Multiomic investigations in neuromuscular diseases

Pediatric neuromuscular disorders encompass all childhood onset diseases affecting the muscle, the neuromuscular junction, peripheral nerve, and the anterior horn cell. The multitude of sites as well as the heterogeneity and rarity of these disorders, make their diagnosis and treatment challenging. Therefore, joint efforts of researchers and clinicians are mandatory to diagnose and treat patients more accurately using integrative systems biology tools. Such appealing approach uses high-throughput technologies to comprehensively study multilayered molecular changes. It is valuable in the neuromuscular diseases field where innovative treatments are being produced. The objectives of this thesis were to apply omics techniques to study the two most common neuromuscular disorders (Spinal muscular atrophy and Duchenne muscular dystrophy) and explore their pathophysiological mechanisms, identify potential diagnosis biomarkers, and better stratify patients. The second objective was to find biomarkers for response to treatment in SMA. Metabolomics study on muscle biopsies of Duchenne patients revealed significant changes in energy and phospholipid metabolisms. SMA metabolic profiling investigations in plasma and CSF confirmed the presence of profound metabolic remodeling in SMA patients. Moreover, we demonstrated that these alterations are more pronounced in the severe phenotype. SMA proteomics studies are ongoing. In conclusion, systems biology tools are powerful for the study of neuromuscular diseases as they allow the discovery of biomarkers, the understanding of the physiopathology and the identification of new therapeutic targets.