Metabolic alterations in Snyder-Robinson syndrome lymphoblasts are ameliorated by phenylbutyrate treatment

Snyder-Robinson syndrome (SRS) is an X-linked polyaminopathy caused by pathogenic variants in the spermine synthase (SMS) gene, resulting in impaired spermine synthesis, accumulation of spermidine, and widespread cellular dysfunction. Although mitochondrial impairment has been implicated in SRS, the impact of SMS deficiency on cellular energy metabolism has not been systematically characterized. In the present study, we performed high-throughput metabolic profiling of 29 patient-derived lymphoblastoid cell lines using Biolog Phenotype Mammalian Microarrays. SRS cells exhibited broad metabolic rewiring, including reduced utilization of galactose, and compensatory increases in the metabolism of d-fructose, maltose, maltotriose, and a- keto-glutaric acid. They also showed attenuated metabolic responses to ionic perturbations and blunted sensitivity to insulin and glucagon, indicating defects in both mitochondrial substrate preference and signal-dependent metabolic regulation. Treatment with phenylbutyrate (PBA), previously shown to modulate polyamine catabolism, partially restored metabolic flexibility and normalized several impaired nutrient pathways. These findings highlight global energy metabolism dysregulation as a hallmark of SRS and support PBA as a promising therapeutic candidate for correcting bioenergetic defects in this disorder.