Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease

Gillian I. Rice, Naoki Kitabayashi, Magalie Barth, Tracy A. Briggs, Annabel C.E. Burton, Maria Luisa Carpanelli, Alfredo M. Cerisola, Cindy Colson, Russell C. Dale, Federica Rachele Danti, Niklas Darin, Begoña De Azua, Valentina De Giorgis, Christian G.L. De Goede, Isabelle Desguerre, Corinne De Laet, Atieh Eslahi, Michael C. Fahey, Penny Fallon, Alex FayElisa Fazzi, Mark P. Gorman, Nirmala Rani Gowrinathan, Marie Hully, Manju A. Kurian, Nicolas Leboucq, Jean Pierre S.M. Lin, Matthew A. Lines, Soe S. Mar, Reza Maroofian, Laura Martí-Sanchez, Gary McCullagh, Majid Mojarrad, Vinodh Narayanan, Simona Orcesi, Juan Dario Ortigoza-Escobar, Belén Pérez-Dueñas, Florence Petit, Keri M. Ramsey, Magnhild Rasmussen, François Rivier, Pilar Rodríguez-Pombo, Agathe Roubertie, Tommy I. Stödberg, Mehran Beiraghi Toosi, Annick Toutain, Florence Uettwiller, Nicole Ulrick, Adeline Vanderver, Amy Waldman, John H. Livingston, Yanick J. Crow

Research output: Contribution to journalArticleResearchpeer-review

12 Citations (Scopus)

Abstract

We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context.

Original languageEnglish
Pages (from-to)166-184
Number of pages19
JournalNeuropediatrics
Volume48
Issue number3
DOIs
Publication statusPublished - 1 Jun 2017

Keywords

  • Aicardi-Goutières syndrome
  • bilateral striatal necrosis
  • dystonia
  • idiopathic basal ganglia calcification
  • spastic paraparesis

Cite this

Rice, G. I., Kitabayashi, N., Barth, M., Briggs, T. A., Burton, A. C. E., Carpanelli, M. L., ... Crow, Y. J. (2017). Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease. Neuropediatrics, 48(3), 166-184. https://doi.org/10.1055/s-0037-1601449