A simple blood test expedites the diagnosis of glucose transporter type 1 deficiency syndrome

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Glucose transporter type 1 (GLUT1) deficiency syndrome (GLUT1‐DS) is caused by impaired glucose transport across the blood–brain barrier and into astrocytes attributed to heterozygous, likely mostly de novo, mutations in the SLC2A1 gene encoding the glucose transporter, GLUT1.1 GLUT1 is a membrane‐bound glycoprotein expressed in erythrocytes, brain microvessels, and glial cells. SLC2A1 mutations limit brain glucose availability and lead to cerebral energy deficiency. As a consequence, GLUT1‐DS manifests with a wide range of neurological symptoms, including cognitive impairment, epilepsy, and permanent and/or paroxysmal motor disorders that usually start in early childhood.1 Early detection of GLUT1‐DS is critical given that the disease is treatable with ketogenic diets3 and, possibly, novel experimental therapies.4
Any neuropediatrician or neurologist can encounter patients with GLUT1‐DS. Its diagnosis is, however, challenging because of the great heterogeneity of symptoms and ages at onset. Besides the classical severe infantile‐onset epileptic encephalopathy, adult‐onset forms have been described with epilepsy or paroxysmal movement disorders as the sole manifestations.6 The 3‐O‐methyl‐D‐glucose (OMG) uptake assay is an important functional measure of glucose transport across the red blood cell (RBC) membrane,7 but is not available on a clinical basis because it implies the use of radioactivity and precautions in blood sample storage and preanalytical steps.8 In a patient whose phenotype suggests GLUT1‐DS, the diagnosis thus relies on lumbar puncture (LP)—that is, low cerebrospinal fluid (CSF) glucose concentration, supported by low CSF lactate—and SLC2A1 molecular analysis. These approaches have some limitations. LP must be performed after at least 6 hours of fasting, is invasive, and runs the risk of complications.9 Moreover, an unequivocal cutoff has not been set to date for CSF glucose, with an heterogeneity in current practice although the most used value is 2.2mM.8 On the other hand, the analysis of the coding regions of SLC2A1 can be tedious, inconclusive in case of variants of unknown significance, or may fail at identifying variants despite a very suggestive clinical and biochemical phenotype.10
A minimally invasive and rapid diagnostic test for GLUT1‐DS, readily available in clinical practice, would be an invaluable tool for the early detection of GLUT1‐DS. Here, we tested a novel diagnostic test on RBCs, using flow cytometry, on a series of consecutive GLUT1 deficient patients with predominant movement disorders, compared to patients with movement disorders attributed to other genetic defects and healthy controls.
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