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A type I interferon signature identifies bilateral striatal necrosis due to mutations in ADAR1
  1. John H Livingston1,
  2. Jean-Pierre Lin2,
  3. Russell C Dale3,
  4. Deepak Gill3,
  5. Paul Brogan4,5,
  6. Arnold Munnich6,
  7. Manju A Kurian7,8,
  8. Victoria Gonzalez-Martinez9,
  9. Christian G E L De Goede10,
  10. Alastair Falconer11,
  11. Gabriella Forte12,
  12. Emma M Jenkinson12,
  13. Paul R Kasher12,
  14. Marcin Szynkiewicz12,
  15. Gillian I Rice12,
  16. Yanick J Crow12,13
  1. 1Department of Paediatric Neurology, Leeds General Infirmary, Leeds, UK
  2. 2General Neurology & Complex Motor Disorders Service, Evelina Children's Neurosciences Centre, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK
  3. 3TY Nelson Department of Neurology, and Neuroimmunology group, The Children's Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia
  4. 4Department of Paediatric Rheumatology, University College London, Institute of Child Health, London, UK
  5. 5Great Ormond Street Hospital NHS Foundation Trust, London, UK
  6. 6Departement de Génétique, INSERM U781, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Hôpital Necker-Enfants Malades (AP-HP), Paris, France
  7. 7Department of Neurology, Great Ormond Street Hospital NHS Foundation Trust, London, UK
  8. 8Neurosciences Unit, Institute of Child Health, University College London, London, UK
  9. 9Department of Neurosurgery, Hôpital Gui de Chauliac, University Hospital of Montpellier, Montpellier, France
  10. 10Department of Paediatric Neurology, Royal Preston Hospital, Preston, UK
  11. 11Department of Paediatrics, Scarborough General Hospital, Scarborough, UK
  12. 12Department of Genetic Medicine, Faculty of Medical and Human Sciences, Institute of Human Development, University of Manchester, Manchester, UK
  13. 13Manchester Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust, St. Mary's Hospital, Manchester, UK
  1. Correspondence to Professor Y J Crow, Department of Genetic Medicine, University of Manchester, St Mary's Hospital, 6th Floor, Oxford Road, Manchester M13 9WL, UK; yanickcrow{at}


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.

  • Clinical genetics
  • Immunology (including allergy)
  • Molecular genetics
  • Neurology

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