Michigan girl diagnosed with rare genetic disorder

KALAMAZOO, Mich. — Marlene Berthoud was an enigma, born with a head full of silvery hair that her father, Bryan Berthoud, compared to the X-Men superhero Storm’s shimmery locks.

“We joked that she has super powers,” said her mother, Kelly Berthoud, because of her bright white hair.

Marlene, whose nickname is Marley, was a medical mystery. None of her doctors had ever treated a patient quite like her.

“Pretty much from birth, we knew that there was a (developmental) delay,” Kelly Berthoud told the Detroit Free Press. “She had to be taught how to eat, so she did not have the suck-swallow reflex that most newborns have.”

Soon after she was born, she had two brain hemorrhages, and her distinctive silver hair began to fall out in clumps. Doctors noted that her head was large for her body. She was also unable to maintain her body temperature and had birth marks as well as vision and hearing problems.

Marley’s parents — both registered nurses living in Mattawan, Mich., a suburb of Kalamazoo — embarked on a three-year journey to solve the puzzle that would explain Marley’s unique medical problems.

“As a mom, that was a really hard time,” Kelly Berthoud said. “They talked about risk factors like cocaine use and things like that. And I’m like, that wasn’t me, but maybe it was because I had a cup of coffee every day? That could have been it. So I placed a lot of the blame on myself because the medical community didn’t give me any answers.”

Dr. Caleb Bupp, a medical geneticist at Spectrum Health’s Helen DeVos Children’s Hospital in Grand Rapids, first met Marley when she was 11 months old.

“She was one of those patients that we see where you feel like she has to have something,” he said. “In fact, I left the folder of the pictures … on my desktop of my computer for months because she was just one of those patients that was just so striking.

“But the challenge is when you don’t know what somebody has, you can’t test them for that thing. And when you don’t know something specific to test for, your medical testing or your genetic testing ends up being quite broad, and it opens you up to not knowing what you might find.”

He suggested drawing Marley’s blood for what’s known as a whole exome genetic sequencing that would broadly analyze her DNA, looking for mutations and other anomalies.

“If we found nothing, my husband and I both agreed then that at the end of this testing, that we were done,” Kelly Berthoud said. “We were not going to go searching further because it was kind of like going down this rabbit hole. We had been through a lot of people just saying, ‘I don’t know. I don’t know.’ And so we were like, we’re going to do this. We’re going to do the whole thing and if we don’t find anything, we’re going to just move forward.”

Bupp said the sequencing test is like a spellcheck of a person’s genetic information, showing where anomalies lie among a person’s roughly 20,000 genes.

Marley’s results showed two mutations. One was ruled out pretty quickly as a cause of her symptoms. The other was a mutation of a gene called ornithine decarboxylase, or ODC1.

“When that result came back, I’ll be honest with you, it didn’t mean anything to me because there was not a known condition or syndrome associated with this,” Bupp said. “I let the family know that we had found this change. Maybe this was something. Maybe it wasn’t.”

About six months later, Andre S. Bachmann, a Michigan State University pediatric researcher, was making a presentation in Grand Rapids about polyamines in children with brain cancer.

Bachmann explained that a drug called DFMO works as a cancer-fighting treatment in those kids by inhibiting the production of ODC proteins that often are found in abundance in pediatric neuroblastoma patients.

Bupp just happened to be in the audience.

“That’s when sort of the light bulb moment came,” Bupp said. “It was like, ‘Oh! My patient, her gene was involved with those polyamine things.’ … Things shifted dramatically from that moment on.”

Bupp reached out to Bachmann through a colleague.

“When Dr. Bupp contacted me … I almost fell out of my chair … because I was so surprised that out of so many genes, Dr. Bupp had identified a mutation in ODC1,” Bachmann said.

“I worked with that gene ODC1 for over 25 years and there has not been a patient with that kind of mutation to our knowledge. … It’s only the first time we’ve discovered a human who has it.”

Bachmann knew of a 1996 study in a mouse with an ODC1 mutation similar to Marley’s. The mouse’s body made too much ODC protein. Marley’s did, too.

And the mouse, like Marley, had no hair.

“They gave (the) mouse DFMO,” Bachmann said, and “the hair started growing back.”

Bachmann and Bupp published their findings recently in the American Journal of Medical Genetics.

They’re appealing to the U.S. Food and Drug Administration for permission to try treating Marley with DFMO, hoping they may have found a therapy that could help Marley not only grow hair again, but perhaps also make progress on some other developmental functions.

The drug already is used safely in children with neuroblastoma and in people with African sleeping sickness, Bachmann noted.

But it’s difficult, Bupp said, to say definitively what symptoms accompany this brand new disorder given that there’s only one patient in the world who has been identified with it.

If other people with similar symptoms are discovered with the same mutation, it will help researchers determine more accurately what happens in the body when this gene overproduces the ODC1 protein, and how DFMO can be best used to treat it.

“Because she’s the first … is every health problem (Marley has) connected to the ODC1 mutation or just some of them?” Bupp said. “What typically happens is more patients will be found with this condition over time, and we’ll be able to line up what issues those patients have and then we’ll be able to further define what are the exact symptoms of this genetic syndrome that defines it more specifically. That is a little bit to be determined.”

Marley is now 3 years old. She wears purple-framed glasses, and wiggles in her mother’s arms.

She is developmentally at the same place as most 6- to 9-month-old babies. She can’t sit up on her own, and doesn’t crawl. She isn’t verbal, but babbles and is very expressive.

“She’s a unicorn,” Kelly Berthoud said. “She’s happy. She loves people. … She loves to interact and be the center of attention.”

Marley waves and then blows a kiss, smiling broadly.

While she knows Marley might never be able to ride a bicycle or do things other kids her age can do with ease, Kelly Berthoud said her little girl has completely changed her outlook on life.

“It’s been so amazing to watch her and the things she works so hard at that we take for granted every day,” Berthoud said. “It’s … changed my life as a person and how I do things. I can’t complain about doing the dishes because I CAN do the dishes.

“I am trying to learn from her every day and it’s hard. I can’t say that I always have a positive attitude about it. I had a dark, depressive postpartum period because you know, everything that I had expected with a child, I was now very aware that wasn’t going to happen. So, I’ve accepted that to a point. I still have very hard days.”

But, she said, she’s learned to celebrate the things Marley has learned to do, like suck from a bottle, swallow food from a spoon, blow kisses, smile and wave.

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