A Rare Success
Kelly Berthoud remembers the day in 2019
when her daughter Marley sprouted her
first eyebrows. Already four years old at the
time, Marley had been hairless for most of
her life, one of several characteristics about
the young girl that scientists and physi-
cians had spent years working to explain.
But with the family ensconced in the living
room on that morning just before Christ-
mas, each tiny blonde hair, now growing
as the result of an experimental drug Mar-
ley had recently started taking, was a gift.
“We were sitting on the couch and the sun-
shine was hitting her just right,” Berthoud
recalls. “I remember whipping my head
around when I noticed.”
Marley had in fact been born with sil-
ver hair, but shortly after, it had fallen out
in thick clumps. Her head was also unusu-
ally large, and a neonatal MRI revealed
that sometime before her birth she had
suffered a brain hemorrhage, leading to
the formation of cysts in the organ’s white
matter. As she grew, Marley started miss-
ing developmental milestones, including
sitting up and learning to speak. The doc-
tors and her parents were at a loss. It would
take a chance meeting between three scien-
tists to jump-start her case, but once Mar-
ley’s team was assembled, it moved quickly.
Within just two years, her symptoms would
be diagnosed as a novel genetic disease,
Bachmann-Bupp syndrome (BABS), and a
promising therapy identified, representing
one of the fastest turnaround times known
for treating a rare disease.
The path to this treatment began in
2016, when Marley’s doctors referred the
family to one of the people the disease
would eventually be named after, Caleb
Bupp, a medical geneticist at the Helen
DeVos Children’s Hospital and the health-
care organization Spectrum Health, both in
Michigan. Initially, Berthoud and her hus-
band, both nurses, grappled with whether
to pursue genetic testing, a fear Bupp
often encounters in his work. Unearthing
an unexpected risk factor or mutation “has
implications for privacy, for insurability, for
all sorts of things that people worry about
with genetics,” he says.After the couple decided to go ahead,
the doctors first checked Marley’s chromo-
somes for large duplications or deletions.
Finding none, Bupp next turned to whole-
exome sequencing, which scans all of the
protein-coding regions in a genome. That
analysis revealed two noteworthy find-
ings—the first was a mutation that causes
Smith-Lemli-Opitz syndrome, but Mar-
ley only had one copy of the disease-linked
variant and the syndrome was recessive.
The other mutation the team identified
was in a gene called ornithine decarbox-
ylase 1 (ODC1), which codes for an enzyme
called ODC that is involved in catalyzing
the production of certain biomolecules.
Running the ODC1 results through
GeneMatcher, a database where clinicians
share data on particular genes, revealed no
known human diseases associated with
Marley’s mutation. “It was the kind of
result that goes back in the drawer,” Bupp
says. But months later, Bupp attended a
talk by Helen DeVos Children’s Hospital
pediatrician Surender Rajasekaran and
Michigan State University cancer biologist
André Bachmann, during which the pair
talked about their work with polyamines,
molecular derivatives of amino acids thatare involved in multiple cellular processes.
“Polyamines are not very well known,
even though they’re absolutely essential
for so many things that the cell has to do,”
says Tracy Murray Stewart, a polyamine
research scientist at Johns Hopkins Med-
icine—including roles in cell growth, sur-
vival, and proliferation. “Nothing happens
without polyamines.”
As it turns out, polyamine synthesis is
mediated by ODC. Making the connection,
Bupp struck up a collaboration with Bach-
mann and Rajasekaran to study a possible
role for polyamines in Marley’s case.
Because of their importance in normal
cell function, disruptions in polyamine syn-
thesis often manifest early in life as cancer,
which is how Bachmann and Rajasekaran
first came to study them. Marley doesn’t
have cancer, but her mutation, located on
one end of ODC1, leads to a buildup of a
truncated form of the enzyme that is much
harder for the body to clear than the nor-20 THE SCIENTIST | the-scientist.com
TAYLOR BALLEK, SPECTRUM HEALTH BEATNOTEBOOKPATH TO TREATMENT: Marley, pictured here
with her father, was diagnosed with the rare
genetic condition Bachmann-Bupp syndrome a
few years ago.