title: A type I interferon signature identifies bilateral striatal necrosis due to mutations in ADAR1.
abstract: BACKGROUND
  We recently observed mutations in ADAR1 to cause a phenotype of bilateral striatal necrosis (BSN) in a child with the type I interferonopathy Aicardi-Goutières syndrome (AGS). We therefore decided to screen patients with apparently non-syndromic BSN for ADAR1 mutations, and for an upregulation of interferon-stimulated genes (ISGs).
  
  
  METHODS
  We performed Sanger sequencing of ADAR1 in a series of patients with BSN presenting to us during our routine clinical practice. We then undertook detailed clinical and neuroradiological phenotyping in nine mutation-positive children. We also measured the expression of ISGs in peripheral blood from these patients, and in children with BSN who did not have ADAR1 mutations.
  
  
  RESULTS
  Nine ADAR1 mutation-positive patients from seven families demonstrated an acute (five cases) or subacute (four cases) onset of refractory, four-limb dystonia starting between 8 months and 5 years of age. Eight patients were developmentally normal at initial presentation. In seven cases, the disease was inherited as an autosomal recessive trait, while two related patients were found to have a heterozygous (dominant) ADAR1 mutation. All seven mutation-positive patients assayed showed an upregulation of ISGs (median: 12.50, IQR: 6.43-36.36) compared to controls (median: 0.93, IQR: 0.57-1.30), a so-called interferon signature, present many years after disease onset. No interferon signature was present in four children with BSN negative for mutations in ADAR1 (median: 0.63, IQR: 0.47-1.10).
  
  
  CONCLUSIONS
  ADAR1-related disease should be considered in the differential diagnosis of apparently non-syndromic BSN with severe dystonia of varying evolution. The finding of an interferon signature provides a useful screening test for the presence of ADAR1 mutations in this context, and may suggest novel treatment approaches.
authors.affiliation: Department of Paediatric Neurology, Leeds General Infirmary, Leeds, UK.
authors.forename: John H
authors.initials: JH
authors.lastname: Livingston
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Lin
authors.forename: Russell C
authors.initials: RC
authors.lastname: Dale
authors.forename: Deepak
authors.initials: D
authors.lastname: Gill
authors.forename: Paul
authors.initials: P
authors.lastname: Brogan
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Manju A
authors.initials: MA
authors.lastname: Kurian
authors.forename: Victoria
authors.initials: V
authors.lastname: Gonzalez-Martinez
authors.forename: Christian G E L
authors.initials: CG
authors.lastname: De Goede
authors.forename: Alastair
authors.initials: A
authors.lastname: Falconer
authors.forename: Gabriella
authors.initials: G
authors.lastname: Forte
authors.forename: Emma M
authors.initials: EM
authors.lastname: Jenkinson
authors.forename: Paul R
authors.initials: PR
authors.lastname: Kasher
authors.forename: Marcin
authors.initials: M
authors.lastname: Szynkiewicz
authors.forename: Gillian I
authors.initials: GI
authors.lastname: Rice
authors.forename: Yanick J
authors.initials: YJ
authors.lastname: Crow
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics*; D016022:Case-Control Studies; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D007370:Interferon Type I / Q000502:physiology*; D008297:Male; D025202:Molecular Diagnostic Techniques; D020125:Mutation, Missense; D016601:RNA-Binding Proteins; D020955:Striatonigral Degeneration / Q000151:congenital* / Q000201:enzymology / Q000235:genetics
chemical_list: D007370:Interferon Type I; D016601:RNA-Binding Proteins; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase
keywords: Clinical genetics; Immunology (including allergy); Molecular genetics; Neurology