title: Paroxysmal choreoathetosis/spasticity (DYT9) is caused by a GLUT1 defect.
abstract: OBJECTIVE
  Mutations in SLC2A1, encoding the glucose transporter type 1 (GLUT1), cause a broad spectrum of neurologic disorders including classic GLUT1 deficiency syndrome, paroxysmal exercise-induced dyskinesia (PED, DYT18), and absence epilepsy. A large German/Dutch pedigree has formerly been described as paroxysmal choreoathetosis/spasticity (DYT9) and linked close to but not including the SLC2A1 locus on chromosome 1p. We tested whether 1) progressive spastic paraparesis, in addition to PED, as described in DYT9, and 2) autosomal dominant forms of hereditary spastic paraparesis (HSP) without PED are caused by SLC2A1 defects.
  
  
  METHODS
  The German/Dutch family and an Australian monozygotic twin pair were clinically (re-)investigated, and 139 index cases with dominant or sporadic HSP in which relevant dominant genes were partially excluded were identified from databanks. SLC2A1 was sequenced in all cases in this observational study and the functional effects of identified sequence variations were tested in glucose uptake and protein expression assays.
  
  
  RESULTS
  We identified causative mutations in SLC2A1 in both families, which were absent in 400 control chromosomes, cosegregated with the affection status, and decreased glucose uptake in functional assays. In the 139 index patients with HSP without paroxysmal dyskinesias, we only identified one sequence variation, which, however, neither decreased glucose uptake nor altered protein expression.
  
  
  CONCLUSIONS
  This study shows that DYT9 and DYT18 are allelic disorders and enlarges the spectrum of GLUT1 phenotypes, now also including slowly progressive spastic paraparesis combined with PED. SLC2A1 mutations were excluded as a cause of HSP without PED in our cohort.
authors.affiliation: Departments of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Y G
authors.initials: YG
authors.lastname: Weber
authors.forename: C
authors.initials: C
authors.lastname: Kamm
authors.forename: A
authors.initials: A
authors.lastname: Suls
authors.forename: J
authors.initials: J
authors.lastname: Kempfle
authors.forename: K
authors.initials: K
authors.lastname: Kotschet
authors.forename: R
authors.initials: R
authors.lastname: Schüle
authors.forename: T V
authors.initials: TV
authors.lastname: Wuttke
authors.forename: S
authors.initials: S
authors.lastname: Maljevic
authors.forename: J
authors.initials: J
authors.lastname: Liebrich
authors.forename: T
authors.initials: T
authors.lastname: Gasser
authors.forename: A C
authors.initials: AC
authors.lastname: Ludolph
authors.forename: W
authors.initials: W
authors.lastname: Van Paesschen
authors.forename: L
authors.initials: L
authors.lastname: Schöls
authors.forename: P
authors.initials: P
authors.lastname: De Jonghe
authors.forename: G
authors.initials: G
authors.lastname: Auburger
authors.forename: H
authors.initials: H
authors.lastname: Lerche
mesh_terms: D000328:Adult; D000483:Alleles; D000818:Animals; D002819:Chorea / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D005260:Female; D005799:Genes, Dominant; D051272:Glucose Transporter Type 1 / Q000235:genetics*; D006801:Humans; D008297:Male; D009128:Muscle Spasticity / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D014430:Twins, Monozygotic / Q000235:genetics*; D014982:Xenopus laevis
chemical_list: D051272:Glucose Transporter Type 1; C495677:SLC2A1 protein, human