title: Episodic ataxia associated with EAAT1 mutation C186S affecting glutamate reuptake.
abstract: BACKGROUND
  Episodic ataxia (EA) is variably associated with additional neurologic symptoms. At least 4 genes have been implicated. Recently, a mutation in the SLC1A3 gene encoding the glutamate transporter EAAT1 was identified in a patient with severe episodic and progressive ataxia, seizures, alternating hemiplegia, and migraine headache. The mutant EAAT1 showed severely reduced uptake of glutamate. The syndrome was designated EA6 and shares overlapping clinical features with EA2, which is caused by mutations in CACNA1A.
  
  
  OBJECTIVE
  To test the role of the SLC1A3 gene in EA.
  
  
  METHODS
  Genetic and functional studies. We analyzed the coding region of the SLC1A3 gene by direct sequencing.
  
  
  METHODS
  Academic research.
  
  
  METHODS
  DNA samples from 20 patients with EA (with or without interictal nystagmus) negative for CACNA1A mutations were analyzed.
  
  
  METHODS
  We identified 1 novel EAAT1 mutation in a family with EA and studied the functional consequences of this mutation using glutamate uptake assay.
  
  
  RESULTS
  We identified a missense C186S mutation that segregated with EA in 3 family members. The mutant EAAT1 showed a modest but significant reduction of glutamate uptake.
  
  
  CONCLUSIONS
  We broadened the clinical spectrum associated with SLC1A3 mutations to include milder manifestations of EA without seizures or alternating hemiplegia. The severity of EA6 symptoms appears to be correlated with the extent of glutamate transporter dysfunction.
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands.
authors.forename: Boukje
authors.initials: B
authors.lastname: de Vries
authors.forename: Hafsa
authors.initials: H
authors.lastname: Mamsa
authors.forename: Anine H
authors.initials: AH
authors.lastname: Stam
authors.forename: Jijun
authors.initials: J
authors.lastname: Wan
authors.forename: Stef L M
authors.initials: SL
authors.lastname: Bakker
authors.forename: Kaate R J
authors.initials: KR
authors.lastname: Vanmolkot
authors.forename: Joost
authors.initials: J
authors.lastname: Haan
authors.forename: Gisela M
authors.initials: GM
authors.lastname: Terwindt
authors.forename: Elles M J
authors.initials: EM
authors.lastname: Boon
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Howard
authors.forename: Rune R
authors.initials: RR
authors.lastname: Frants
authors.forename: Robert W
authors.initials: RW
authors.lastname: Baloh
authors.forename: Michel D
authors.initials: MD
authors.lastname: Ferrari
authors.forename: Joanna C
authors.initials: JC
authors.lastname: Jen
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
mesh_terms: D000328:Adult; D001923:Brain Chemistry / Q000235:genetics; D002531:Cerebellum / Q000378:metabolism / Q000503:physiopathology; D004252:DNA Mutational Analysis; D027341:Excitatory Amino Acid Transporter 1 / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D018698:Glutamic Acid / Q000378:metabolism*; D006429:Hemiplegia / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders / Q000235:genetics / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012640:Seizures / Q000235:genetics / Q000503:physiopathology; D013132:Spinocerebellar Degenerations / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D027341:Excitatory Amino Acid Transporter 1; D005819:Genetic Markers; C493394:SLC1A3 protein, human; D018698:Glutamic Acid