The Boy Missing an Entire Type of Brain Cell

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MRIs of the boy's brain
MRIs of the boy’s brain showed structural abnormalities.OOSTERHOF ET AL / AMERICAN JOURNAL OF HUMAN GENETICS

Even before he was born, it was clear that the boy’s brain was unusual—so much so that his expecting parents flew from rural Alaska to Seattle, where specialists could attend to their son from birth. That is how James Bennett first met the boy, then a days-old infant struggling to breathe. The baby’s head was too big. The structures in his brain looked wrong. Bennett, a pediatric geneticist at Seattle Children’s, was tasked with figuring out why.

The answer was ultimately stranger than doctors could have imagined: The boy’s brain was missing an entire type of cell, called microglia, the result of mutations in a single gene, called CSF1R. Doctors had never seen anything like it.

Microglia make up 10 percent of the brain’s cells, but they are not neurons and therefore have long been overlooked. The boy’s case makes their importance unmistakable. In the absence of microglia, the boy’s neurons still grew to fill his skull, but they ended up in the wrong places and made the wrong connections. Microglia, scientists have started to realize, guide the development of the brain.

“There wasn’t any part of the brain that wasn’t involved and affected in this child,” Bennett says. A part of the baby’s cerebellum jutted at an odd angle. His ventricles, normally small fluid-filled cavities in the brain, were too large. And a dense bundle of nerves that is supposed to connect the brain’s left and right hemispheres, called the corpus callosum, had entirely failed to develop.

In petri dishes and in animals, scientists had previously observed how microglia guide developing neurons to the right locations, creating the highly organized layers that make up the brain. They also prune connections between neurons. “Things get off track pretty quickly when you start manipulating the functions of microglia,” says Stephen Noctor, a developmental neurobiologist at the University of California at Davis who was not involved in examining the boy. To better understand the CSF1R gene, Bennett teamed up with zebra-fish biologists. In fish, turning off the gene disrupts a cellular pathway necessary for corpus-callosum neurons to grow in humans.

Kim Green, a neurobiologist at the University of California at Irvine, notes that mutant mice lacking microglia have broadly similar patterns of disorganization in their brains. These mice models essentially predicted what would happen in a human. Green had just never expected to see a person without microglia. “It’s absolutely remarkable,” he says.

The boy’s brain helped unlock these scientific mysteries. But he was ultimately still a boy, a very sick one with worried young parents. Their son’s condition was so severe, it turns out, because he had inherited two faulty copies of the CSF1R gene—one from each parent. His parents happened to carry the same rare mutation because they are cousins.

In adults, just one copy of a CSF1R mutation can lead to a brain disorder called adult-onset leukoencephalopathy with axonal spheroids and pigmented glia, which causes memory loss and eventually dementia beginning in one’s 40s. When the boy’s DNA-sequencing results came back, Bennett realized that he had to explain to the parents their own CSF1R mutation and their risks of developing the disorder. They were relieved, he says, to understand what was wrong with their child, but perhaps too overwhelmed to fully take in what it meant for their lives. The couple spoke with a genetic counselor before their son’s DNA sequencing, and Bennett says he arranged to have them meet with another genetic counselor back in Alaska, where they returned home.

This story has no miracle cure or happy ending. The boy died in Alaska at 10 months old of likely related causes, and Bennett says the family agreed to an autopsy. They have since lost touch. The phone numbers he has for them no longer work. He told me that he recently got hold of the mother’s sister, in an attempt to tell the family about the research made possible by their child. It’s a delicate balance: He feels a duty to inform, but he understands that the parents might not want to be reminded of their dead son.

A pediatric geneticist’s job, Bennett said, is often to diagnose extremely rare conditions, which push up against the limits of the human body. “On any day, you can find a patient you spend the rest of your career thinking about,” he said. The boy is one of them.

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