Early Diagnosis of the GLUT1 Deficiency Syndrome With a Blood Based Test (METAglut1)

Evaluation of METAglut1 Diagnostic Test Performances in Patients With a Clinical Suspicion of GLUT1 Deficiency Syndrome

European Commission, Assistance Publique - Hôpitaux de Paris, Cemka-Eval, Ministry for Health and Solidarity, France, French National Authority for Health

The study aims at validating the diagnostic performances of the METAglut1, a blood in vitro diagnostic test, for the simple and early diagnosis of the Glut1 deficiency syndrome (Glut1DS, or De Vivo disease). The blood test will be carried out prospectively on patients presenting with a clinical suspicion of Glut1DS, blindly from the reference strategy, which consists in a lumbar puncture for glycorrhachia measurement, completed by a molecular analysis. The study will be conducted in more than 40 centers in France on up to 3,000 patients for 2 years.

The Glut1 Deficiency Syndrome (Glut1DS) is a debilitating, proteiform neurometabolic disorder caused by an impairment in the glucose transporter Glut1 at the cell surface. Patients suffer from seizures, movement disorders and intellectual disabilities. A timely diagnosis is of prime importance as this haploinsufficiency can be improved by the so-called ketogenic diet. By diagnosing Glut1DS early, based on symptoms associated with Glut1DS, healthcare providers can prescribe the Keto diet therapy early in the disease progression, which could prevent impairment of central nervous system function caused by the disease. Therefore, an early diagnosis of Glut1DS for its treatment is crucial. Currently, the disease is very difficult to diagnose correctly and in a timely manner. The current diagnosis practice requires a lumbar puncture in order to determine if hypoglycorrhachia occurs. The diagnosis result is then supported by the detection of a heterozygous pathogenic variant in slc2a1 gene. This diagnosis procedure is time consuming, expensive, and requires a geneticist's data interpretation. Currently, ketogenic diet therapy is the most efficient therapy for Glut1DS. METAglut1 is a first-in-kind IVD device used to aid in the diagnosis of the Glut1 Deficiency Syndrome (Glut1DS) by quantifying the cell surface expression level of the glucose transporter 1 (Glut1) on circulating human red blood cells. The METAglut1 IVD is primarily intended for use in pediatric patients older than 3 months, of both sexes, of any ethnic origin. The METAglut1 IVD may also be used to aid in the diagnosis of Glut1DS in adults with late onset symptoms. The METAglut1 IVD is authorized for marketing in the European Union pursuant to the CE mark and is currently being distributed in France. The study aims to validate the diagnostic performances of METAglut1. It will last for 2 years, more than 40 centers will participate in the study across France. Up to 3,000 patients with symptoms compatible with Glut1DS will be included prospectively; each of them will be tested for METAglut1, in parallel and blindly of the reference strategy. The METAglut1 test is performed by Laboratoire CERBA (Saint-Ouen l'Aumône, France). A retrospective cohort of already diagnosed patients will also be analyzed to add more data. Concordance analysis with the glycorrhachia, the first biochemical dosage involved in the reference strategy, will be performed, and overall diagnostic performances of METAglut1 calculated. Before to start analysis, a thorough data management plan was implemented with on-site monitoring, automated controls of eCRF and recoding after queries and data reviewing.

Glut1 Deficiency Syndrome, De Vivo Disease, Seizures, Movement Disorders, Intellectual Disability, Ataxia

The METAglut1 test is performed on each patient, in parallel and blindly of the reference diagnostic strategy which is performed through the current practice (lumbar puncture (LP) performed in the fasting state with glycemia measured right before LP, followed by genetic analyses (targeted slc2a1 analysis or gene panels or whole exome sequencing).

The METAglut1 test is performed blindly of the reference strategy. METAglut1's result masking is maintained for the investigator on the one hand, and the glycorrhachia value masking is maintained for the centralized testing laboratory in charge of METAglut1 on the other hand.

The METAglut1 test is performed on all patients included in the study. In parallel, patients included prospectively (based on a clinical suspicion) benefit from the reference diagnostic strategy through the current practice, starting with a lumbar puncture for glycorrhachia dosage.

Patients with confirmed Glut1DS diagnosis Already diagnosed patients are included retrospectively as well as patients with pending diagnosis at inclusion (inconsistent biological or genetic data).

A blood draw is performed on each patient for the METAglut1 test, and sent to Laboratoire CERBA, Saint-Ouen l'Aumône, France, for sample analysis.

This analysis will be performed on patients with a diagnosis of certainty, either positive or negative, in the prospective cohort. For this analysis two subgroups are distinguished: Patients with lumbar puncture, molecular analysis of the slc2a1 gene and METAglut1 testing. Patients with at least lumbar puncture and METAglut1 testing.

These analysis will be performed on patients with a diagnosis of certainty in the prospective cohort. For this analysis two subgroups are distinguished:. Patients with at least lumbar puncture and METAglut1 testing. Patients with at least molecular analysis of the slc2a1 gene and METAglut1 testing.

These analysis will be performed on patients with a diagnosis of certainty in the retrospective cohort and cumulated cohort (prospective and retrospective). For this analysis two subgroups are distinguished:. Patients with at least lumbar puncture and METAglut1 testing. Patients with at least molecular analysis of the slc2a1 gene and METAglut1 testing.

This analysis will be performed on patients with at least lumbar puncture and METAglut1 testing and with a diagnosis of certainty, either positive or negative, in the cumulative cohort (prospective and retrospective).

In a sensitivity analysis, the threshold of positivity of the METAglut1™ assay will vary between 75% and 80% and performances calculations will be reported for this variation.

The time between clinical suspicion of Glut1DS and diagnosis will be calculated and compared between different diagnostic strategies

Prospective patients - Inclusion Criteria: Clinical suspicion of the GLUT1 Deficiency Syndrome Retrospective patients - Inclusion Criteria: Patients with confirmed Glut1DS diagnosis Patients with pending diagnosis at inclusion (inconsistent biological or genetic data) Exclusion Criteria (for both cohorts): Patients under 3 months of age Sickle cell disease S/S Abnormal imaging

The data that support the findings of this study are available from the corresponding authors on reasonable request. Permissions are required to gain access to the data resources, subject to successful registration and application process.

Gras D, Cousin C, Kappeler C, Fung CW, Auvin S, Essid N, Chung BH, Da Costa L, Hainque E, Luton MP, Petit V, Vuillaumier-Barrot S, Boespflug-Tanguy O, Roze E, Mochel F. A simple blood test expedites the diagnosis of glucose transporter type 1 deficiency syndrome. Ann Neurol. 2017 Jul;82(1):133-138. doi: 10.1002/ana.24970.