title: ADORA2A polymorphism predisposes children to encephalopathy with febrile status epilepticus.
abstract: OBJECTIVE
  Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a childhood encephalopathy following severe febrile seizures, leaving neurologic sequelae in many patients. However, its pathogenesis remains unclear. In this study, we clarified that genetic variation in the adenosine A2A receptor (ADORA2A), whose activation is involved in excitotoxicity, may be a predisposing factor of AESD.
  
  
  METHODS
  We analyzed 4 ADORA2A single nucleotide polymorphisms in 85 patients with AESD. The mRNA expression in brain samples, mRNA and protein expression in lymphoblasts, as well as the production of cyclic adenosine monophosphate (cAMP) by lymphoblasts in response to adenosine were compared among ADORA2A diplotypes.
  
  
  RESULTS
  Four single nucleotide polymorphisms were completely linked, which resulted in 2 haplotypes, A and B. Haplotype A (C at rs2298383, T at rs5751876, deletion at rs35320474, and C at rs4822492) frequency in patients was significantly higher than in controls (p = 0.005). Homozygous haplotype A (AA diplotype) had a higher risk of developing AESD (odds ratio 2.32, 95% confidence interval 1.32-4.08; p = 0.003) via a recessive model. mRNA expression was significantly higher in AA than AB and BB diplotypes, both in the brain (p = 0.003 and 0.002, respectively) and lymphoblasts (p = 0.035 and 0.003, respectively). In lymphoblasts, ADORA2A protein expression (p = 0.024), as well as cellular cAMP production (p = 0.0006), was significantly higher in AA than BB diplotype.
  
  
  CONCLUSIONS
  AA diplotype of ADORA2A is associated with AESD and may alter the intracellular adenosine/cAMP cascade, thereby promoting seizures and excitotoxic brain damage in patients.
authors.affiliation: Department of Developmental Medical Sciences, Graduate School of Medicine, University of Tokyo, Japan.
authors.forename: Mayu
authors.initials: M
authors.lastname: Shinohara
authors.forename: Makiko
authors.initials: M
authors.lastname: Saitoh
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nishizawa
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ikeda
authors.forename: Shinichi
authors.initials: S
authors.lastname: Hirose
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Takanashi
authors.forename: Junko
authors.initials: J
authors.lastname: Takita
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kikuchi
authors.forename: Masaya
authors.initials: M
authors.lastname: Kubota
authors.forename: Gaku
authors.initials: G
authors.lastname: Yamanaka
authors.forename: Takashi
authors.initials: T
authors.lastname: Shiihara
authors.forename: Akira
authors.initials: A
authors.lastname: Kumakura
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kikuchi
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Toyoshima
authors.forename: Tomohide
authors.initials: T
authors.lastname: Goto
authors.forename: Hideo
authors.initials: H
authors.lastname: Yamanouchi
authors.forename: Masashi
authors.initials: M
authors.lastname: Mizuguchi
mesh_terms: D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D020641:Polymorphism, Single Nucleotide; D043705:Receptor, Adenosine A2A / Q000235:genetics*; D003294:Seizures, Febrile / Q000235:genetics*; D013226:Status Epilepticus / Q000235:genetics*
chemical_list: D043705:Receptor, Adenosine A2A
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