Neuropediatrics 2017; 48(03): 166-184
DOI: 10.1055/s-0037-1601449
Original Article
Georg Thieme Verlag KG Stuttgart · New York

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

Gillian I. Rice
1   Division of Evolution and Genomic Sciences, Manchester Academic Health Science Centre, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
,
Naoki Kitabayashi
2   Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR 1163, Paris, France
3   Sorbonne-Paris-Cité, Institut Imagine, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris Descartes University, Paris, France
,
Magalie Barth
4   Department of Genetics, CHU Angers, Angers, France
,
Tracy A. Briggs
1   Division of Evolution and Genomic Sciences, Manchester Academic Health Science Centre, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
5   Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, St Mary's Hospital, Manchester, United Kingdom
,
Annabel C.E. Burton
6   Department of Paediatrics and Child Health, St George's University Hospitals NHS Foundation Trust, London, United Kingdom
,
Maria Luisa Carpanelli
7   Department of Child Neurology and Psychiatry, A. Manzoni Hospital, Lecco, Italy
,
Alfredo M. Cerisola
8   Department of Pediatric Neurology, Facultad de Medicina, UDELAR, Montevideo, Uruguay
,
Cindy Colson
9   Clinique de Génétique, Hôpital Jeanne de Flandre, CHU Lille, Lille, France
,
Russell C. Dale
10   Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, University of Sydney, Sydney, Australia
,
Federica Rachele Danti
11   Department of Developmental Neurosciences, Institute of Child Health, UCL, London, United Kingdom
12   Department of Neurology, Great Ormond Street Hospital, London, United Kingdom
13   Department of Paediatrics, Child Neurology and Psychiatry, Sapienza University, Rome, Italy
,
Niklas Darin
14   Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden
,
Begoña De Azua
15   Department of Pediatrics, Hospital Son Llátzer, Palma de Mallorca, Spain
,
Valentina De Giorgis
16   Child Neurology and Psychiatry Unit, C. Mondino National Neurological Institute, Pavia, Italy
,
Christian G.L De Goede
17   Department of Paediatric Neurology, Royal Preston Hospital, Preston, United Kingdom
,
Isabelle Desguerre
18   Department of Paediatric Neurology, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
,
Corinne De Laet
19   Nutrition and metabolic Unit, Hôpital Universitaire des Enfants Reine Fabiola, Brussels, Belgium
,
Atieh Eslahi
20   Department of Medical Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
,
Michael C. Fahey
21   Department of Paediatrics, Monash University, Melbourne, Australia
,
Penny Fallon
22   Department of Paediatric Neurology, St George's University Hospitals NHS Foundation Trust, London, United Kingdom
,
Alex Fay
23   Department of Neurology, University of California, California, San Francisco, United States
,
Elisa Fazzi
24   Unit of Child Neurology and Psychiatry, Department of Clinical and Experimental Sciences, Civil Hospital, University of Brescia, Brescia, Italy
,
Mark P. Gorman
25   Department of Neurology, Boston Children's Hospital, Boston, United States
,
Nirmala Rani Gowrinathan
26   Department of Neurology, Kaiser Permanente, Los Angeles, United States
,
Marie Hully
18   Department of Paediatric Neurology, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
,
Manju A. Kurian
11   Department of Developmental Neurosciences, Institute of Child Health, UCL, London, United Kingdom
12   Department of Neurology, Great Ormond Street Hospital, London, United Kingdom
,
Nicolas Leboucq
27   Neuroradiologie, CHU de Montpellier, Montpellier, France
,
Jean-Pierre S-M Lin
28   General Neurology and Complex Motor Disorders Service, Evelina Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom
,
Matthew A. Lines
29   Department of Pediatrics, University of Ottawa, Ottawa, Canada
,
Soe S. Mar
30   Department of Pediatric Neurology, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, United States
,
Reza Maroofian
31   Medical Research, RILD Wellcome Wolfson Centre, Exeter Medical School, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom
,
Laura Martí-Sanchez
32   Department of Child Neurology, Hospital Sant Joan de Déu, Esplugues de Llobregat, Catalonia, Spain
,
Gary McCullagh
33   Department of Paediatric Neurology, Royal Manchester Children's Hospital, Manchester, United Kingdom
,
Majid Mojarrad
20   Department of Medical Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
,
Vinodh Narayanan
34   Neurogenomics Division, Center for Rare Childhood Disorders, TGen – The Translational Genomics Research Institute, Phoenix, United States
,
Simona Orcesi
16   Child Neurology and Psychiatry Unit, C. Mondino National Neurological Institute, Pavia, Italy
,
Juan Dario Ortigoza-Escobar
32   Department of Child Neurology, Hospital Sant Joan de Déu, Esplugues de Llobregat, Catalonia, Spain
,
Belén Pérez-Dueñas
32   Department of Child Neurology, Hospital Sant Joan de Déu, Esplugues de Llobregat, Catalonia, Spain
,
Florence Petit
9   Clinique de Génétique, Hôpital Jeanne de Flandre, CHU Lille, Lille, France
,
Keri M. Ramsey
34   Neurogenomics Division, Center for Rare Childhood Disorders, TGen – The Translational Genomics Research Institute, Phoenix, United States
,
Magnhild Rasmussen
35   Department of Clinical Neurosciences for Children, and Unit for Congenital and Hereditary Neuromuscular Disorders, Oslo University Hospital, Oslo, Norway
,
François Rivier
36   Department of Neuropédiatrie and CR Maladies Neuromusculaires, CHU de Montpellier, France
37   PhyMedExp, University of Montpellier, INSERM U1046, CNRS UMR 9214, Montpellier, France
,
Pilar Rodríguez-Pombo
38   Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma Madrid, CIBERER, IDIPAZ, Madrid, Spain
,
Agathe Roubertie
36   Department of Neuropédiatrie and CR Maladies Neuromusculaires, CHU de Montpellier, France
39   INSERM U1051, Institut des Neurosciences de Montpellier, Montpellier, France
,
Tommy I. Stödberg
40   Neuropediatric Unit, Karolinska University Hospital, Stockholm, Sweden
,
Mehran Beiraghi Toosi
41   Department of Pediatric Neurology, Ghaem Medical Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
,
Annick Toutain
42   Service de Génétique, CHU de Tours, Tours, France
,
Florence Uettwiller
43   Pediatric Immunology-Hematology and Rheumatology Unit, Institut Imagine, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
44   Department of Allergology and Clinical Immunology, CHRU Tours, Tours, France
,
Nicole Ulrick
45   Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States
,
Adeline Vanderver
45   Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States
,
Amy Waldman
45   Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States
,
John H. Livingston
46   Department of Paediatric Neurology, Leeds General Infirmary, Leeds, United Kingdom
,
Yanick J. Crow
1   Division of Evolution and Genomic Sciences, Manchester Academic Health Science Centre, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
2   Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR 1163, Paris, France
3   Sorbonne-Paris-Cité, Institut Imagine, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris Descartes University, Paris, France
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Weitere Informationen

Publikationsverlauf

09. Januar 2017

21. Februar 2017

Publikationsdatum:
10. April 2017 (online)

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.

Funding

Y.J.C. acknowledges funding from the European Research Council (GA 309449: Fellowship to Y.J.C.), ERA-NET Neuron (MR/M501803/1), and a state subsidy managed by the National Research Agency (France) under the “Investments for the Future” (ANR-10-IAHU-01). T.A.B. acknowledges funding from the NIHR. V.N. and K.M.R. acknowledge the clinical support of the C4RCD Research Group.


 
  • References

  • 1 Liddicoat BJ, Chalk AM, Walkley CR. ADAR1, inosine and the immune sensing system: distinguishing self from non-self. Wiley Interdiscip Rev RNA 2016; 7 (02) 157-172
  • 2 Hartner JC, Walkley CR, Lu J, Orkin SH. ADAR1 is essential for the maintenance of hematopoiesis and suppression of interferon signaling. Nat Immunol 2009; 10 (01) 109-115
  • 3 Liddicoat BJ, Piskol R, Chalk AM. , et al. RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science 2015; 349 (6252): 1115-1120
  • 4 Pestal K, Funk CC, Snyder JM, Price ND, Treuting PM, Stetson DB. Isoforms of RNA-editing enzyme ADAR1 independently control nucleic acid sensor MDA5-driven autoimmunity and multi-organ development. Immunity 2015; 43 (05) 933-944
  • 5 Rice GI, Kasher PR, Forte GM. , et al. Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature. Nat Genet 2012; 44 (11) 1243-1248
  • 6 Livingston JH, Lin JP, Dale RC. , et al. A type I interferon signature identifies bilateral striatal necrosis due to mutations in ADAR1. J Med Genet 2014; 51 (02) 76-82
  • 7 Crow YJ, Zaki MS, Abdel-Hamid MS. , et al. Mutations in ADAR1, IFIH1, and RNASEH2B presenting as spastic paraplegia. Neuropediatrics 2014; 45 (06) 386-393
  • 8 La Piana R, Uggetti C, Olivieri I. , et al. Bilateral striatal necrosis in two subjects with Aicardi-Goutières syndrome due to mutations in ADAR1 (AGS6). Am J Med Genet A 2014; 164A (03) 815-819
  • 9 La Piana R, Uggetti C, Roncarolo F. , et al. Neuroradiologic patterns and novel imaging findings in Aicardi-Goutières syndrome. Neurology 2016; 86 (01) 28-35
  • 10 Palisano R, Rosenbaum P, Walter S, Russell D, Wood E, Galuppi B. Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol 1997; 39 (04) 214-223
  • 11 Eliasson AC, Krumlinde-Sundholm L, Rösblad B. , et al. The Manual Ability Classification System (MACS) for children with cerebral palsy: scale development and evidence of validity and reliability. Dev Med Child Neurol 2006; 48 (07) 549-554
  • 12 Hidecker MJ, Paneth N, Rosenbaum PL. , et al. Developing and validating the Communication Function Classification System for individuals with cerebral palsy. Dev Med Child Neurol 2011; 53 (08) 704-710
  • 13 Tojo K, Sekijima Y, Suzuki T. , et al. Dystonia, mental deterioration, and dyschromatosis symmetrica hereditaria in a family with ADAR1 mutation. Mov Disord 2006; 21 (09) 1510-1513
  • 14 Heale BS, Keegan LP, McGurk L. , et al. Editing independent effects of ADARs on the miRNA/siRNA pathways. EMBO J 2009; 28 (20) 3145-3156
  • 15 Hayashi M, Suzuki T. Dyschromatosis symmetrica hereditaria. J Dermatol 2013; 40 (05) 336-343
  • 16 Kono M, Matsumoto F, Suzuki Y. , et al. Dyschromatosis symmetrica hereditaria and Aicardi-Goutières syndrome 6 are phenotypic variants caused by ADAR1 mutations. J Invest Dermatol 2016; 136 (04) 875-878
  • 17 Crow YJ. Type I interferonopathies: a novel set of inborn errors of immunity. Ann N Y Acad Sci 2011; 1238: 91-98
  • 18 Crow YJ, Manel N. Aicardi-Goutières syndrome and the type I interferonopathies. Nat Rev Immunol 2015; 15 (07) 429-440
  • 19 Crow YJ, Chase DS, Lowenstein Schmidt J. , et al. Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. Am J Med Genet A 2015; 167A (02) 296-312
  • 20 Rice GI, Forte GM, Szynkiewicz M. , et al. Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study. Lancet Neurol 2013; 12 (12) 1159-1169
  • 21 Rice GI, Melki I, Frémond ML. , et al. Assessment of type I interferon signaling in pediatric inflammatory disease. J Clin Immunol 2017; 37 (02) 123-132
  • 22 Toth AM, Li Z, Cattaneo R, Samuel CE. RNA-specific adenosine deaminase ADAR1 suppresses measles virus-induced apoptosis and activation of protein kinase PKR. J Biol Chem 2009; 284 (43) 29350-29356
  • 23 Kavanagh D, McGlasson S, Jury A. , et al. Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature. Blood 2016; 128 (24) 2824-2833
  • 24 Akwa Y, Hassett DE, Eloranta ML. , et al. Transgenic expression of IFN-alpha in the central nervous system of mice protects against lethal neurotropic viral infection but induces inflammation and neurodegeneration. J Immunol 1998; 161 (09) 5016-5026
  • 25 Campbell IL, Krucker T, Steffensen S. , et al. Structural and functional neuropathology in transgenic mice with CNS expression of IFN-alpha. Brain Res 1999; 835 (01) 46-61
  • 26 Barlow CF, Priebe CJ, Mulliken JB. , et al. Spastic diplegia as a complication of interferon Alfa-2a treatment of hemangiomas of infancy. J Pediatr 1998; 132 (3 Pt 1): 527-530
  • 27 Michaud AP, Bauman NM, Burke DK, Manaligod JM, Smith RJ. Spastic diplegia and other motor disturbances in infants receiving interferon-alpha. Laryngoscope 2004; 114 (07) 1231-1236
  • 28 Vitali P, Scadden AD. Double-stranded RNAs containing multiple IU pairs are sufficient to suppress interferon induction and apoptosis. Nat Struct Mol Biol 2010; 17 (09) 1043-1050
  • 29 Frémond ML, Rodero MP, Jeremiah N. , et al. Efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in the treatment of vasculopathy associated with TMEM173-activating mutations in 3 children. J Allergy Clin Immunol 2016; 138 (06) 1752-1755