School-Stage Differences in the Mindset-Resilience-Burnout Network: A Bayesian Network Analysis.

Snyder–Robinson syndrome (SRS), first described in 1969 by Snyder and Robinson, is a rare X-linked intellectual developmental disorder characterized by a constellation of clinical features, including early-onset osteoporosis, kyphoscoliosis, hypotonia, asthenic build, and distinctive craniofacial dysmorphisms such as facial asymmetry, macrocephaly, thin upper lip, and midface hypoplasia [–]. Seizures of varying severity have been reported in some patients with SRS, typically manifested by early childhood [, , , –]. SRS is caused by hemizygous hypomorphic mutations in the spermine synthase () gene [, , , , , –], encoding a key enzyme in polyamine biosynthesis, which catalyzes the aminopropyl transfer from decarboxylated S-adenosylmethionine to spermidine to generate spermine []. Spermidine and spermine are the two most abundant polyamines in several tissues – although the concentrations of individual polyamines vary substantially in different cell types – and are essential for many fundamental cellular activities through binding to proteins, DNA and RNA []. The catabolism of spermidine and spermine also regulates cellular activities through modulating the homeostasis of consumed substrate acetyl-CoA and the byproducts, reactive oxygen species (ROS) and aldehydes [, ]. Mutations in reduce spermine synthase activity, resulting in decreased spermine levels and an accumulation of spermidine, which disrupts intracellular polyamine homeostasis and causes widespread metabolic and cellular dysfunction [–, –]. Specifically, accumulation of spermidine results in elevated spermidine catabolism, which consumes more acetyl-CoA and produces more ROS and aldehydes [, ]. Reduced acetyl-CoA pool impairs protein acetylation, including histone acetylation, which broadly regulates gene expression []. High levels of ROS and aldehydes damage cellular membrane structures, such as mitochondria and lysosomes [, ]. Although some molecular effects of a disrupted polyamine pathway have been described, the correlation between mutations and the SRS phenotype remains largely unknown. Considering the potential epigenetic and protein downstream changes resulting from mutations, we employed a functional approach to assess metabolic alterations in blood-derived cells from individuals with SRS, aiming to better understand the pathogenic mechanisms of this condition, identify potential targets for treatment, and eventually assess the efficacy of candidate drugs. Our previous studies showed sugar metabolism alteration in SRS patient cells, likely resulting from dysregulated mitochondrial activity []. We also demonstrated that phenylbutyrate (PBA) destabilizes spermidine/spermine acetylase 1 (SAT1), the rate-limiting enzyme for spermidine catabolism, and partially restores mitochondrial function in SRS models and patient cells []. This study extends and integrates our previous studies by significantly adding more patient-derived lymphoblastoid cell lines and systematically examining the effect of PBA and other metabolic effectors on carbon source utilization in SRS.