Child with rare genetic syndrome treated within 2 years

It is difficult to diagnose a rare disease. Identifying a treatment can take years of trial and error. At the fortuitous intersection of research expertise, a sick patient in this case a child, and innovative technology, Bachmann-Bupp syndrome has gone from a list of symptoms to a treatment. succeeded in just 16 months.

The article chronicling this ultra-rapid scientific response to Bachmann-Bupp syndrome was published in the open access journal eLife.

For more than 25 years, André Bachmann, professor of pediatrics at Michigan State University, has studied the ODC1 gene. This gene and its protein product ODC, which produces polyamines, are crucial for cell survival and contribute to many developmental processes, including muscle tone and motor skills in children.

From Bachmann’s research, he also knew that the drug difluoromethylornithine, or DFMO, (sometimes called eflornithine), had previously been successful and approved by the Food and Drug Administration to treat other illnesses related to ODC problems. like African sleeping sickness and hirsutism (excessive hair growth). It has also been studied in clinical trials in colon cancer and pediatric neuroblastoma.

In 2018, Caleb Bupp, a medical geneticist at Helen DeVos Children’s Hospital in Grand Rapids and clinical assistant professor in the Department of Pediatrics and Human Development at Michigan State University College of Human Medicine, had an unusual patient. Three-year-old Marley Berthoud’s symptoms included a large head, complete hair loss, poor muscle tone and developmental delays. She couldn’t hold her head up, feed herself, crawl, or communicate.

When Bupp sequenced the Marley exome (the part of the human genome that contains the genetic code to make proteins), he discovered a mutation in his ODC1 gene. Bupp recalled a presentation by Surender Rajasekaran, Pediatric Critical Care Physician to Helen DeVos and Assistant Professor in the Department of Pediatrics and Human Development at Michigan State University College of Human Medicine, and Bachmann about ODC1, and he contacted them. .

The mutation in Marley’s ODC1 gene caused his body to build up a lot of ODC proteins which were building up in his system. Bachmann knew from his previous work that DFMO deactivates ODC proteins.

“We can’t stop his body from building up ODC protein, but we can make the protein inactive,” Bachmann said.

Bupp was encouraged by previous research by Bachmann showing that DFMO was safe and had minimal side effects in patients, especially children. With his family’s approval, Marley began taking DFMO in 2019. This was the world’s first single-patient study approved by the FDA to treat a patient with an ODC1 mutation using DFMO. .

“From the discovery of the syndrome to the patient’s first dose, it took less than two years,” Bachmann said. “It usually doesn’t happen that quickly.”

While Bachmann, Bupp, Rajasekaran, and Berthoud’s family waited to see if DFMO would work, Marley’s symptom list was officially named Bachmann-Bupp syndrome by Online Mendelian Inheritance in Man, an online database. on human genes and genetic disorders.

“It rarely happens,” Bachmann said. “From today, and for many years to come, medical students will learn Bachmann-Bupp syndrome and it all started at MSU.”

Since she started taking DFMO, Marley has made tremendous progress. She has gained muscle tone, which means she can hold her head up, spoon feed, and crawl, but the most visible sign of success has been new hair growth.

“It’s amazing,” Bachmann said. “When I first saw a photo of her, I couldn’t believe she had grown so much hair in a year, and she managed to sled down a hill on her own.”

Seeing all of these external advancements was promising, but Bupp wanted to dig deeper to learn more about the internal changes that occur inside Marley’s body as a result of the DFMO treatment. Bupp contacted Metabolon, a health technology company based in Morrisville, North Carolina, which has developed a tool to detect biomarkers of rare diseases and response to treatment.

Metabolon’s Precision Metabolomics technology could test Marley’s blood samples before and during treatment to find out exactly how his body’s metabolism responded to DFMO treatment and the effect the drug was having on his body.

“There’s not really a regular lab test you can do to look at this, so working with Metabolon has given us a window into Marley’s biochemistry that wouldn’t have been possible otherwise,” said Bupp. “What we saw in the numbers matched what we saw with our eyes – his body was changing inside, too.”

The result of what was going on inside Marley’s body confirmed that the DFMO was working and was just as impressive as what was going on outside.

“Now Marley uses sign language when she couldn’t communicate before,” Bupp said. “My heart melted when she was able to give me a high five for the first time.”

Republished courtesy of Michigan State University. Photo: The patient variant falls on the messy C-terminus of the ODC, where the two active sites are made up of amino acids from each of the two ODC proteins forming a dimer. Credit: eLife 2021; 10: e67097

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