Fanconi anemia (FA) is best known as a DNA-repair disorder with profound hematologic consequences and a high lifetime cancer risk. But for many patients, day-to-day life is shaped just as much by a different kind of instability: difficulty gaining weight, maintaining muscle, and sustaining energy. Those clinical observations have long been recognized, yet the mechanistic picture of “what goes wrong” metabolically has remained unclear – in part because routine assessments can struggle to capture metabolism as a dynamic, time-resolved process.
In a recent study, a team of researchers from the Translational Metabolomics Facility and Division of Pathology and Laboratory Medicine at Cincinnati Children’s Hospital Medical Center, USA, tackled that gap by pairing a stable-isotope glucose tracer challenge with parallel readouts of whole-body energy expenditure, plasma metabolite labeling, and endocrine signals. The approach follows carbon flow rather than static concentrations, allowing the team to interrogate fuel selection and nutrient handling in real time in a rare-disease cohort.
Here, co-authors Sara Vicente-Muñoz and Lindsey Romick discuss what pushed the work beyond cancer-centric metabolomics, how they designed the analytical workflow to behave under clinical constraints, and what the results suggest about metabolic vulnerability in Fanconi anemia.
What initially motivated your team to investigate how Fanconi anemia affects whole-body energy metabolism?
Lindsey Romick: I began studying FA in 2012, with a focus on the high prevalence of head and neck squamous cell carcinomas (HNSCCs) in this population. At that time, the attention was on the role (if any) HPV played in the early onset and high incidence of HNSCC in this community. My background in metabolomics led me to explore the metabolic differences between head and neck cancer cells that either had an intact (i.e. normal) or defective FA pathway – being that which is observed in an individual diagnosed with FA.
I focused my efforts on surveillance and diagnosis of cancer in persons with FA, as it was and continues to be a key area of research with many unanswered questions. Lucky for me, my research allowed me to attend and present my findings at the annual Fanconi Anemia Scientific Symposium, hosted by the Fanconi Cancer Foundation (FCF), formerly the Fanconi Anemia Research Fund (FARF). FA is a rare disease, and so being able to be surrounded by the top experts in the world and learn from them once a year is truly invaluable.
As well as being in the presence of so many top FA clinicians and basic scientists, FCF did something that would ultimately reshape my entire career as a researcher: they began to hold FA Adult Retreats in tandem with the annual scientific meetings. This allowed adults with FA and their loved ones to play a more active role in the science itself, enabling them to voice what they felt was important for us, as scientists, to focus on.
As I began immersing myself in conversations with persons with FA – hearing their stories, their everyday struggles, and the questions that they wanted answered – a theme started to emerge. They (persons with FA) simply wanted to look and feel “normal,” to gain and maintain weight, build muscle mass and strength, and maintain a healthy amount of fat mass. These same desires were felt among both adults with FA and the parents/caregivers of children with FA, as this complication is commonly presented in infancy.
[sidebar]
Why Metabolism Matters
Romick: In 2018, at the annual FA Scientific Symposium, I met a young adult with FA named Jack Timperley. Jack and I had long, in-depth conversations about his struggles. He had to work incredibly hard to maintain his weight, essentially never stopping his calorie intake – only for his body to burn straight through it, never seeming to use it to build muscle, store fat, or provide sustained energy. I watched that constant need to think about calories take a significant toll on Jack’s quality of life on a daily basis.
This is when my research focus turned from cancer metabolism to whole body metabolism and improving quality of life for those experiencing metabolic dysfunction due to complications from FA. Jack and many others with FA had a voice in helping to develop the clinical research study presented within our manuscript, and we are forever grateful for their participation and support of this work.
Unfortunately, Jack passed away in 2024 from complications associated with his disease. His fight and passion to not only advocate for himself, but others suffering with FA, helped push this research forward immeasurably.
[sidebar end]
Could you briefly explain how your approach allowed you to track nutrient processing in real time?
Sara Vicente-Muñoz: Think of it like putting a GPS tracker on your nutrients. We gave participants a drink containing glucose where all six carbon atoms were "tagged" with carbon-13 – a heavier, stable isotope that is completely safe but distinguishable from regular carbon-12. Once ingested, we could follow those tagged carbons as they traveled through the body's metabolic pathways.
In our study, we combined stable isotope tracers with three parallel assessments: indirect calorimetry to measure energy expenditure in real time, NMR spectroscopy to track labeled metabolites in blood samples collected over four hours, and hormone profiling. NMR was particularly effective for this work because it can unambiguously identify compounds and accurately measure carbon-13 enrichment. It also lets us trace metabolic pathways atom by atom, showing exactly where those carbon-13 atoms end up – for example, in lactate via glycolysis, in TCA-cycle intermediates, or in ketone bodies produced through fat metabolism.
However, a persistent challenge with NMR is that when you have complex mixtures of both labeled and unlabeled metabolites, the spectra become heavily overlapped, which makes comprehensive quantitative analysis difficult. It is like the difference between looking at a photograph and watching a feature-length movie. Traditional metabolomics provides a snapshot of what is present at a single moment, whereas isotope tracing shows you the dynamic flow, where molecules come from, where they're going, and how fast they're moving through different pathways.
Did any of your results surprise you?
Vicente-Muñoz: The biggest finding was this profound metabolic inflexibility. Individuals with FA appeared to bypass normal glucose oxidation entirely, even when glucose was available.
What really got our attention was the magnitude of the ketogenic response. After drinking the glucose solution, instead of their bodies efficiently burning that sugar for energy, we saw blood sugar staying persistently high, energy expenditure actually dropping, and a dramatic shift toward burning fat with elevated ketone production. It felt almost as if their metabolism had chosen to ignore available glucose.
It represented a fundamental rewiring of how the body prioritizes fuel sources. Normally, metabolism has flexibility; your body smoothly transitions between burning carbs when they're available and fats when they're not. Persons with FA, however, seemed locked into fat oxidation mode, unable to make that metabolic transition.
That rigidity or metabolic inflexibility was the real revelation. The implications are profound: it could change how we advise them nutritionally and reshape how we think about their elevated cancer risk.
What was the biggest challenge in measuring these subtle metabolic fluxes, and how did you overcome it?
Vicente-Muñoz: The complexity of the isotopic data itself was probably our biggest obstacle. When you are tracking carbon-13 through metabolic pathways, you are not just looking at simple peaks – you are deconvoluting complex isotopomer patterns that require specialized expertise to be interpreted correctly. Each metabolite can exist in multiple isotopic forms, depending on how many labeled carbons it incorporates and where those labels end up in the molecule.
We also had to coordinate three distinct analytical readouts in parallel: indirect calorimetry for real-time energy measurements, serial blood sampling for NMR metabolomics, and hormone profiling – all while working with a rare disease population where every participant is precious. The timing had to be perfect as metabolic flux is so dynamic; miss your collection window by even 30 minutes and you risk losing critical information about how quickly pathways are turning over.
The analytical pipeline to process and interpret these complex isotopic datasets required specialized expertise. It was not just about detecting the labeled molecules, but understanding the biological story they're telling. Which pathways are active? Which are blocked? How does carbon flow change over time?
Working with a rare disease population added another layer of complexity. With only eight individuals with Fanconi anemia enrolled in the study, every data point mattered immensely. We could not afford technical variability or failed sample collections. We were working with people who are medically fragile, and these aren't experiments you can easily repeat.
The expertise required to process and interpret these complex datasets really cannot be overstated. It's not just about detecting the labeled molecules or running the spectrometer; it's about understanding the biological story they are telling, the underlying chemistry, and having the computational tools to bridge between raw spectroscopic data and meaningful metabolic insights. Our challenge was to integrate multiple data sets: metabolomics, indirect calorimetry, hormone profiles, and anthropometric measurements, into a coherent picture that displayed what was happening metabolically in these patients.
How do these findings change the way we think about where metabolic vulnerability sits in Fanconi anemia?
Romick: I think that anyone who studies or treats patients with FA would agree that nothing about the disease is simple or straightforward.
FA is incredibly complex because, although the FA pathway is disrupted in every cell due to mutations in FA genes, the consequences can vary widely across organ systems. We know from work conducted by Susanne Wells at CCHMC and many others that metabolic activity differs markedly – among other features – between fluids like blood and solid tissues such as liver or skin in people with FA.
If we take a step back and think about cancer in the general population, we know that lower-carbohydrate diets and “glucose starvation” paired with chemotherapy and radiation are beneficial in some cancer types. This isn’t that surprising in and of itself, as we know that glucose is the main fuel for cancer cells – so if you deprive them of their fuel, they'll inevitably struggle.
We know that cancers in the FA population are aggressive, and that patients often cannot be treated with standard chemotherapies because of the inherent toxicity they experience. As a result, we need to find ways to slow tumor progression and growth, so that surgical resection becomes a more viable option.
On average, Americans consume roughly 50 percent carbohydrates, compared with 35 percent fats and 15 percent proteins, on a daily basis. Anecdotally, I’ve found that carbohydrate intake in people with FA is often higher, as many comment that they “crave” carbohydrates. If we can replace a portion of those simple sugars with healthy fats and protein, we give the body time to “catch up” and more effectively sense and process nutrients. In doing so, we may also limit easy access to the nutrients that pre-cancerous cells rely on to grow and expand into cancer cells and, ultimately, solid tumors.
Looking ahead, what are the next steps for your team?
Romick: We’re currently preparing to launch a new clinical research study at Cincinnati Children’s Hospital Medical Center in children and adults with FA that aims to modify diet so participants consume around 40 percent carbohydrates per day, while maintaining their usual caloric intake. This is in collaboration with Stella Davies, director of the Division of Bone Marrow Transplantation and Immune Deficiency at Cincinnati Children’s, and Meng Wang, Assistant Professor of Nutritional Sciences at Cornell University. We will be monitoring overall metabolic health, along with hormones and cancer biomarkers, as participants transition to a lower-carbohydrate diet and work to maintain it over time.
We’ve only scratched the surface in using isotope tracing to understand FA and other diseases suspected to involve metabolic dysfunction. Our study traced the fate of glucose in people with FA, but we have yet to test whether similar patterns emerge when tracing nutrients tied more directly to fat metabolism or protein synthesis. More broadly, applying isotope tracers prior to tumor resection in this vulnerable population (and others) could provide key insights into how metabolism differs between tumor tissue and adjacent normal tissue – helping to inform more targeted, personalized therapeutic approaches.
Lindsey E. Romick is Director of the Translational Metabolomics Facility in the Division of Pathology and Laboratory Medicine at Cincinnati Children’s Hospital Medical Center, USA, and an Associate Professor in the Department of Pathology and Laboratory Medicine at the University of Cincinnati College of Medicine, USA.
Sara Vicente-Muñoz is a Staff Scientist in the Translational Metabolomics Facility within the Division of Pathology and Laboratory Medicine at Cincinnati Children’s Hospital Medical Center, USA.
Newsletters
Receive the latest analytical science news, personalities, education, and career development – weekly to your inbox.
