By the time her mother received the doctor’s email, Yuna Lee
was already 2 years old, a child with a frightening medical mystery. Plagued
with body-rattling seizures and inconsolable crying, she could not speak, walk
or stand.
“Why is she suffering so much?” her mother, Soo-Kyung Lee,
anguished. Brain scans, genetic tests and neurological exams yielded no
answers. But when an email popped up suggesting that Yuna might have a mutation
on a gene called FOXG1, Soo-Kyung froze.
“I knew,” she said, “what that gene was.”
Almost no one else in the world would have had any idea. But
Soo-Kyung is a specialist in the genetics of the brain—“a star,” said Robert
Riddle, a program director in neurogenetics at the National Institute of
Neurological Disorders and Stroke. For years, Soo-Kyung, a developmental
biologist at Oregon Health and Science University, had worked with the FOX
family of genes.
“I knew how critical FOXG1 is for brain development,” she
said.
She also knew harmful FOXG1 mutations are exceedingly rare
and usually not inherited — the gene mutates spontaneously during pregnancy.
Only about 300 people worldwide are known to have FOXG1 syndrome, a condition
designated a separate disorder relatively recently. The odds her own daughter
would have it were infinitesimal.
“It is an astounding story,” Dr. Riddle said. “A basic
researcher working on something that might help humanity, and it turns out it
directly affects her child.”
Suddenly, Soo-Kyung, 42, and her husband Jae Lee, 57,
another genetics specialist at O.H.S.U., had to transform from dispassionate
scientists into parents of a patient, desperate for answers…
Balancing the missions of science and motherhood, Soo-Kyung
has begun doing what she is uniquely positioned to do: aiming her research
squarely at her daughter’s disorder. With Jae’s help, she is studying how the
FOXG1 gene works and why mutations like Yuna’s are so devastating.
“Our ultimate goal is to find a better treatment for FOXG1
syndrome patients,” she said. Her day-to-day goal is helping Yuna make slivers
of developmental progress.
Yuna is now a sweet-natured 8-year-old still wearing a toddler’s
onesie over a diaper. “Cognitively she’s about 18 months,” Jae, her father,
said.
A major achievement would be getting Yuna to indicate when
her diaper is wet. Or to stand when they prop her against a kitchen corner and
remove their hands for a split second. “If Yuna doesn’t fall down right away,”
Soo-Kyung said, “we consider that a success.”…
When their daughter was born in Houston in January 2010,
southeast Texas experienced a rare snowfall. It inspired the Lees, then
professors at Baylor College of Medicine, to name her “Yuna,” meaning “snow
girl” in a Korean dialect, with the middle name “Heidi” for its allusion to
snowy peaks.
“She was perfectly normal,” Jae said. “We were joking, ‘What
will come later?’ Yuna’s mom is a very smart person, so we thought, ‘Well, she
will make the world better.’”
But soon, things seemed off. Yuna often failed to respond to
sounds. She struggled to swallow milk from breast or bottle. What she did
swallow she vomited. “She looked like someone with malnutrition,” Soo-Kyung
said.
A doctor said her head circumference was not growing enough.
Then Yuna began having seizures , often sending the Lees to the emergency room.
She cried so persistently that Soo-Kyung had to assure neighbors Yuna was not
being abused.
“What did I do wrong?” Soo-Kyung grilled herself. Had she
eaten something while pregnant that infected Yuna? “I was traveling a lot
during the pregnancy to attend seminars — was I too stressed?”…
Shortly after Yuna’s second birthday, Soo-Kyung traveled to
Washington, D.C. to serve on a National Institutes of Health panel reviewing
grant proposals from brain development researchers. At dinner, she found
herself next to Dr. David Rowitch, a respected neonatologist and neuroscientist
she knew only by reputation.
“She started to tell me what’s going on with her daughter,”
recalled Dr. Rowitch, professor and head of pediatrics at the University of
Cambridge who was then at the University of California San Francisco. He was
stumped but offered to send Yuna’s brain scans to “the world’s expert” in
neuroradiology: Dr. Jim Barkovich at U.C.S.F.
Dr. Barkovich said Yuna’s scans revealed “a very unusual
pattern,” one he had not seen in decades of evaluating brain images sent to him
from around the world. Yuna’s cerebral cortex had abnormal white matter,
meaning “there were probably cells dying,” he said, and the corpus callosum,
the corridor across which cells in the left and right hemispheres communicate,
was “way too thin.”
Searching scientific literature, he said, “I found a gene
that seemed to be expressed in that area
and found that when it was mutated it caused a very similar pattern.” That gene
was FOXG1.
FOXG1 is so crucial that its original name was “Brain Factor
1,” said Dr. William Dobyns, a professor of pediatrics and neurology at
University of Washington, who published a 2011 study recommending a separate
diagnosis: FOXG1 syndrome. “It’s one of the most important genes in brain
development.”
FOXG1 provides blueprints for a protein that helps other
genes switch on or off. It helps with three vital fetal brain stages:
delineating the top and bottom regions, adjusting the number of nerve cells
produced and “setting up the organization of the entire cortex,” Dr. Dobyns
said.
So, when Dr. Barkovich’s email said he “would not be
surprised if this is a FOXG1 mutation,” Soo-Kyung’s heart shuddered. “That’s
unthinkable,” she despaired.
Yuna’s neurologist declined to authorize FOXG1 gene
analysis, considering the possibility improbable — and irrelevant because it
would not change Yuna’s treatment, Soo-Kyung said. So she decided to sequence
the gene herself, preparing to seek university permission since her lab only
worked with animals. Then, she became pregnant again. That provided
justification for professional analysis of Yuna’s gene to determine if there
was a heritable mutation the Lees could have also transmitted to their second
child.
When results showed a FOXG1 mutation, Soo-Kyung requested
the raw data, hoping the lab had messed up. But scanning the data, Soo-Kyung
spotted the problem instantly: Yuna was missing one nucleotide, Number 256 in
the 86th amino acid of one copy of FOXG1, which has 489 amino acids…
Long before Yuna was born, Soo-Kyung stumbled upon research
she found fascinating, showing that mice missing both FOXG1 genes did not form
brains. That would apply to humans, too. “There’s nobody who is missing two
copies of the gene,” said Dr. Riddle of the National Institute of Neurological
Disorders and Stroke. “They don’t survive.”
Soo-Kyung told Jae she wanted to someday study how FOXG1
drives brain development. “Then Yuna arrived,” Jae said.
Now, studying mouse brains, the Lees have identified genes
that interact with FOXG1, helping explain why one crippled copy of FOXG1
damages the corpus callosum’s ability to transmit signals between hemispheres.
“We now understand how this gene works and why,” Soo-Kyung
said.
Many mysteries remain. Individual FOXG1 mutations affect
gene function differently, so one FOXG1 patient’s symptoms can vary from
another’s. For example, Charles A. Nelson III, an expert in child development
and neurodevelopmental disorders at Boston Children’s Hospital and Harvard
Medical School, evaluated two 10-year-old patients with mutations in different
locations and markedly distinct levels of impairment.
Since patients like Yuna, with one dysfunctional and one
functional FOXG1 gene, produce half the necessary FOXG1 protein, Soo-Kyung
wonders if gene therapy could restore some protein or boost protein activity in
the good gene.
But because FOXG1 is crucial so early in development, Dr.
Rowitch said, “I don’t think you can just go back when the baby’s born and
build the brain back up.”
https://www.nytimes.com/2018/04/23/health/genes-mutation-foxg1-brain.html
Courtesy of a colleague
See: http://childnervoussystem.blogspot.com/2017/11/foxg1-syndrome.html