Metabolic landscape of inborn errors of metabolism

Metabolomics is a powerful tool to identify the complex metabolic characteristics of human diseases. Inborn errors of metabolism (IEMs) are Mendelian diseases caused by inherited defects in metabolic enzymes, nutrient transporters, and other components of the human metabolic network. Using metabolomics to assess metabolic anomalies in patients with IEMs can help characterize these diseases and clarify the impact of genomic variants. Here we present a cohort of 474 subjects recruited from Mendelian disease clinics, including 242 patients with known or suspected IEMs and their family members. Through metabolomics of plasma and patient-derived fibroblast lines, we uncovered genotype-specific metabolic alterations in 57 different IEMs, providing a detailed view of the impact of single metabolic defects in humans. We report widespread metabolite-metabolite associations and show how departures from inter-metabolite congruence help pinpoint metabolic defects in IEMs. By comparing metabolic anomalies between plasma and fibroblasts from the same patient, we identify marked differences in the systemic and cell-autonomous impact of IEMs. We show how shared patterns of metabolomic anomalies can help categorize patients with suspected IEMs, providing diagnostic clarity to pinpoint causative genetic defects. This study provides resources including a database of metabolomic features in blood and cells from dozens of rare diseases, and analytical tools to assist in data analysis and advance understanding of genetically dictated metabolic aberrations in humans.