Untargeted Metabolomics for Diagnosis, Monitoring, and Understanding the Pathophysiology of Inherited Metabolic Disorders

Inherited metabolic disorders (IMDs) encompass a diverse and expanding group of rare diseases caused by genetic disruptions mainly in metabolic enzymes and transporters. Clinical diagnosis of IMDs presents significant challenges due to phenotypic heterogeneity, nonspecific symptoms, and the limited scope of current targeted biochemical assays typically available. Recent advances in mass spectrometry-based untargeted metabolomics offer promising solutions to several of these challenges by simultaneous detection and relative quantification of thousands of metabolites, not relying on any prior hypotheses. With the expansion of genetic diagnostics via whole-exome and whole-genome sequencing, metabolic insights are often crucial for understanding the pathogenicity of genetic variants of unknown significance, often enabling a clear diagnosis for patients. This review details current applications of untargeted metabolomics in IMDs, including biomarker discovery and elucidation of previously unknown pathophysiological mechanisms. Successful examples of biomarker identification in well-studied IMDs, such as pyridoxine-dependent epilepsy and phenylketonuria, are highlighted to provide novel disease insights. Additionally, we address technical and interpretation challenges inherent to this methodology, particularly concerning metabolite identification, high-dimensional data complexity, and limited patient numbers. Emerging analytical technologies and data analysis approaches are highlighted that are poised to mitigate these challenges in the upcoming years. Finally, we provide an outlook on future directions, emphasizing the complementary roles of targeted and untargeted metabolomics and the prospects for the identification of new therapeutic targets as well as therapy monitoring for the clinical management of IMDs.