A Novel Plasma Biomarker for Snyder Robinson Syndrome (X-Linked Spermine Synthase Deficiency)

Background: Snyder-Robinson syndrome (SRS) is a rare X-linked mental retardation syndrome caused by mutations in the spermine synthase (SMS) gene. SMS dysfunction causes a reduction in intracellular spermine, a polyamine involved in various cellular processes. To date, the diagnosis of SRS relied on an elevated spermidine/spermine ratio in lymphoblasts and/or sequencing of the SMS gene.

Case: We report the case of a male monozygotic twins presenting with dysmorphic features, developmental delay, and progressive microcephaly. From the age of 12 months, recurrent irregular myoclonic jerks occurred in both twins and serial spasms in twin A. The EEG showed an abnormal background activity and multifocal and generalized spike waves. Myoclonic seizures were refractory and both boys suffered from additional atonic and tonic seizures as well as atypical absences. At the age of 15 months, they developed a severe encephalopathy with frequent seizures, loss of milestones, and impairment of visual interaction. A transient choreoathetotic movement disorder was observed consecutively. Twin B suffered a nontraumatic clavicular fraction at 23 months, both showed osteopenia. The twins were included in our local research project on metabolic–genetic research into epileptic encephalopathies.

Methods: An untargeted plasma metabolomics analysis was performed by liquid chromatography high-resolution mass spectrometry (LC-MS). Genetic analysis was performed by whole-exome sequencing (WES).

Results: Statistical analysis of LC-MS data showed a distinct plasma metabolomics profile when compared with controls. The concurrent WES analysis revealed a novel SMS missense mutation. Among the discriminating metabolites, we identified n-acetylspermidine, which showed a 300-fold relative increase versus age-matched controls.

Conclusion: In a combined metabolomic–genetic approach, we identified elevated N-acetylspermidine as a novel plasma biomarker in twin boys with a pathogenic mutation of the SMS gene. This discovery will facilitate recognition of SRS and will allow monitoring of potential therapeutic interventions.

Keywords: Snyder-Robinson syndrome, exome, metabolomics, novel SMS-missense mutation, novel plasma biomarker.