Prospective Multicenter Validation of a Simple Blood Test for the Diagnosis of Glut1 Deficiency Syndrome

Background and Objective GLUT1 deficiency syndrome (Glut1DS) is a treatable neurometabolic disease that causes a wide range of neurologic symptoms in children and adults. However, its diagnosis relies on an invasive test, that is, a lumbar puncture (LP) to measure glycorrhachia, and sometimes complex molecular analyses of the SLC2A1 gene. This procedure limits the number of patients able to receive the standard of care. We wished to validate the diagnostic performance of METAglut1, a simple blood test that quantifies GLUT1 on the erythrocyte surface. Methods We performed a multicenter validation study in France, involving 33 centers. We studied 2 patient cohorts: a prospective cohort consisting of patients with a clinical suspicion of Glut1DS explored through the reference strategy, that is, LP and analyses of the SLC2A1 gene, and a retrospective cohort that included patients previously diagnosed with Glut1DS. All patients were blind-tested with METAglut1. Results We analyzed 428 patients in the prospective cohort, including 15 patients newly diagnosed with Glut1DS, and 67 patients in the retrospective cohort. METAglut1 was 80% sensitive and >99% specific for the diagnosis of Glut1DS. Concordance analyses showed a substantial agreement between METAglut1 and glycorrhachia. In the prospective cohort, the positive predictive value of METAglut1 was slightly higher than that of glycorrhachia. METAglut1 succeeded to identify patients with Glut1DS with SCL2A1 mosaicism and variants of unknown significance. Discussion METAglut1 is an easily performed, robust, and noninvasive diagnostic test for the diagnosis of Glut1DS, which allows wide screening of children and adults, including those with atypical forms of this treatable condition. Classification of Evidence This study provides Class I evidence that a positive METAglut1 test accurately distinguishes patients with suspected GLUT1 deficiency syndrome from other neurologic syndromes as compared with invasive and genetic testing.

[1]  I. Scheffer,et al.  ILAE definition of the Idiopathic Generalized Epilepsy Syndromes: Position statement by the ILAE Task Force on Nosology and Definitions , 2022, Epilepsia.

[2]  Yan Liu,et al.  Clinical and Genetic Characteristics of Chinese Children With GLUT1 Deficiency Syndrome: Case Report and Literature Review , 2021, Frontiers in Genetics.

[3]  J. Kramer,et al.  Ketogenic Diet in Glut 1 Deficiency Through the Life Cycle: Pregnancy to Neonate to Preschooler , 2021, Child neurology open.

[4]  I. Scheffer,et al.  Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group , 2020, Epilepsia open.

[5]  P. V. van Hasselt,et al.  Glucose transporter type 1 deficiency syndrome and the ketogenic diet , 2019, Journal of Inherited Metabolic Disease.

[6]  Alireza Paikari,et al.  Association between GLUT1 and HbF Levels in Red Blood Cells from Patients with Sickle Cell Disease , 2019, Blood.

[7]  D. Pilz,et al.  Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort , 2019, Brain : a journal of neurology.

[8]  F. Mochel,et al.  Long-term follow-up in an open-label trial of triheptanoin in GLUT1 deficiency syndrome: a sustained dramatic effect , 2019, Journal of Neurology, Neurosurgery, and Psychiatry.

[9]  F. Villani,et al.  Screening of SLC2A1 in a large cohort of patients suspected for Glut1 deficiency syndrome: identification of novel variants and associated phenotypes , 2019, Journal of Neurology.

[10]  Jianzhong Su,et al.  Clinical Aspects of Glucose Transporter Type 1 Deficiency: Information From a Global Registry , 2017, JAMA neurology.

[11]  S. Auvin,et al.  A simple blood test expedites the diagnosis of glucose transporter type 1 deficiency syndrome , 2017, Annals of neurology.

[12]  B. Burnytė,et al.  Novel mutation in a patient with late onset GLUT1 deficiency syndrome , 2017, Brain and Development.

[13]  K. Engelstad,et al.  Diagnosing Glucose Transporter 1 Deficiency at Initial Presentation Facilitates Early Treatment. , 2016, The Journal of pediatrics.

[14]  P. Striano,et al.  The role of SLC2A1 mutations in myoclonic astatic epilepsy and absence epilepsy, and the estimated frequency of GLUT1 deficiency syndrome , 2015, Epilepsia.

[15]  N. Boddaert,et al.  From splitting GLUT1 deficiency syndromes to overlapping phenotypes. , 2015, European journal of medical genetics.

[16]  Bale,et al.  Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology , 2015, Genetics in Medicine.

[17]  M. Vidailhet,et al.  GLUT1 deficiency syndrome: an update. , 2014, Revue neurologique.

[18]  Ron A. Wevers,et al.  Cerebrospinal Fluid Glucose and Lactate: Age-Specific Reference Values and Implications for Clinical Practice , 2012, PloS one.

[19]  J. Klepper.  GLUT1 deficiency syndrome in clinical practice , 2012, Epilepsy Research.

[20]  Ying Wei,et al.  Glut1 deficiency syndrome and erythrocyte glucose uptake assay , 2011, Annals of neurology.

[21]  E. Cuenca-León,et al.  Paroxysmal exercise-induced dyskinesia, writer's cramp, migraine with aura and absence epilepsy in twin brothers with a novel SLC2A1 missense mutation , 2010, Journal of the Neurological Sciences.

[22]  B. Weschke,et al.  Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder. , 2010, Brain : a journal of neurology.

[23]  K. Engelstad,et al.  The spectrum of movement disorders in Glut‐1 deficiency , 2010, Movement disorders : official journal of the Movement Disorder Society.

[24]  F. Mottaghy,et al.  GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak. , 2008, The Journal of clinical investigation.

[25]  M. Sitbon,et al.  Erythrocyte Glut1 Triggers Dehydroascorbic Acid Uptake in Mammals Unable to Synthesize Vitamin C , 2008, Cell.

[26]  R. Christensen,et al.  The erythrocyte indices of neonates, defined using data from over 12 000 patients in a multihospital health care system , 2008, Journal of Perinatology.

[27]  Marco Craveiro,et al.  Isolated receptor binding domains of HTLV-1 and HTLV-2 envelopes bind Glut-1 on activated CD4+ and CD8+ T cells , 2007, Retrovirology.

[28]  Hong Yang,et al.  Glut‐1 deficiency syndrome: Clinical, genetic, and therapeutic aspects , 2005, Annals of Neurology.

[29]  M. Sitbon,et al.  The Ubiquitous Glucose Transporter GLUT-1 Is a Receptor for HTLV , 2003, Cell.

[30]  R. V. Van Heertum,et al.  Imaging the metabolic footprint of Glut1 deficiency on the brain , 2002, Annals of neurology.

[31]  F. Hanefeld,et al.  Autosomal dominant Glut‐1 deficiency syndrome and familial epilepsy , 2001, Annals of neurology.

[32]  J. Vera,et al.  GLUT1-Deficiency: Barbiturates Potentiate Haploinsufficiency in Vitro , 1999, Pediatric Research.

[33]  S. Harik,et al.  Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. , 1991, The New England journal of medicine.

[34]  J. R. Landis,et al.  The measurement of observer agreement for categorical data. , 1977, Biometrics.