Quirks & Quarks

Learning from tragedy: Researchers crack medical mystery behind baby's lack of critical brain cells

Dr. James Bennett and other scientists undertook a "diagnostic odyssey" to identify the cause of an extremely rare condition that cut an infant's life tragically short.

'I don't think we should forget how much can be learned just from a single patient with a rare disease'

The MRIs of the baby's brain when he was two days old showed structural abnormalities. (Oosterhof et al/American Journal of Human Genetics/Cell Press )
Listen7:46

Originally published on May 18, 2019.

From the moment he was born, the baby boy needed a lot of medical support. He had an enlarged head and some very significant brain abnormalities.

"Every single part of his brain was affected," said Dr. James Bennett, a physician and researcher from Seattle Children's Hospital, who saw the infant the day he was born. "There was no connection between the left side and the right side of his brain."

And he said there was too much fluid on the child's brain — that the spaces holding fluid around the brain were enlarged. And the white matter — the part of the brain that connects the neurons — was decreased and abnormal.

The child lived only 10 months, but he left behind an invaluable legacy in his short life by helping scientists like Bennett understand a crucial type of brain cell that he didn't have.

Bennett had never seen a medical mystery like this before, so he was determined to figure out what was wrong with the infant. He and other scientists undertook a "diagnostic odyssey" to identify the cause of this extremely rare condition.

"One of the things about being a pediatric geneticist is on any given day you can see a patient you could spend the rest of your life or your career thinking about," Bennett, who is also an assistant professor of pediatric genetics at the University of Washington told Quirks & Quarks host Bob McDonald.

The results of this undertaking were recently published in the American Journal of Human Genetics.

The baby's name and date of death were not released in the interest of patient confidentiality.

The child's diagnosis

Bennett performed a technique called exome genetic sequencing on the infant's DNA to look for mutations that could help explain the baby's condition. He found a mutation in both copies of a specific gene that he thought could be the culprit.

"What was interesting is that mutations in this gene had been previously associated with an adult onset neurodegenerative condition that occurs in your 40s or your 50s," said Bennett.

The condition typically arises when there's only one mutation in a single copy of the gene. This infant had a mutation in both of his copies of the gene.

If you only have one mutation, maybe you could get an adult onset disease, but if you had two mutations in the gene, you can get a more severe early onset pediatric, even prenatal onset of disease.- Dr. James Bennett, Seattle Children's Hospital and the University of Washington

"If you only have one mutation, maybe you could get an adult onset disease," said Bennett, "but if you had two mutations in the gene, you can get a more severe early onset pediatric, even prenatal onset of disease."

The gene, known as CSF1R, was previously thought to be responsible for the maintenance and production of a cell type known as macrophages that give rise to other types of cells. One was microglia, a type of cell previously thought to only be involved in the brain's immune system. 

"You know, it was a little bit uncertain at the time when we first found this result if this was truly the child's diagnosis or not, but I felt confident about it because it really explained many aspects of his disease," added Bennett.

New understanding of microglia's role in brain development

After the infant died, his parents allowed Bennett and his team to perform an autopsy of his brain. That's when they saw the definitive clue.

"When we looked in the brain, we found that there was essentially no microglia. And to my knowledge, a human brain without microglia had never been described or reported before."

This definitely shows, I think, that when you start off life without microglia, you get widespread congenital brain malformations.- Bennett

In the last five to 10 years, scientific evidence has been mounting — especially in studies in animals — that microglia might be playing more of a role in the brain than simply as part of the immune system.

"This definitely shows, I think, that when you start off life without microglia, you get widespread congenital brain malformations," said Bennett.

"I think it provides some of the most definitive evidence that in a human, microglia are required for proper brain development."

Microglia helping build neural wiring in brain

To figure out how the microglia cells may be impacting brain development, Bennett turned to an expert in microglial biology in the Netherlands who developed zebrafish with no microglia. This is how they were able to identify a protein that was significantly altered in the zebrafish brains.

I don't think we should forget how much can be learned from just a single patient with a rare disease. This is an example of that.- Bennett

"What was really cool was we were able to take that sort of basic science discovery and then go back to the brain of our patient and show that, indeed, our patient also had decreased levels of this protein," said Bennett.

"What's very interesting about that is that the neurons that express this protein really do send out wires to other parts of the brain," which Bennett thinks is why "this child had decreased amount of wires … in his brain, meaning decreased amounts of white matter and a failure of the connection between the left and right side of the brain."

"I don't think we should forget how much can be learned from just a single patient with a rare disease. This is an example of that." 

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