Non-invasive functional testing facilitates diagnostic confirmation in glucose transport 1 deficiency syndrome

Abstract

Background

Glucose transporter type 1 deficiency syndrome (Glut1DS) is an autosomal dominant neurometabolic disorder caused by pathogenic variants in SLC2A1, resulting in impaired glucose transport across the blood-brain barrier. Manifestations include epilepsy, movement disorders, and developmental delay. Historically, diagnosis is made by a combination of clinical phenotype, cerebrospinal fluid (CSF) analysis showing hypoglycorrhachia and identifying a pathogenic variant in SLC2A1. Manifestations are often refractory to symptomatic medications. Classical ketogenic or modified Atkins diet should be started early and is highly effective in mitigating symptoms.

Methods and results

We report a 5-year-old, developmentally normal female who presented with early onset absence seizures at eight months of age that were refractory to treatment with ethosuximide. Electroencephalogram showed a generalised 3 Hz spike and wave activity suggestive of absence seizures. CSF glucose level was 2.1 mmol/L (reference range 2.8–4.4 mmol/L) with CSF: blood glucose ratio 0.48 (normal range 0.41–0.88). Epilepsy gene panel testing identified a de novo variant of unknown significance in SLC2A1 (c.730 A>G (p.Met244Val)). Given the diagnostic uncertainty, direct quantification of Glut1 by flow cytometry (METAglut1 assay) was performed on whole blood, demonstrating a 25 % reduction in Glut1 protein expression at the proband's red blood cell membrane, consistent with Glut1DS. She was started on the modified Atkins diet with complete cessation of absence seizures after 24 h on the diet, was later weaned off ethosuximide and remained seizure free.

Conclusions

Non-invasive Glut1 testing can be performed with rapid turnaround (2 h from sample preparation to results) in suspected Glut1DS patients, facilitating diagnostic confirmation and early treatment initiation.