N⁸‐acetylspermidine as a potential plasma biomarker for Snyder‐Robinson syndrome identified by clinical metabolomics

Abstract

Clinical metabolomics has emerged as a powerful tool to study human metabolism in health and disease. Comparative statistical analysis of untargeted metabolic profiles can reveal perturbations of metabolite levels in diseases and thus has the potential to identify novel biomarkers. Here we have applied a simultaneous genetic-metabolomic approach in twin boys with epileptic encephalopathy of unclear etiology. Clinical exome sequencing identified a novel missense mutation in the spermine synthase gene (SMS) that causes Snyder-Robinson syndrome (SRS). Untargeted plasma metabolome analysis revealed significantly elevated levels of N(8)-acetylspermidine, a precursor derivative of spermine biosynthesis, as a potential novel plasma biomarker for SRS. This result was verified in a third patient with genetically confirmed SRS. This study illustrates the potential of metabolomics as a translational technique to support exome data on a functional and clinical level. Abstract Clinical metabolomics has emerged as a powerful tool to study human metabolism in health and disease. Comparative statistical analysis of untargeted metabolic profiles can reveal perturbations of metabolite levels in diseases and thus has the potential to identify novel biomarkers. Here we have applied a simultaneous genetic-metabolomic approach in twin boys with epileptic encephalopathy of unclear etiology. Clinical exome sequencing identified a novel missense mutation in the spermine synthase gene (SMS) that causes Snyder-Robinson syndrome (SRS). Untargeted plasma metabolome analysis revealed significantly elevated levels of N 8 -acetylspermidine, a precursor derivative of spermine biosynthesis, as a potential novel plasma biomarker for SRS. This result was verified in a third patient with genetically confirmed SRS. This study illustrates the potential of metabolomics as a translational technique to support exome data on a functional and clinical level.

Plasma metabolomics reveals a diagnostic metabolic fingerprint for mitochondrial aconitase (ACO2) deficiency

“…Mass-spectrometry based metabolomics has led to the discovery of novel biomarkers and disease-associated metabolic profiles in as yet uncharacterized genetic diseases [9, 10]. Here we performed comparative untargeted metabolomics on the plasma of eight ACO2 deficient patients of four unrelated families against a matched control cohort and report a diagnostic metabolic fingerprint in plasma for mitochondrial aconitase 2 deficiency.…”

Untargeted Metabolomics for Metabolic Diagnostic Screening with Automated Data Interpretation Using a Knowledge-Based Algorithm

“…Computational phenotype analysis has been proven successful in exome prioritization [6,7] and is likely to also have great potential for the prioritization of IEM, provided that a patient's phenotype is described as comprehensively as possible. Fourth, we support the (4) addition of biomarkers that are identified by untargeted metabolomics studies to the library [3,[8][9][10][11], (5) the inclusion of additional [12] or newly discovered IEM, and (6) the testing of the algorithm in other body fluids, like cerebrospinal fluid [4] or urine [13].…”

“…Moreover, the development of the R Shiny application ensures that we can present the algorithm as an easily accessible diagnostic tool for NGMS. In addition, since the number of known IEM is, in conjunction the number of potential biomarkers for IEM [3,[8][9][10][11], expanding at an unprecedented pace [12], it gets increasingly hard for laboratory specialists to keep knowledge up-to-date. The expected library, which serves as the input for the diagnostic algorithm, can be easily expanded with newly discovered IEM, as well as new biomarkers, provided that the markers included in the library are validated and that the algorithm can correctly preselect the IEM in a patient sample.…”

The human phenotype of ornithine decarboxylase superactivity: A new syndrome

“…Bupp et al () described elevation of putrescine in red blood cells, while Rodan et al () reported elevation of N‐acetylputrescine in plasma from one patient. The latter is reminiscent of what has been reported in Snyder‐Robinson syndrome, where the accumulated substrate undergoes N‐acetylation, and the elevated N‐acetylated product (N8‐acetylspermidine) can be identified via plasma metabolomics (Abela et al, ). Thus, biochemical screening for this condition seems feasible.…”