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.
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.
