From splitting GLUT1 deficiency syndromes to overlapping phenotypes

Abstract

Introduction

Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a rare genetic disorder due to mutations or deletions in SLC2A1, resulting in impaired glucose uptake through the blood brain barrier. The classic phenotype includes pharmacoresistant epilepsy, intellectual deficiency, microcephaly and complex movement disorders, with hypoglycorrhachia, but milder phenotypes have been described (carbohydrate-responsive phenotype, dystonia and ataxia without epilepsy, paroxysmal exertion-induced dystonia).

The aim of our study was to provide a comprehensive overview of GLUT1DS in a French cohort.

Methods

265 patients were referred to the French national laboratory for molecular screening between July 2006 and January 2012. Mutations in SLC2A1 were detected in 58 patients, with detailed clinical data available in 24, including clinical features with a focus on their epileptic pattern and electroencephalographic findings, biochemical findings and neuroimaging findings.

Results

53 point mutations and 5 deletions in SLC2A1 were identified. Most patients (87.5%) exhibited classic phenotype with intellectual deficiency (41.7%), epilepsy (75%) or movement disorder (29%) as initial symptoms at a medium age of 7.5 months, but diagnostic was delayed in most cases (median age at diagnostic 8 years 5 months). Sensitivity to fasting or exertion in combination with those 3 main symptoms were the main differences between mutated and negative patients (p < 0.001). Patients with myoclonic seizures (52%) evolved with more severe intellectual deficiency and movement disorders compared with those with Early Onset Absence Epilepsy (38%). Three patients evolved from a classic phenotype during early childhood to a movement disorder predominant phenotype at a late childhood/adulthood.

Conclusions

Our data confirm that the classic phenotype is the most frequent in GLUT1DS. Myoclonic seizures are a distinctive feature of severe forms. However a great variability among patients and overlapping through life from milder classic phenotype to paroxysmal-prominent- movement-disorder phenotype are possible, thus making it difficult to identify definite genotype–phenotype correlations.

Introduction

Glucose transporter type-1 deficiency syndrome (GLUT1DS) (OMIM # 606777) is due to altered glucose transport into the brain caused by mutations in SLC2A1 encoding a trans-membrane protein (Seidner et al., 1998, Wang et al., 2000). Hypoglycorrhachia (<10th percentile), caused by impaired glucose transport, with a cerebrospinal fluid (CSF) to blood ratio below the 25th percentile and CSF lactate below the 10th percentile, are the key diagnostic features (De Vivo et al., 1991, Klepper et al., 1999, Klepper and Voit, 2002, Leen et al., 2013). GLUT1DS often presents as a haploinsufficiency disorder resulting from de novo SLC2A1 mutations in most cases, or an autosomal dominant pattern of inheritance (Brockmann et al., 2001, Klepper et al., 2001), autosomal recessive pattern has been described infrequently (Pearson et al., 2013, Rotstein et al., 2010). Approximately 70–80% of GLUT1DS patients carry SLC2A1 mutations (De Giorgis and Veggiotti, 2013) being either nonsense, missense, insertion, deletion, frameshift or splice-site and leading to absence or loss of function of the transporter (transporter function) (Leen et al., 2010, Seidner et al., 1998, Wang et al., 2000).

Early descriptions of GLUT1DS emphasized the combination of early onset drug resistant infantile seizures, developmental delay, acquired microcephaly, complex movement disorders, spasticity and ataxia (De Vivo et al., 2002, Klepper and Leiendecker, 2007). This phenotype is now defined “classic” (GLUT1DS1) with variable severity, ranging from mild motor and cognitive dysfunction between epileptic attacks to severe neurological disability. Since the seminal description, several clinical variants have been reported (Brockmann, 2009) including (i) carbohydrate responsive symptoms (correlation between fasting and neurological symptoms) (Akman et al., 2010), (ii) predominant ataxia or dystonia without seizures and (iii) paroxysmal exercise-induced dyskinesia with or without epilepsy (Brockmann, 2009, Pons et al., 2010, Schneider et al., 2009, Suls et al., 2008, Weber et al., 2008, Zorzi et al., 2008). Moreover, numerous additional presentations have been reported: choreoathetosis (Friedman et al., 2006), alternating hemiplegia (Rotstein et al., 2009), and intermittent ataxia/dystonia and migraine (De Giorgis and Veggiotti, 2013). Otherwise, a broader spectrum of epilepsy syndromes have been recognized including early-onset absence epilepsy (EOAE) beginning before age 4 years (Arsov et al., 2012a, Mullen et al., 2010, Suls et al., 2009), idiopathic generalized epilepsy (Arsov et al., 2012b, Striano et al., 2012), myoclono-astatic epilepsy (Mullen, 2011), focal seizures (Wolking et al., 2014) and infantile spasms (Pong et al., 2012). To date, no consensual classification of GLUT1DS on clinical grounds exists: some authors distinguish classic and non classic phenotypes, others split the disorder into (a) classic and complex phenotypes with intellectual disability (ID) in combination with epilepsy or a movement disorder, (b) “epilepsy-dominant” phenotype with seizures as the main symptom with or without movement disorders but without ID, and (c) “movement-disorder-dominant” phenotype without ID, nor seizures (Leen et al., 2014).

In light of these recent data, the aim of this study was to provide a comprehensive overview of the natural history of GLUT1DS using the thorough retrospective analysis of a cohort of 24 GLUT1DS French patients. We discuss the influence of the epileptic phenotype on the evolution of other features of the disease (ID, MD). Finally, we address the question of whether the definition of patient subgroups based on the clinical presentation is meaningful to predict their outcome.