Ondine's Curse

Question 1

What happen if there is no phox2b neurones or they are dysfunctional ?

Answer 1

you suffer inadequate breathing

Question 2

What disease does ondines curse match?

Answer 2

CCHS- congenital central hypoventilation syndrome

she cursed her husband to have to stay awake to breathe as if he fell asleep he would forget to breathe and die

Question 3

What are the symptoms of CCHS?

Answer 3

usually presents with adequate breathing while you are awake and diminished respiratory effort while your sleeping and in extreme cases patients may require ventilation help while they sleep - life threatening hypoventilation during sleep
life-long disease
inability to appropriately adapt ventilation to environmental demands nor arouse from sleep in response to physiologic compromise
altered or absent perception of shortness of breath when awake
diminished tidal volumes and monotonous respiratory rates in both behaviour states
individual require a tracheostomy with mechanical ventilation during sleep and in severe cases additional mechanical ventilation or diaphragm pacing while awake

Question 4

What is the cause of CCHS?

Answer 4

mutations in the phox2b gene- causes substantial changes in cell functioning as phox2b is a transcription factor
mutation is an expansion = polyalanine repeat
- the more repeats the more disrupted the gene and the more severe the syndrome is

Question 5

How do ccRTN phox2b neurones act as chemoreceptors?

Answer 5

increase activity when inspired co2 or H+ increases
may be the central chemoreceptors
play an important role in respiration
express the RNA encoding the transcription factor phox2b

Question 6

Other than the RTN are phox2b cells expressed else where?

Answer 6

other cells around the brainstem express it

Question 7

What type of neurones are the phox2b-ir neurones of the RTN?

Answer 7

they are glutamatergic
identified as glutamatergic due to expression of vesicular glutamate transporter 2 which takes glutamate into vesicles
also showed that they didn’t express GAD67 so they are not GABAergic

Question 8

What 2 factors are expressed in other phox2b positive cells but not in ccRTN phox2b cells ?

Answer 8

phox2b is present within cholingeric (ChAT) and catecholaminergic (TH) cells
BUT the phox2b cells that are ccRTN cells dont contain these 2 markers and are present in the ventral medulla- restricted cells

Question 9

What was demonstrated about phox2b expression in rodents ?

Answer 9

in the medulla/pons there are other phox2b cells including those in the NTS that are involved in autonomic and respiratory control

Question 10

What is not present in phox2b mutant mice?

Answer 10

ccRTN cells are absent
these mice had the same mutation as ondines curse, 27 alanine repeat
demonstrated that it was only the ccRTN phox2b cells that were missing not all the phox2b cells due to the transgenic mice model

Question 11

What was seen in the phox2b 27ala/+mice ?

Answer 11

using plethysmography - the mutants dont breathe as regularly or respond to hypercapnia compared to wt
the mutants also suffer from more apnoea- periods with no breathing in a 5 mine period of recording
mice die neonatally - humans with this mutation dont die neonatally so it may not be an exact model for human but it helps to determine whats wrong with humans

Question 12

In the phox2b 27ala/+mice what was shown about the activity in the when visualised by fluorescence calcium imaging ?

Answer 12

there was limited respiration and not much rhythmicity of calcium levels in the RTN whereas in the WT there was rhythmic fluorescence changes

Question 13

What cell types seem to be normal in phox2b mutant mice?

Answer 13

pre-BotC and 5ht cells

Question 14

How did they record how CCHS patients breathe when they are awake ?

Answer 14

they used surface scalp electroencephalographic signal recordings with a 12 electrode cap
averaged tracings examined for the presence of an inspiratory premotor activity in the form of a slow upward shift of the EEG signal starting between 2 and 0.5s before inspiration- pre-inspiratory potential
it demonstrated signals within the supplementary motor cortex

Question 15

Why might humans not die neonatally from a phox2b mutation yet mice do ?

Answer 15

because humans have higher cortical control and therefore they can tell themselves to breathe
people with CCHS teach themselves to breathe without conscious thought

Question 16

What was the difference seen between control patients and CCHS patients when looking at their EEG recordings in different states?

Answer 16

in control subjects, normal breathing and even when carbon dioxide stimulated breathing there is no activity within the supplementary motor cortex, there is only activity within this area when you tell the people to think about breathing
conversely
in CCHS patients there is activity in the supplementary motor cortex just before inspiration under normal conditions and when you tell them to think about breathing their recordings are similar to the control group because they are always thinking about breathing

Question 17

What is the theory of breathing during an awake state and why are CCHS patients able to breathe during this state?

Answer 17

in awake state RTN receives central command but so does the rest of respiratory central pattern generator therefore RTN only supplies little fraction of drive
subsequently if no RTN is present like with CCHS then they can still breathe in this state as the rest of the CPG is receiving central commands

Question 18

What is the theory of breathing during sleep state and why are CCHS patients unable to breathe during this state?

Answer 18

in sleep the central command for breathing is missing so therefore breathing driven by co2 is via the RTN
if no RTN like CCHS patients then breathing is not possible - no cortical function telling you to breathe

Question 19

What surprise discovery was seen in a CCHS patient ?

Answer 19

in 2006 looked at patients breathing during increased co2 and there was no response, she required ventilation when she slept
when her breathing was looked at again in 2009 in same conditions the ventilation had increased
HOW had this process corrected its breathing ???
the only thing that had changed was the fact the woman had started taking desogesterol, a progesterone agonist
it is now under clinical trial