Using Metabolomics to Understand Rare Pediatric Diseases

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LCGC sat down with Annie Evans, senior director of research at Metabolon, to discuss how the company is using metabolomics to identify inborn errors of metabolism in children.

Metabolomics, or the study of metabolites, is playing an increasingly important role in personalized medicine. Although relatively new compared to other methods, scientists have used metabolomics to identify biomarkers for disease diagnosis.

Life sciences company Metabolon is using metabolomics to screen for inborn errors of metabolism in children. LCGC sat down with Annie Evans, senior director of research and development at Metabolon, to discuss how the company is investigating metabolomics as a method for identifying pediatric diseases in children. Evans will be delivering a talk on this topic at the AAPS conference in October.

Analytical Techniques for Metabolomics

Q. What are the most common analytical techniques used in metabolomics?

A: Most analytical metabolomics companies use a combination of liquid chromatography and mass spectrometry (LC–MS). Some do very heavily targeted metabolomics—looking for specific sets of analytes—and they'll go down an LC–MS targeted application route where they really optimize the chromatography settings to be able to achieve good resolution and specificity for those specific analytes.

There's also a group of metabolomics practitioners that are in the untargeted space, where you can have a more generic LC–MS method and you're attempting to detect as many molecules as you possibly can. You keep your technology or MS detection as open as you can to be able to detect all the signals that you want. There are some folks that rely on nuclear magnetic resonance (NMR). With NMR you get the benefit of being quantitative, which is obviously very helpful, but NMR is not as sensitive as MS. It can't generally detect as many molecules or the diversity of the molecules like MS can.

Q. What other technology are you exploring?

A: We're watching the developments in ion mobility spectrometry (IMS) very closely. We love chromatography, always have, but it is a source of some of our highest variability. Columns—age, peak, recall, quality—all degrade over time.

If we can rely on some different technologies, such as orthogonal technologies, to be able to rely a little bit less on the LC system, we look for that. Ion mobility is something that's up and coming and we feel that it may ultimately allow us to replace our chromatographic methods. It's not there yet for small molecules. Where you see a lot of success with ion mobility is in the lipids space—there are some great data showing how well ion mobility can separate lipid species — but for small molecules it’s just not capable of enough resolution yet to give us what we need.

Inborn errors of metabolism

Q. How are you using metabolomics in your work with children?


A: We have collaborated with clinicians in Texas for the last seven to ten years. Every week they send us samples from babies they have been unable to diagnose. The child will have been flagged as having a potential inborn error of metabolism through the inborn screening efforts. By running our discovery methodology, we've been able to increase their diagnosis rate by a factor of six.

I find this particularly moving as I see the human side of this. I'm a parent myself, and I can't imagine what it feels like to be a mom or a dad not knowing what's going on with your child. You know something's not right, but the doctors can’t give you a diagnosis.

By introducing metabolomics, we are looking at 1000 molecules in these children and comparing those levels to those from a healthy infant. This allows us to immediately pinpoint where the issue is. That doesn't mean there's going to be a cure, or that there’s an answer to save that child, but it gives the parents the information to know what's ahead of them. It also gives them the chance to find a network of people to help them understand what the prognosis is for their child.

Q. Can you give us an example of how this has worked in practice?

A: In many of these cases children have been poked and prodded and had so many tests run, and doctors still have no idea what is going on with them. One of these patients came to us when she was four or five years old, and doctors had no idea what was going on. She was developmentally delayed, with very little muscle strength. She had bulging eyes, no hair on her body, she couldn't talk, and she had very poor reflex for swallowing.

The doctors performed a genome sequencing, and they found a mutation that they thought might be relevant to her disease, but it was not a known mutation or a known disease. There happened to be another researcher who was doing research in mice with a similar mutation to this little girl, and he was treating the mice with a specific drug. The doctors said, why don't we give this medicine to this little girl?, but FDA told them, you have to show us that it's going to be efficacious to her, and that this is ultimately not going to hurt her.

Her doctors came to us and said, we want to be able to show that this medicine will help her. We ran her samples before she started her treatment, and after a couple of doses we were able to show complete resolution of her metabolic defect with this molecule. FDA therefore gave permission to keep her on this medicine. She's now gaining muscle tone, she's swallowing, and she's growing hair. Her life has radically changed.

I've been working with MS and LC since I was studying for my PhD. This has always been something I have loved. Seeing this application helping children with rare diseases, helping them get a disease diagnosis, and seeing the impact on people's lives is not something I ever expected to witness in my career as a chemist. But I do and it's phenomenal.

This interview has been edited for length and clarity.


Woods, L. Accelerating the Understanding of Metabolomics in Disease Through Improved Sensitivity. The Column 2022, 18 (5), 13–16.