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.

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

Glucose transporter type 1 (GLUT1) deficiency syndrome (GLUT1-DS) leads to a wide range of neurological symptoms. Ketogenic diets are very efficient to control epilepsy and movement disorders. We tested a novel simple and rapid blood test in 30 patients with GLUT1-DS with predominant movement disorders, 18 patients with movement disorders attributed to other genetic defects, and 346 healthy controls. We detected significantly reduced GLUT1 expression only on red blood cells from patients with GLUT1-DS (23 patients; 78%), including patients with inconclusive genetic analysis. This test opens perspectives for the screening of GLUT1-DS in children and adults with cognitive impairment, movement disorder, or epilepsy. Ann Neurol 2017;82:133-138.

A de novo 10p11.23-p12.1 deletion recapitulates the phenotype observed in WAC mutations and strengthens the role of WAC in intellectual disability and behavior disorders.

Chromosomal microarray analysis has become a powerful diagnostic tool in the investigation of patients with intellectual disability leading to the discovery of dosage sensitive genes implicated in the manifestation of various genomic disorders. Interstitial deletions of the short arm of chromosome 10 represent rare genetic abnormalities, especially those encompassing the chromosomal region 10p11-p12. To date, only 10 postnatal cases with microdeletion of this region have been described, and all patients shared a common phenotype, including intellectual disability, abnormal behavior, distinct dysmorphic features, visual impairment, and cardiac malformations. WAC was suggested to be the main candidate gene for intellectual disability associated with 10 p11-p12 deletion syndrome. Here, we describe a new case of de novo 10p11.23-p12.1 microdeletion in a patient with intellectual disability, abnormal behavior, and distinct dysmorphic features. Our observation allows us to redefine the smallest region of overlap among patients reported so far, with a size of 80 Kb and which contains only the WAC gene. These findings strengthen the hypothesis that haploinsufficency of WAC gene might be likely responsible for intellectual disability and behavior disorders. Our data also led us to propose a clinical pathway for patients with this recognizable genetic syndrome depending on the facial dysmorphisms. © 2016 Wiley Periodicals, Inc.

Sleep architecture impairment in epileptic children and putative role of anti epileptic drugs.

The comorbidity between epilepsy and sleep disorders is well documented. However, the mechanisms underlining this comorbidity are not fully understood. The putative role of anti epileptic drugs in sleep architecture disturbances in epileptic children needs to be explored. In this study, we analysed sleep architecture of 75 epileptic children (30 females and 45 males), aged from 4 to 15 years (mean-age: 8.3 years). They were divided in three groups according to their antiepileptic treatments: NT group: no antiepileptic treatment (n = 20), MT group: monotherapy (n = 29) and PT group: polytherapy (n = 26). All underwent video-polysomnographic recordings to assess main sleep parameters: stages of light sleep and slow waves sleep, REM sleep, total sleep time and awakenings. Percentages of paroxystic activity duration (PA) on TST were also calculated and classified in three subgroups: (<5%, 5% ≤ PA ≤ 20% and >20%). As result, significant decreases of REM sleep and of the sleep efficiency as well as significant increased awakenings were observed in PT group comparing to the NT group. No significative difference was found concerning the light sleep and slow waves sleep. A correlation was also observed between awakenings and PA. First, our data confirm that sleep disorders remain a hidden companion of childhood epilepsy. Second, we demonstrate that anti epileptic drugs may have some causal contribution. Diagnosing sleep disturbances should be part of the management of childhood epilepsy and should be taken into account in the choice of therapeutic strategy.

Sleep-disordered breathing in children with congenital muscular dystrophies.

OBJECTIVE: Most types of neuromuscular diseases are known to be associated with a high risk of sleep-disordered breathing. We performed a prospective study in a well individualized group of muscular disorders, congenital muscular dystrophies (CMD), to characterize the frequency of sleep-disordered breathing and thereby to determine the potential usefulness of sleep studies in such patients. METHODS: Twenty CMD children (12 F, 8 M, aged 4-17 years) were included. Using overnight polysomnography, we determined the following parameters: sleep stages, sleep latency, sleep efficiency index, wake time duration, total sleep time (TST), apnea/hypopnea index (AHI), arterial blood oxygen saturation, and nocturnal paroxysmal EEG activity. RESULTS: As compared to healthy controls, we detected in our study group frequent awakenings, a decreased TST (mean 448 ± 44.4 min) and a decreased REM duration (mean 11.5 ± 3.5% of TST). Significant increase in wake time duration (28-90 min) and decrease in REM duration were observed in 12 patients. An apnea/hypopnea syndrome was detected in 13 patients (65%) with central apneas in 8, obstructive apneas in 2 and 3 mixed apneas in 3 patients. AHI was >10 in 3 cases, <10> 5 in 4 cases and were concomitant with blood oxygen de-saturation in four cases. NPA were detected in 10 patients ranging from 10 to 40% of TST. INTERPRETATION: Our results confirm the high incidence of sleep disordered breathing in children with CMD, and thereby, the usefulness of overnight polysomnography recordings in such patients.