Teacher Amy McTighe goes through the “cable classroom” with Hayley Mogul, 15, at The Children’s Institute in Squirrel Hill. Hayley’s parents have donated their two daughters’ cells to science so researchers can rewind cellular development to see what caused their genetic mutations. The ultimate goal is treatment and prevention.
By David Templeton / Pittsburgh Post-Gazette
As siblings, Hayley and Bari Mogul share biological characteristics.
Unfortunately one that they share is a rare metabolic disorder that causes dangerously low blood sugar whenever they get ill or stressed out.
But, as also happens, the siblings have differences.
Rare gene mutations affect sisters
Chicago-area sisters Hayley and Bari Mogul are undergoing therapy at The Children's Institute while researchers study their gene mutations with hope of eventual treatment for others. (Video by Nate Guidry; 12/28/2013)
So along with a shared metabolic disorder, Hayley, 15, has a mutation of the RAI1 gene resulting in the Smith-Magenis syndrome with its characteristic effects -- obesity, a sleep disorder and behavioral problems. Bari, 9, has a mutation in her GRIN2B gene, causing neurological and development problems in the autism spectrum.
Since Nov. 4, the girls have been receiving specialized therapy at The Children's Institute in Squirrel Hill while their parents -- Robyn, 47, and Steven, 45 -- are being trained to continue the therapies once the family returns home next Saturday to Northbrook, Ill.
But the story goes beyond the impacts on the girls and their parents.
The Moguls have donated their daughters' cells to science so researchers can rewind cellular development to the embryo stage to see what caused the gene mutations and at what point in cell development. The ultimate goal is treatment and prevention.
"Bari and Hayley are two of the rarest kids known to mankind," Mr. Mogul said. "They have an underlying metabolic disorder that only two others in the world share."
Adding to the rarity, he said, Hayley's mutation of RAI1 and Bari's mutation of GRIN2B each are shared by only about 20 others. His daughters likely won't benefit from the studies of their cells.
"What we're generally hoping for is something much larger," he said. "I think the girls' conditions are so rare that they can really offer something huge. This is for the betterment of people with rare diseases and the advancement of humankind."
When Hayley got the flu at 16 months old, she fell unconscious, her eyes rolling in her head. Doctors were surprised to learn that her blood-sugar levels had dropped nearly to zero, with no explanation why.
At Children's Memorial Hospital in Chicago (now Lurie Children's Hospital), clinical geneticist Barbara Burton began investigating the medical mystery and why Hayley was obese with low muscle tone, behavior problems and delays in development.
Medical tests and biopsies failed to reveal the cause. Suspecting a genetic disorder, Dr. Burton said she warned the Moguls they faced a one-in-four chance that their second child would share the disorder.
Even though they had a mere 6 percent chance of having two children with the unexplained metabolic condition, Bari also was born with the metabolic condition -- along with her own set of unexplained problems.
"They hit it both times," Dr. Burton said. "They are a very unlucky family."
Working on the metabolic problem, Dr. Burton sent the girls to Duke University, Washington University in St. Louis, the University of Chicago and University Hospitals Case Medical Centers in Cleveland. She also sent biopsy tissue and blood samples to France for evaluation without success.
All known causes of low blood sugar were checked off the list, including glycogen-storage disease in the liver.
In 2008, Dr. Burton gave a speech in California about the Mogul medical mystery. That's where she learned about the NIH's relatively new undiagnosed diseases program, which accepted the girls for evaluation. There they sequenced each girl's "exome" -- a small portion of the human genome where the majority of disease-causing gene mutations occur. The exomes solved the mystery.
The shared metabolic disorder involves two mutations in the gene associated with glucose (or blood sugar) metabolism. The exome also revealed Hayley had Smith-Magenis syndrome, a developmental disorder that causes obesity, production of sleep-inducing melatonin during the day rather than night, and behavior issues. The syndrome affects one in 25,000 people, but her type of RAI1 mutation is extremely rare.
Due to the GRIN2B mutation, Bari's development is slower than her sister's. She doesn't speak and can't eat normally.
Everyone faces the risk of genetic mutations.
"In making eggs and sperm, the DNA have to replicate themselves, and it's not a perfect process," Dr. Burton said. "Accidents can occur and mutations are the basis of evolution. But most are deleterious, so you get mutations that cause disorders, and each girl got a different one."
Understanding the process of how gene mutations lead to specific problems is key to prevention and medical interventions. "If the genes are producing a harmful product, maybe we can turn it off as a solution," Dr. Burton said. "We hope to learn what goes on when the normal process is disrupted."
Prior to Nov. 4, no therapies existed for Hayley.
But an NIH official referred the Moguls to The Children's Institute, home of the nation's only therapeutic program for children with the Prader-Willi syndrome. The institute customized that program for Hayley, and with such success that the Moguls anticipate she may return to school after a 21/2-year lapse in education.
Conveniently for the Moguls, the institute also offers a feeding-disorder program, which has weaned Bari off a baby bottle and baby food in favor of a cup and pureed adult food. Her compulsive interest in "Sound of Music" songs, especially "Do-Re-Mi," also makes her responsive to music therapy. Bari has been on a bicycle for the first time and now is babbling, possibly indicating attempts to speak.
"There has been a big difference in the girls," Ms. Mogul said. "They really needed help, and [The Children's Institute] was the way to get help for both of them."
Robyn and Steven Mogul represent another remarkable part of the story, Dr. Burton said, noting their willingness "to go the distance to figure out" what's affecting their daughters.
They care for their daughters day and night. Hayley is incontinent and Bari isn't yet potty trained. Hayley being awake throughout the night disrupts her parents' sleep. Both ambulatory, Hayley and Bari require round-the-clock care and supervision.
"It's been a long journey with them. It really has been. Wow," Dr. Burton said. "But they always have a smile on their faces. You never hear them complaining, and they do it with such grace and with such a good attitude that it is just unbelievable. I don't know how they do it day after day."
Working temporarily in a Pittsburgh office of his employer, UBS Financial Services, Mr. Mogul said his daughters have made notable progress but the odyssey continues. As long as the family remains together, "we are fine."
"It makes you figure out real quick what's important in life," he said. "There's no question about it, you can replace a lot of things in life -- money, the house, the car. But you can't replace a family."
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