From 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.
Neurology. 2023 Jun 6;100(23):e2360-e2373. doi: 10.1212/WNL.0000000000207296. Epub 2023 Apr 19.
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 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.
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 gene, and a retrospective cohort that included patients previously diagnosed with Glut1DS. All patients were blind-tested with METAglut1.
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 mosaicism and variants of unknown significance.
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.
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.
GLUT1 缺乏综合征（Glut1DS）是一种可治疗的神经代谢疾病，可导致儿童和成人出现广泛的神经症状。然而，其诊断依赖于有创性检查，即腰椎穿刺（LP）以测量糖脑脊液，有时还需要对 基因进行复杂的分子分析。该程序限制了能够接受标准治疗的患者数量。我们希望验证 METAglut1 的诊断性能，这是一种简单的血液测试，可定量红细胞表面的 GLUT1。
我们在法国进行了一项多中心验证研究，涉及 33 个中心。我们研究了 2 个患者队列：一个前瞻性队列，由通过参考策略（即 LP 和 基因分析）探索有 Glut1DS 临床可疑的患者组成；一个回顾性队列，其中包括先前诊断为 Glut1DS 的患者。所有患者均接受 METAglut1 盲法检测。
我们对前瞻性队列中的 428 例患者进行了分析，包括 15 例新诊断的 Glut1DS 患者和 67 例回顾性队列患者。METAglut1 对 Glut1DS 的诊断具有 80%的敏感性和>99%的特异性。一致性分析显示，METAglut1 与糖脑脊液之间存在高度一致性。在前瞻性队列中，METAglut1 的阳性预测值略高于糖脑脊液。METAglut1 成功识别了具有 Glut1DS 镶嵌性和未知意义变异的患者。
METAglut1 是一种易于操作、稳健且非侵入性的诊断测试，可用于诊断 Glut1DS，可广泛筛查儿童和成人，包括那些具有这种可治疗疾病的非典型形式的患者。
这项研究提供了 I 级证据，表明与有创性和基因检测相比，阳性 METAglut1 检测可准确区分疑似 GLUT1 缺乏综合征患者与其他神经综合征患者。
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