title: From splitting GLUT1 deficiency syndromes to overlapping phenotypes.
abstract: BACKGROUND
  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.
authors.affiliation: AP-HP, Necker-Enfants Malades Hospital, Department of Pediatric Neurology, Paris, France. Electronic address: marie.hully@nck.aphp.fr.
authors.forename: Marie
authors.initials: M
authors.lastname: Hully
authors.affiliation: AP-HP, Bichat Hospital, Biochemistry and Genetic Laboratory, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Vuillaumier-Barrot
authors.affiliation: AP-HP, Bichat Hospital, Biochemistry and Genetic Laboratory, Paris, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Le Bizec
authors.affiliation: AP-HP, Necker-Enfants Malades Hospital, Department of Pediatric Radiology, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.affiliation: AP-HP, Necker-Enfants Malades Hospital, Department of Neurophysiology, Paris, France.
authors.forename: Anna
authors.initials: A
authors.lastname: Kaminska
authors.affiliation: Evelina London Children's, Hospital Children's Neurosciences Centre, Block D, First Floor, SouthWing, St Thomas' Hospital, Westminster Bridge Road, London SE1 7EH, United Kingdom.
authors.forename: Karine
authors.initials: K
authors.lastname: Lascelles
authors.affiliation: AP-HP, Necker-Enfants Malades Hospital, Department of Pediatric Metabolic Disorders, Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
authors.affiliation: University Hospital of Toulouse, Children Hospital, Department of Pediatric Neurology, Toulouse, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Cances
authors.affiliation: University Hospital of Lyon, Department of Pediatric Neurology, Lyon, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: des Portes
authors.affiliation: University Hospital of Montpellier, Department of Pediatric Neurology, Montpellier, France.
authors.forename: Agathe
authors.initials: A
authors.lastname: Roubertie
authors.affiliation: AP-HP, Trousseau Hospital, Department of Pediatric Neurology, Paris, France.
authors.forename: Diane
authors.initials: D
authors.lastname: Doummar
authors.affiliation: Hospital of St-Brieuc, Department of Pediatrics, St-Brieuc, France.
authors.forename: Anne
authors.initials: A
authors.lastname: LeBihannic
authors.affiliation: AP-HP, Pitié-Salpêtrière Hospital, Department of Neurology, Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Degos
authors.affiliation: University Hospital of Strasbourg, Department of Pediatric Neurology, Strasbourg, France.
authors.forename: Anne
authors.initials: A
authors.lastname: de Saint Martin
authors.affiliation: University Hospital of Strasbourg, Department of Medical Genetics, Strasbourg, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Flori
authors.affiliation: Pellegrin Hospital, University Hospital of Bordeaux, Department of Pediatric Neurology, Bordeaux, France.
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Pedespan
authors.affiliation: University Hospital of Rouen, Department of Medical Genetics, Rouen, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Goldenberg
authors.affiliation: University Hospital of Rouen, Department of Neonatology and Pediatric Reanimation, Rouen, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Vanhulle
authors.affiliation: University Hospital of Rouen, Metabolic Biochemistry Department, Rouen, France.
authors.forename: Soumeya
authors.initials: S
authors.lastname: Bekri
authors.affiliation: AP-HP, Trousseau Hospital, Department of Pediatric Neurology, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Roubergue
authors.affiliation: AP-HP, Trousseau Hospital, Department of Pediatric Neurology, Paris, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Heron
authors.affiliation: Pays d'Aix Hospital, Department of Pediatrics, Aix en Provence, France.
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Cournelle
authors.affiliation: University Hospital of Nantes, Pediatric Intensive Care Unit, Nantes, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Kuster
authors.affiliation: University Hospital of Nantes, Pediatric Intensive Care Unit, Nantes, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Chenouard
authors.affiliation: University Hospital of Poitiers, Department of Pediatrics, Poitiers, France.
authors.forename: Marie-Noelle
authors.initials: MN
authors.lastname: Loiseau
authors.affiliation: AP-HP, Necker-Enfants Malades Hospital, Department of Pediatric Metabolic Disorders, Paris, France.
authors.forename: Vassili
authors.initials: V
authors.lastname: Valayannopoulos
authors.affiliation: AP-HP, Necker-Enfants Malades Hospital, Department of Pediatric Neurology, Paris, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Chemaly
authors.affiliation: AP-HP, Necker-Enfants Malades Hospital, Department of Pediatric Neurology, Paris, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Gitiaux
authors.affiliation: AP-HP, Bichat Hospital, Biochemistry and Genetic Laboratory, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Seta
authors.affiliation: AP-HP, Necker-Enfants Malades Hospital, Department of Pediatric Neurology, Paris, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Bahi-Buisson
mesh_terms: D000293:Adolescent; D000328:Adult; D002239:Carbohydrate Metabolism, Inborn Errors / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D055423:Diet, Ketogenic; D004827:Epilepsy / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D051272:Glucose Transporter Type 1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000172:deficiency* / Q000235:genetics; D009069:Movement Disorders / Q000235:genetics; D009123:Muscle Hypotonia / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D012189:Retrospective Studies; D012640:Seizures / Q000235:genetics; D055815:Young Adult
chemical_list: D051272:Glucose Transporter Type 1; D009004:Monosaccharide Transport Proteins; C495677:SLC2A1 protein, human
keywords: Child; Epilepsy; Genotype; Glut1 deficiency syndrome (GLUT1DS); Outcome; Phenotype