Insights into a Rare Metabolic Disease

A holistic view

To address these complexities, researchers around Matthias R. Baumgartner, a leading expert in metabolic disorders and head of the Division of Metabolism at the University Children’s Hospital Zurich, adopted a data-driven “multi-omics” strategy. SMOC was an important partner of the research project. Multi-omics combines genomics (DNA), transcriptomics (RNA), proteomics (proteins), and metabolomics (metabolites) to build detailed molecular profiles and provide a holistic view of cellular function. The goal is to connect genetic mutations with functional outcomes, potentially revealing new biomarkers and therapeutic targets.

With the support of Co-PI and the head of research, Sean Froese, a multidisciplinary team brought together expertise in data generation, data analysis and clinical medicine. The project is part of the PHRT program and was conducted in close collaboration between ETH Zurich, EPFL, and the University Children’s Hospital Zurich. Reflecting on the past few years, Baumgartner says, “Having the PHRT funding opportunity was a breakthrough for our research. Without it, the project could not have made such progress.”

The scientists first analyzed 210 fibroblast lines from individuals with MMA using high-throughput techniques. The team found that in addition to the known gene defects, new variants in this metabolic pathway could also cause this disorder. These discoveries expanded the known genetic landscape of MMA. Drawing from multiple parallel investigations, which received additional funding from the Swiss National Science Foundation and ITINERARE, a University of Zurich Research Priority Program on Rare Diseases, the team used patient-derived fibroblasts and neurons to detect fundamental disease mechanisms and explore novel therapeutic strategies. It’s a brilliant example of how multi-omics profiling is able to support clinical research and to clarify disease mechanisms.

Neurological findings

To support the breadth of the investigation, the research team established robust infrastructure for data handling and patient sample processing. Over 250 clinically characterized samples were biobanked using standardized protocols. A centralized bioinformatics platform was developed to analyze sequencing and protein data efficiently. The first papers have been published, and Baumgartner emphasizes: “Having post-doctoral fellow Patrick Forny as first author and Sean Froese as last author, highlights their pivotal roles as clinical investigators in the project.”

Recognizing that MMA often affects neurological function, the research team, led by PhD student Matthew Denley, also reprogrammed patient fibroblasts into induced pluripotent stem cells (iPSCs) and differentiated them into neurons. This allowed for direct observation of MMA’s effects on brain-like cells. These findings offer compelling cellular explanations for the developmental delays and neurological symptoms seen in MMA patients. They also point to promising therapeutic avenues, such as enhancing mitochondrial resilience and mitigating oxidative stress.