Novel CSF biomarkers of GLUT1 deficiency syndrome: implications beyond the brain’s energy deficit

Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a neurometabolic disorder due to heterozygous SLC2A1 mutations that lead to defective glucose transport into brain. The clinical hallmarks are intellectual disability, movement disorders, and drug-resistant epilepsy. Most patients respond to ketogenic diet therapy that provides the brain with ketones as an alternative energy source. Next-generation metabolic screening (NGMS), an untargeted metabolomics-based approach, was used to identify new biomarkers of GLUT1DS.

We compared metabolic CSF profiles from 11 patients with GLUT1DS to those of 116 controls. For annotation of newly identified features, we used ion-pair liquid chromatography tandem mass spectrometry and infrared ion spectroscopy to elucidate the structure of the corresponding metabolites.

Targeted analysis confirmed that patients with GLUT1DS have decreased CSF glucose and lactate levels, and at group level increased glutamine. Using untargeted metabolomics, we identified three reliable and reproducible novel features significantly decreased in patients, namely gluconic + galactonic acid, xylose-α1-3-glucose and xylose-α1-3-xylose-α1-3-glucose. CSF concentrations of gluconic + galactonic acid may be reduced as these metabolites may serve as alternative substrates for the pentose phosphate pathway. Both oligosaccharides are thought to originate from glycosylated proteins; their decreased levels could be the consequence of insufficient glucose as one of two substrates for O-glucosylation.

Our results may improve the biochemical diagnosis of GLUT1DS. They also imply that brain glucose deficiency in GLUT1DS may cause disruptions at the cellular level that go beyond energy metabolism, underlining the importance of searching treatment strategies directly targeting cerebral glucose uptake.
Keywords: GLUT1DS, SLC2A1, metabolomics, cerebrospinal fluid, O-glucosylation