Two years into treatment, girl with genetic disorder discovered by MSU docs drastically improved

EAST LANSING — Kelly Berthoud could tell there was something wrong with her daughter almost immediately after giving birth. Her head was large for her body and she couldn't eat on her own.

Doctors soon found a brain hemorrhage in Kelly's daughter, Marley, but couldn’t determine what caused it. As she grew older, Marley lost her once-full head of hair. She couldn’t hold her head up, couldn’t crawl and continued to struggle to eat. The Berthouds' neurologist encouraged them to seek answers at the expert level. 

The Mattawan family ended up in the office of Dr. Caleb Bupp, medical geneticist at Helen DeVos Children’s Hospital in Grand Rapids and a professor of pediatrics in Michigan State University’s College of Human Medicine. Bupp first met Marley when she was an 11-month-old. At the time, she had low muscle tone and no hair.

Her symptoms were caused by a then-unknown genetic disorder now called Bachmann-Bupp Syndrome, named for Bupp and André Bachmann, another MSU researcher who helped discover it. Since Marley's diagnosis, only seven other cases have been identified.

Now, nearly two years into treatment that took doctors just 16 months to identify, researchers are stunned by Marley's progress.

“It’s just remarkable on so many levels,” said Bachmann, a professor of pediatrics in the MSU College of Human Medicine and co-author of a paper detailing the medical discovery.

More:Michigan girl's genetic disorder stumped doctors for a reason: It's a first

Bachmann-Bupp Syndrome stems from a mutation of the ODC1 gene, which contributes to the production of polyamines that are key to cell survival. They also contribute to development in children, including muscle tone and motor skills. 

When Bupp first encountered Marley, he'd coincidentally listened to a presentation on the ODC1 gene by Bachmann, who has studied the gene for more than two decades, and Dr. Surender Rajasekaran, a pediatric intensive care unit physician at Helen DeVos hospital and assistant professor in the Department of Pediatrics and Human Development at MSU's College of Human Medicine.

Bupp reached out to Bachmann, who knew the Food and Drug Administration had approved the drug difluoromethylornithine to treat diseases linked to ODC problems, including African sleeping sickness and hirsutism, a condition in women that results in excessive hair growth.

“The series of events that had to happen to get to where we are right now, it’s not just the treatment, it’s how we came together,” Bachmann said. “You truly cannot plan something like that. You can’t sit down and say, ‘Hey, let’s do this project.’ We just didn’t know. It’s serendipity.”

Difluoromethylornithine works by deactivating ODC proteins, which were building up in Marley’s body. At the recommendation of the doctors, she began taking difluoromethylornithine in November 2019, becoming the first single-patient study approved by the FDA to treat an ODC1 mutation with the drug. 

They’ve already seen drastic improvements. 

In the two years since Marley began taking the medication, she's seen an increase in muscle tone and can hold her head up. She can feed herself with a spoon and scoot across the floor. And, most notably, her once-bare head is covered in new hair. 

“A lot of days there were just blank stares and not interacting with her environment,” said Kelly Berthoud. “She’s kind of awakened since the treatment.” 

‘Oh my word, it’s actually working’

Today, Marley is an interactive 6-year-old girl. She can’t speak verbally, but uses sign language to tell Mom what she wants. 

Marley's physical mobility is among her biggest improvements. Since beginning treatment, she went from struggling to hold her head up to sitting upright on the floor and using her arms and legs to scoot around. Her mom often finds her moving toward the cabinet and asking for her favorite snack — crackers — using sign language. 

Bupp has a photograph with Marley from the day she started treatment, where she's holding a 3D model of her ODC1 gene. She had no hair and her body drooped into his due to her lack of muscle, he said.

A month into treatment, she sprouted eyebrows.

“It was like, ‘Oh my word, it’s actually working,’” Bupp said.

Then came a stream of photographs and videos from Marley’s family, showing her sitting on her own, standing with support, putting food into her mouth and asking for a snack.

“She’s five or six years old and zooming through developmental milestones,” Bupp said. “It does seem like her brain, a cloud is lifting. Watching her scoot around on her bottom at her house is just stunning, based on the first interactions we had with her where she just would lay in her mom’s arms.” 

Turnarounds like the one Marley is experiencing aren’t common, Bupp said, and the road to those improvements wasn't easy for Marley or her mother. 

Once Marley's treatment began, Kelly Berthoud was able to take stock of the toll it took not knowing what was wrong with her daughter. She was constantly exhausted, she said. Depression and self-blame set in. Finding a treatment proved beneficial for both Marley and her mother's health.

“There’s a lot of guilt that gets released,” Rajasekaran said. “Parents realize ‘this is not something that I did wrong.'”

A global change

It’s gratifying for the researchers to see Marley doing so well after starting from square one.

“We didn’t know what to expect when we first started this,” Rajasekaran said. 

The researchers were concerned that Marley may have a negative reaction to the difluoromethylornithine — that she may not be able to tolerate it or that it could harm her other organs. 

So far, though, none of those concerns have come to fruition. Marley hasn’t experienced any illness as a result of her treatment. 

“It’s like a global change in her,” Bupp said. “This does not happen very much in genetic conditions and it’s exciting to think about for her and other kids.”

Difluoromethylornithine, also known as DFMO, comes from the manufacturer as a powder, which the hospital's research pharmacy mixes into a liquid suspension. Marley’s parents give it to her through a feeding tube twice a day. It also comes in tablets. 

It’s unknown how long Marley will have to take the drug, but Bupp expects it could be for the rest of her life. They hope to continue researching Bachmann-Bupp Syndrome in the coming years.

MSU and Spectrum Health have helped pay for the research so far, Bachmann said, and he hopes to see more funding. But securing money from the National Institutes of Health and other organizations to research rare conditions is its own challenge. 

“They would rather fund a research project that affects a lot of patients rather than one that affects a handful of patients,” Rajasekaran said.

That means hoping for donations and other philanthropic gifts. 

Over the past few years, parents with children exhibiting symptoms similar to Marley's have reached out to Bupp. A mother from California found Kelly on Facebook to talk about Bachmann-Bupp Syndrome and went to see Bupp a few weeks ago, she said. 

Berthoud is happy to share her story with others, but she warns that every child is different and might not respond to the treatment as well as her daughter has.

There are plenty of unknowns as the Berthoud’s look toward Marley’s future. Doctors don’t know whether she’ll ever be able to walk. But it’s the present that matters, Berthoud said, and right now Marley continues to improve as she takes the medication.

“We don’t predict anything bad will happen. Right now, we’re comfortable where we’re at,” she said. “It’s such a unique position to be in. We don’t know what to expect. It’s also scary as a parent. Nobody can look at my kid and say this is what we need to do for the rest of their life.” 

Contact Mark Johnson at 517-377-1026 or at majohnson2@lsj.com. Follow him on Twitter at @ByMarkJohnson.