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Prospective Multicenter Validation of a Simple Blood Test for the Diagnosis of Glut1 Deficiency Syndrome
Fanny Mochel1, Domitille Gras2, Marie-Pierre Luton2
1From the Hôpital La Pitié-Salpêtrière (F.M., M-P.L., C.D.), Assistance-Publique Hôpitaux de Paris, Inserm U1127; Sorbonne University (D.Gras), Inserm U1127, CNRS UMR7225, Paris Brain Institute; U1141 Neurodiderot (D.Gras), équipe 5 InDev, Inserm, CEA, UP UNIACT, Neurospin, Joliot, DRF, CEA-Saclay; Metafora Biosystems (M.N., V.P.); Institut de Génétique Moléculaire de Montpellier (D.Giovannini), Univ. Montpellier, CNRS; Service de Neurologie Pédiatrique (M.A.), Hôpital Necker-Enfants Malades, Assistance-Publique Hôpitaux de Paris; Service de Génétique (M.B.), Centre Hospitalier Universitaire Angers; Service de Neuropédiatrie (A.D.S-M.), Hôpital de Hautepierre, Strasbourg; Sorbonne Université (D.D.), Service de Neuropédiatrie-Pathologie du développement, Hôpital Trousseau AP-HP.SU, FHU I2D2, Paris; Service de Neurologie et Réanimation Pédiatrique (N.E.), APHP, Hôpital Raymond Poincaré, Garches; Service de Neurologie Pédiatrique (A.G.), Hôpital Nord, Grenoble; Service de Neurologie Pédiatrique (C.H.L.C.), et Unité de recherche clinique, module plurithématique sous axe pédiatrique CI 1436, Hôpital des enfants, CHU Toulouse; Service de Neurologie Pédiatrique (C.H.), Hôpital La Timone, Assistance-Publique Hôpitaux de Marseille; Service de Neuropédiatrie (S.N.T.T.), CRMR Epilepsies Rares, Hôpital Roger Salengro, Lille; Service de Neuropédiatrie et handicaps (M.P.), Hôpital pédiatrique Gatien de Clocheville, CHU de Tours; Pole Mère Enfant (S.R.), Centre Hospitalier de la Côte Basque, Bayonne; Service de Neuropédiatrie (A.R.), Hôpital Mère-Enfant, Nantes; Département de Neuropédiatrie, Centre d'investigation Clinique Inserm (A.R.), INM, Univ Montpellier, INSERM U 1298, CHU Montpellier, CIC1411; Service de Pédiatrie (C.Sarret), Hôpital Estaing, CHU Clermont-Ferrand; Service de Neurologie Pédiatrique (C.Sevin), Hôpital Bicêtre, Assistance-Publique Hôpitaux de Paris; Service de Neurologie Pédiatrique (D.V.), Hôpital Femme Mère Enfant, Centre Hospitalier de Lyon; Institut de Génétique Moléculaire de Montpellier (M.S.), Univ. Montpellier, CNRS; Laboratoire Cerba (J-M.C.), Saint-Ouen l'Aumône, France; Department of Pediatrics (R.P.), Aghia Sofia Hospital, University of Athens, Greece; Department of Neurology (A.G-C.), Hospital Sant Joan de Déu, Barcelona, Spain; Service de Biochimie et Génétique (S.V.), Hôpital Bichat Claude Bernard, APHP, Paris; CRMR Leukofrance Service de neuropediatrie (O.B-T.), Hôpital Robert Debré, AP-HP, Paris; UMR1141, Neurodiderot Université de Paris, France; Department of Pediatrics (D.C.D.V.), Columbia University Irving Medical Center, New York. fanny.mochel@upmc.fr.
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.
