NMR-Based Urine Metabolic Profiling of Cri-du-Chat Syndrome

Cri-du-chat syndrome (CDCS) is a rare genetic disorder caused by a partial deletion of chromosome 5. Common features include intellectual disability, developmental delays, microcephaly, and a characteristic high-pitched cry. Although CDCS has been extensively studied from genetic and developmental perspectives, its metabolic implications remain poorly understood. This study aimed to investigate alterations in metabolic pathways involved in the pathological mechanisms of CDCS through urine metabolomic profiling using nuclear magnetic resonance (NMR) spectroscopy. Sixty-three participants were grouped into children, adolescents, and adults. For the first time, an NMR-based metabolomic signature for CDCS was reported, revealing 33 urinary metabolites and providing new insights into syndrome-related biochemical alterations. Statistical analyses revealed significant metabolic alterations compared to control subjects, particularly involving branched-chain and aromatic amino acids, as well as organic acids associated with energy production. Enrichment analysis further highlighted age-specific pathways impacted by the syndrome. In children, pathways related to phenylalanine, tyrosine, and tryptophan biosynthesis and metabolism, as well as butanoate and glyoxylate metabolism, were affected. Adolescents showed prominent alterations in phenylalanine biosynthesis and metabolism, while adults exhibited disruptions in taurine, hypotaurine, beta-alanine, and histidine metabolism. Altogether, these findings demonstrate pervasive impairments in amino-acid metabolism and energy homeostasis, elucidating key biochemical mechanisms that underlie the physiological manifestations of CDCS and highlighting potential metabolic pathways for future therapeutic exploration.