for signals to fire, leading to innappropriate signals passing through.

Question 10

R680H and HYPOXIA

Answer 10

Inactivates faster but does not show persistent current in normal experimental conditions
- In presence of IC acidosis, it does have a persistent current.
- In acidosis, 0.62 current is left in WT (as consequence to acidosis), but its 1.41 left with R608H (fractional data)
- Links with HYPOXIA > cells go into anaerobic respiration due to lack of oxygen, lactic acidosis in cells, predispose those w this mutation to die.