Tiny patient prompts advance in neurogenetics.

The medical community knows that a tiny group of cells in the brain stem tells humans when to breathe. These cells can sense the buildup of carbon dioxide in the blood, thanks in part to a protein called connexin. Carbon dioxide latches onto connexin, which then spurs cells to signal when it’s time to breathe. Neurons fire, the diaphragm moves down, and the person inhales.

Babies start breathing in the womb, inhaling and exhaling irregularly at first, and then gradually more and more, until the day when they’re born and have to do it all the time. But premature babies sometimes have trouble. They stop breathing periodically, sometimes for 20 or 30 seconds at a time. Sometimes they’re fine, and sometimes they’re not, and doctors struggle to help them.

That may soon change, however, due to a two-month-old patient at UConn Health with a rare connexin mutation.

The patient was just two months old, deaf, blind, and covered in thick, leathery, cracked skin. The baby presented with disordered breathing that left the patient’s oxygen levels too low. The two-month old patient had been referred to UConn Health for his skin condition, but neonatal researchers were concerned by the baby’s breathing troubles. Premature babies often have trouble breathing, but two-month-olds rarely do.

The team began searching for information about the baby’s mutation, which was at a spot on the genome called connexin26. Related mutations are known to result in deafness, blindness, or skin trouble. But no one had ever reported disordered breathing, at least not in humans. The group had looked at just this type of mutation-related breathing disruption in rats in past studies and hoped this past study might help find a therapy for the patient.

The researchers knew that a common connexin mutation blocked expression of the protein altogether. Having one copy of that mutation is a common cause of inherited deafness; having two copies is lethal in utero. But the patient had one normal copy, and one connexin26 mutation. So what was causing the patient’s health problems?

The team expressed the connexin26 mutation in human astrocytes. Astrocytes are the most abundant cells in the brain and do many things, including signalling to neurons. The current study found that astrocytes with the connexin26 mutation couldn’t bind to carbon dioxide. This specific connexin mutation was dominant, and suppressed expression of the normal protein. Such mutant cells were oblivious to dangerously high carbon dioxide levels, and this almost certainly explained the baby’s disordered breathing. It was also the first time a direct link between the connexin channel, carbon dioxide, and respiration had been shown in humans.

While the team were looking at the mutation’s effect on human cells they began to review recordings of the breathing patterns of the patient, trying to see if there was anything that could give advance warning of a bad breathing episode. There’s not much in the medical literature about the breathing patterns of newborn infants, and the researchers began to wonder if they were even looking at the right things.

The group began carefully sifting the data, looking at records of normal breathing, of bad breathing, and most importantly at the recordings taken minutes before the start of a bad breathing episode, searching for subtle differences that could serve as warning signs.

What the team has found so far has been suggestive. The team state that healthy breathing rhythms are similar to healthy heartbeats. Both of them have slight blips and variations here and there. Heart rhythms have been studied extensively, and cardiologists know that if a heart starts to beat too simplistically regularly, a heart attack is likely in the coming hours. The team is gathering recordings of many more premature infants and developing an algorithm that should eventually be able to pinpoint when a baby’s breathing pattern goes awry.

Sadly, the findings couldn’t help this tiny patient, but the researchers hope their early warning system will be able to save other infants, alerting health care providers to dangerous breathing patterns before a baby gets into serious trouble.  As well as linking the genetics of the brain to manifested irregular respiration.

Source:  University of Connecticut