Metabolomic Studies in Inborn Errors of Metabolism: Last Years and Future Perspectives

Abstract

The inborn errors of metabolism (IEMs or Inherited Metabolic Disorders) are a heterogeneous group of diseases caused by a deficit of some specific metabolic pathways. IEMs may present with multiple overlapping symptoms, sometimes difficult delayed diagnosis and postponed therapies. Additionally, many IEMs are not covered in newborn screening and the diagnostic profiling in the metabolic laboratory is indispensable to reach a correct diagnosis. In recent years, Metabolomics helped to obtain a better understanding of pathogenesis and pathophysiology of IEMs, by validating diagnostic biomarkers, discovering new specific metabolic patterns and new IEMs itself. The expansion of Metabolomics in clinical biochemistry and laboratory medicine has brought these approaches in clinical practice as part of newborn screenings, as an exam for differential diagnosis between IEMs, and evaluation of metabolites in follow up as markers of severity or therapies efficacy. Lastly, several research groups are trying to profile metabolomics data in platforms to have a holistic vision of the metabolic, proteomic and genomic pathways of every single patient. In 2018 this team has made a review of literature to understand the value of Metabolomics in IEMs. Our review offers an update on use and perspectives of metabolomics in IEMs, with an overview of the studies available from 2018 to 2022.

Disease spectrum, prevalence, genetic characteristics of inborn errors of metabolism in 21,840 hospitalized infants in Chongqing, China, 2017-2022

“…The same disease tended to present with significant phenotypic variability due to individual differences, and different diseases also exhibited similar phenotypes, making diagnosis challenging. Considering that pre-symptomatic diagnosis was crucial for timely intervention, especially for treatable IEMs, early screening and diagnosis have become important strategies for reducing mortality and morbidity rates in children with IEMs ( Cossu et al, 2023 ).…”

Splice-Modulating Antisense Oligonucleotides as Therapeutics for Inherited Metabolic Diseases

“…Herein, integrating the knowledge on the diversity of ASOs’ mechanisms, chemistry, and design, we provide suggestions on improving and optimizing the development of therapeutic ASOs towards targeting IEMs: Splice modulation, rather than RNase H-mediated RNA degradation, is the first choice when choosing an appropriate ASO mechanism of action for IEM treatment. This is due to the fact that most IEMs are monogenic disorders [ 259 ], and an IEM is usually caused by the defective expression of an enzyme resulting from a specific ORF-destructing mutation. A splice-modulating ASO can be designed to skip the mutation-induced pseudoexon, restore the ORF, and consequently recover the synthesis of functional enzyme.…”