In 2016, Marley Berthold was born. But doctors, and her parents, noticed some concerning signs. Marley’s silver hair had fallen out in clumps; she had macrocephaly (an abnormally large head) and had suffered a brain hemorrhage while in the womb. Over the next two years, Marley missed various developmental milestones. She had language difficulties and could not really sit up on her own. Eventually, after 2 years, Marley was diagnosed with an extremely rare and novel genetic disease called Bachmann-Bupp syndrome, or BABS.
According to The Scientist, Marley’s diagnostic and treatment journey eventually led doctors to pursue difluoromethylornithine (DFMO), a therapeutic option more commonly used for African trypanosomiasis. After repurposing DFMO, Marley’s condition has significantly improved, signifying a path forward for other families touched by BABS.
Bachmann-Bupp Syndrome (BABS)
To begin, what is Bachmann-Bupp syndrome? Due to the low number of diagnosed cases, researchers are still learning about Bachmann-Bupp syndrome and its manifestations. Orphanet currently describes the syndrome as:
A rare disorder of ornithine metabolism characterized by global developmental delay, alopecia, macrocephaly, and dysmorphic facial features (including high and broad forehead, hypertelorism, ptosis, blepharophimosis, downslanting palpebral fissures, deep-set eyes, large ears, and retrognathia or high arched palate).
Additional symptoms and characteristics may include:
- Low muscle tone
- Sensorineural hearing loss
- Abnormal muscle tightness due to prolonged contractions
- White matter abnormalities in the brain
- Undescended testicles
- Enlarged lateral ventricles
- Periventricular cysts
- Clinodactyly (abnormally bent or curved fingers)
- Small and underdeveloped (hypoplastic) nails
Marley’s Story
After Marley was born, her family was referred to the Helen DeVos Children’s Hospital and Spectrum Help, where they met a medical geneticist named Caleb Bupp. As you can probably tell, Bupp was one of the people for whom Bachmann-Bupp syndrome was named. During this time, Marley underwent genetic testing and whole-exome sequencing. Bupp discovered that Marley had two gene mutations: one linked to Smith-Lemli-Opitz syndrome (though this is not what Marley has, as 2 mutated genes are required) and one in the ODC1 gene. Normally, ODC1 encodes for the production of the ODC enzyme.
However, after further research, Bupp came across a potential difficulty: these particular mutations were not linked to any known diseases. But later, when discussing polyamines with pediatrician Surender Rajasekaran and cancer biologist André Bachmann, something stuck out to Bupp. ODC mediates polyamine synthesis. Could an issue with this synthesis cause Marley’s symptoms and condition?
The team decided to research more. They discovered that the ODC1 mutation caused shorter ODC enzymes and proteins that the body had difficulty clearing. Ultimately, this led to a variety of health issues. As the team brainstormed what to do next, Bachmann thought of treating Marley with DFMO.
DFMO and Bachmann-Bupp Syndrome
DFMO has been approved for use in patients with African trypanosomiasis for over 30 years. Outside of African trypanosomiasis, researchers have also evaluated DFMO for colon cancer and neuroblastoma. Pre-clinical research from the mid-1990s also highlighted a mouse model which showed similar characteristics to Marley and benefited from DFMO therapy. In a cellular culture, Bachmann, Bupp, and Rajasekaran saw that DFMO lowered ODC activity, making it a potential candidate.
At age 4, Marley began taking DFMO, which was provided for compassionate use. Within just one month of treatment, Marley began growing eyebrows. Then, within 6 months, Marley had grown eyelashes and blonde hair; she could sit up and begin moving around on her own. The white matter in her brain became increasing myelinated and her polyamines became more stable. While Marley has experienced some behavioral difficulties while on treatment, her family is just thrilled at Marley’s progression.
Following Marley’s diagnosis, there have been at least eight other patients diagnosed across the world. However, researchers believe this number will increase as more is learned about Bachmann-Bupp syndrome.
