Exploring Proteomic Alterations in Intellectual Disability: Insights from Hyperlipidemia and Hyperphosphatasia...

A significant increase of neurodevelopment disorders (NDDs) among children presents growing healthcare challenge worldwide. Owing to heterogenic, multifactorial nature of NDDs, understanding pathophysiology of disease, finding effective methods for the early detection and intervention of NDDs has become extremely complex. This study aims to investigate the molecular mechanisms of NDDs, focusing on the associations between hyperphosphatasia (HPP) and hyperlipidemia (HLD) in patients with intellectual disability (ID). Blood samples from 800 study participants (ID patients and healthy individuals, HC) were analyzed for the biochemical differences. Among them, 105 ID patients with uniquely altered biochemical profiles (ID-HPP, n = 28; ID-HLD, n = 77) and 65 HC samples were further investigated for nLC-MS/MS-based proteomic analysis. A total of 354 proteins were identified in label-free quantitative proteomic analysis of the all groups (ID-HPP, ID-HLD, and HC). The ID-HPP and ID-HLD groups each had distinct protein profiles compared to HC, with 28 and 85 differentially expressed proteins, respectively. The ID-HLD group had 66 unique proteins, whereas ID-HPP had 9 unique proteins, with 19 proteins common among the subgroups of ID. Pathway analysis of common proteins revealed shared pathways as the complement system and lipoprotein metabolism disruptions, but distinct pathway disturbances: toll-like receptor and integrin signaling in ID-HPP, and hemostatic pathway dysregulation in ID-HLD. These findings elucidate systemic pathway abnormalities in NDDs, including ID.