Trans-omic Analysis of a Rare Inborn Error of Metabolism – PHRT


Trans-omic Analysis of a Rare Inborn Error of Metabolism

Short Summary

Methylmalonic aciduria is a rare, inherited metabolic disease that may be deadly in the newborn or childhood period and is currently without a cure. We are investigating the causes and disease processes of methylmalonic aciduria by combining clinical and biochemical information with a multi-omic investigation of patient tissue. We expect the integration of these diverse information types to lead to identification of as yet unknown or poorly understood disease mechanisms and ultimately to novel individualized therapeutic options.


This pioneer project on MMA aims to collect a multidimensional bio-molecular dataset from patient cells and relate it back to the clinical and biochemical information of each patient in order to identify common and patient-specific disease mechanisms. Using hundreds of patient fibroblast samples collected over several decades, we will compare the results of whole genome sequencing, RNA sequencing, and large scale proteomics for each patient, as well metabolomics from representative patients, with their respective clinical and biochemical information taken at diagnosis. Integration of these data layers and comparison against non-affected controls will be used to find key differences caused by the disease.


Metabolic diseases are commonly understudied entities, primarily due to their rarity. This project will generate a dataset at a magnitude and precision never before used for inherited metabolic diseases. The better understanding of MMA will help guide clinical prognosis and eventually decision-making, while in parallel provide new insights into disease mechanisms which can be targeted to develop novel treatment approaches. This project may serve as a new paradigm of rare metabolic disease research and can be used as a template to study other monogenic diseases.


Inherited metabolic diseases are individually rare, but collectively common. Methylmalonic aciduria (MMA) is a typical inherited metabolic disease whereby patients frequently present in the first few days of life and, if left untreated, may progress to coma and death. Those patients who survive into later life often have long-term organ-specific complications, including kidney failure, severe neurological problems, and impaired vision. Although the monogenic causes of MMA are known, there is currently no cure. The development of causative treatments has been hindered in part by a lack of understanding of the dysfunction caused by disease at the cellular level and how this relates to disease progression in individual patients.

Pioneer Project

Prof. Dr. med. Matthias Baumgartner

Division of Metabolism, University Children’s Hospital Zurich


  • Division of Metabolism, University Children’s Hospital Zurich
  • Molecular Systems Biology and BioMedical Proteomics Platform, ETH Zurich
  • Genome Center Health 2030, Geneva
  • Biomedical Informatics, Department of Computer Science, ETH Zürich

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