She’s one of a kind

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Seven months pregnant with her first child, Kelly Berthoud’s world began to shatter.

“I developed polyhydramnios, which is too much amniotic fluid,” the Mattawan, Michigan, resident said. “They did a bunch of testing and extra ultrasounds, but nothing was identified as being abnormal. We had to wait it out and see.”

On March 13, 2015, baby Marlene arrived. But not in the way Berthoud and her husband, Bryan, had expected.

“There were definitely some neurological deficits,” Berthoud said. “She couldn’t regulate her temperature or blood sugar. She was on oxygen. They did an MRI.”

Marley was whisked off to the neonatal intensive care unit at a hospital in the Kalamazoo area.

Doctors determined she had suffered a significant brain hemorrhage in utero, which kept her from developing the suck and swallow reflex that circulates amniotic fluid.

A neurologist visited the Berthouds in the NICU.

“She thought this was all very strange—a healthy mom, a healthy pregnancy—she said this type of hemorrhage doesn’t just happen,” Berthoud said.

Baby Marley underwent test after test to determine what caused the brain hemorrhage, but no answers. At just a few weeks old, her hair fell out and doctors determined she suffered from hearing loss.

By the time she was 6 months old, still with no answers, the neurologist encouraged the family to seek genetic testing.

Several genetic tests came back negative.

Genetic testing

The neurologist then referred Marley to Caleb Bupp, MD, a Spectrum Health medical geneticist.

Dr. Bupp performed whole exome sequencing, which he describes as “sort of a spell check of all your genetic information.”

The test revealed a genetic mutation in Marley’s ODC1 gene, but that particular gene did not have any known genetic conditions associated with it at that time.

Dr. Bupp pressed on.

Through Surender Rajasekaran, MD, medical director of research at Spectrum Health Helen DeVos Children’s Hospital, he connected with Andre Bachmann, PhD, a researcher at Michigan State, who is an expert in polyamines. These are compounds in the body that are important in development and growth. The ODC1 gene is involved in processing polyamines.

“ODC1 and polyamines have long been studied, just not really in humans,” Dr. Bupp said. “In fact, there is a mouse that was created for research with an ODC1 mutation very similar to Marley’s over 20 years ago. And that mouse had some similarities such as losing all its hair.

“Our research looked further at Marley’s genetic change and then proved that it caused her body to process polyamines improperly,” he said. “So we proved in a human what had been shown decades before (in a mouse)… This solves a bit of a mystery.”

Dr. Bupp said the hope is this discovery could lead to a treatment someday.

“We are looking at what this means for Marley,” Dr. Bupp said. “There is a medication, DFMO, which was shown to help the mice with this genetic change when it was studied in the past. We are looking at whether treatment is possible for Marley, but that’s a difficult challenge because she is the only patient diagnosed with this condition.”

A poster child

This all makes Marley pretty famous medically. Her mom describes her as a “poster child” for the mutation.

“It turned into a big article writeup in a medical journal,” Berthoud said. “It’s hard to understand because it’s at such a molecular level, but I can explain it to people. It’s really exciting for me because I do believe knowledge is power.

“Basically, this is identification of a new genetic disorder,” she said. “She is the only one they have any kind of research on. It’s crazy to think this is a new thing that she’s the poster child for.”

Berthoud hopes when the news of Marley’s genetic condition spreads, it could lead to more inroads in research.

“Not a ton of people are researching genetics,” Berthoud said. “I feel with this being published, more people can know about this. I feel like getting our story out there to our community is a real positive thing for us.”

Berthoud isn’t kidding herself.

“You can’t fix a genetic mutation,” she said. “But are there things we can do to support her? Now that we know there are abnormalaties in her cells, is there therapy that can be done? There was a medication that was mentioned, but there are still a lot of things that need to be looked at.”

‘So many people love this little girl’

Marley is 3 1/2 years old chronologically, but much younger in actions. She can’t talk and she can’t walk.

“She’s very physically and developmentally delayed,” Berthoud said. “She has the mental capacity of a 6- to 9-month-old. She looks at us and smiles, but when we ask her a question, we don’t know if her nods really mean much.”

Marley has been in physical and occupational therapy since birth. She recently enrolled in a preschool special education program four days a week.

“Her teachers are amazing,” Berthoud said. “Everyone kind of rallied around this girl. It’s so heartwarming to see. We do need a whole team. We cannot raise her by ourselves.”

Berthoud said after Marley was born, she blamed herself and grew depressed.

“You were expecting something completely normal and looking forward to all of those things in her life and they were taken away,” Berthoud said. “They determined I had post traumatic stress syndrome. I went through a dark phase. But seeing people that want to help has helped to heal me. So many people love this little girl.”

Marley’s happy demeanor is almost infectious. People are drawn to her.

“She is so happy,” Berthoud said. “When people meet her, they ask, ‘What can we do? We want to be around her more.’ It’s awesome to have the support and to have so many people on our side.”

There are finally good days, she said. But the hard days are many still.

“When I see other kids meeting milestones and we’re not, it’s difficult for me,” she said. “I have accepted that our milestones are just very different. We celebrate in a different way and we celebrate the little things because that’s what we have to go on. That’s our life.”

Through blood tests, Berthoud and her husband have learned that their genetic makeup had nothing to do with Marley’s mutation.

“That was a nice sense of closure,” she said. “It was a freak accident that happened and we don’t know why. I got what we think was influenza right around the same time that the brain hemorrhage happened. Is that something that could have caused this, we don’t know. It’s hard to piece together.”

But she hopes genetic researchers someday might, with Marley as the inspiration.

“She’s the gold standard of this genetic mutation,” Berthoud said. “She’s the one being researched in all this. They’re saying the developmental delay is probably because of the brain hemorrhage. They say her hair loss is probably from the genetic mutation. As a parent, any information I get is helpful. We’re helping to pave the way so somebody else can have this information from the get-go. It makes me feel helpful.”

Dr. Bupp said the Berthoud family’s willingness to participate in research will have an immense impact.

“We started with little more than an idea, and they were so kind to work with us to unravel this mystery slowly,” Dr. Bupp said. “They have been exceedingly patient, which is important because research doesn’t happen quickly. And also wonderfully thoughtful, asking good questions, being engaged in the process and really taking this information to heart as to what it means for their family and their sweet daughter.”

The research could ultimately help many others.

“In theory, this condition could end up being treatable, so it could potentially someday be included in the newborn screen,” Dr. Bupp said. “This discovery truly has the potential to have a worldwide impact.”

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