Detecting inborn errors of metabolism by targeted metabolomics: a Victorian experience

Background: Traditional screening methods for inborn errors of metabolism (IEM) have been limited to the analysis of specific metabolites classes. Tandem mass spectrometry (TMS) can simultaneously analyse many classes of metabolites and has potential as a more ‘agnostic’ screening method. We present our Victorian experience in detecting IEM using this method since 2004. Methods: Electrospray ionisation TMS in positive and negative ion modes detected organic acids, amino acids, acylcarnitines and other selected metabolites. Analysis was performed in urine samples using flow injection analysis with targeted multiple reaction monitoring transitions. Results: 53,879 urine samples were analysed from 2004–2022. Diagnoses included clinically unsuspected IEMs such as cerebrotendinous xanthomatosis, alkaptonuria, creatine transporter defect, hyperoxaluria type III, glutaric aciduria type I, steroid 21 hydroxylase, short chain enoyl Co-A hydratase, aromatic L-amino acid decarboxylase, purine nucleoside phosphorylase, adenylosuccinate lyase and fructose 1,6 biphosphatase deficiencies. Diagnosis facilitated management and an end to the diagnostic odyssey of patients. Other benefits included: 1) follow-up of abnormal newborn screening results, 2) reduction in the number of urine organic acid analyses. Conclusion: Targeted urine metabolomics is a wide-ranging test enabling diagnosis of unsuspected and suspected IEM cases. It also serves as a platform for new IEM biomarkers.