Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1
Authors: Crow Yanick J. , Chase Diana S. , Lowenstein Schmidt Johanna , Szynkiewicz Marcin , Forte Gabriella M.A. , Gornall Hannah L. , Oojageer Anthony , Anderson Beverley , Pizzino Amy , Helman Guy , Abdel‐Hamid Mohamed S. , Abdel‐Salam Ghada M. , Ackroyd Sam , Aeby Alec , Agosta Guillermo , Albin Catherine , Allon‐Shalev Stavit , Arellano Montse , Ariaudo Giada , Aswani Vijay , Babul‐Hirji Riyana , Baildam Eileen M. , Bahi‐Buisson Nadia , Bailey Kathryn M. , Barnerias Christine , Barth Magalie , Battini Roberta , Beresford Michael W. , Bernard Geneviève , Bianchi Marika , Billette de Villemeur Thierry , Blair Edward M. , Bloom Miriam , Burlina Alberto B. , Luisa Carpanelli Maria , Carvalho Daniel R. , Castro‐Gago Manuel , Cavallini Anna , Cereda Cristina , Chandler Kate E. , Chitayat David A. , Collins Abigail E. , Sierra Corcoles Concepcion , Cordeiro Nuno J.V. , Crichiutti Giovanni , Dabydeen Lyvia , Dale Russell C. , D′Arrigo Stefano , De Goede Christian G.E.L. , De Laet Corinne , De Waele Liesbeth M.H. , Denzler Ines , Desguerre Isabelle , Devriendt Koenraad , Di Rocco Maja , Fahey Michael C. , Fazzi Elisa , Ferrie Colin D. , Figueiredo António , Gener Blanca , Goizet Cyril , Gowrinathan Nirmala R. , Gowrishankar Kalpana , Hanrahan Donncha , Isidor Bertrand , Kara Bülent , Khan Nasaim , King Mary D. , Kirk Edwin P. , Kumar Ram , Lagae Lieven , Landrieu Pierre , Lauffer Heinz , Laugel Vincent , Piana Roberta La , Lim Ming J. , Lin Jean‐Pierre S.‐M. , Linnankivi Tarja , Mackay Mark T. , Marom Daphna R. , Marques Lourenço Charles , McKee Shane A. , Moroni Isabella , Morton Jenny E.V. , Moutard Marie‐Laure , Murray Kevin , Nabbout Rima , Nampoothiri Sheela , Nunez‐Enamorado Noemi , Oades Patrick J. , Olivieri Ivana , Ostergaard John R. , Pérez‐Dueñas Belén , Prendiville Julie S. , Ramesh Venkateswaran , Rasmussen Magnhild , Régal Luc , Ricci Federica , Rio Marlène , Rodriguez Diana , Roubertie Agathe , Salvatici Elisabetta , Segers Karin A. , Sinha Gyanranjan P. , Soler Doriette , Spiegel Ronen , Stödberg Tommy I. , Straussberg Rachel , Swoboda Kathryn J. , Suri Mohnish , Tacke Uta , Tan Tiong Y. , te Water Naude Johann , Wee Teik Keng , Mary Thomas Maya , Till Marianne , Tonduti Davide , Maria Valente Enza , Noel Van Coster Rudy , van der Knaap Marjo S. , Vassallo Grace , Vijzelaar Raymon , Vogt Julie , Wallace Geoffrey B. , Wassmer Evangeline , Webb Hannah J. , Whitehouse William P. , Whitney Robyn N. , Zaki Maha S. , Zuberi Sameer M. , Livingston John H. , Rozenberg Flore , Lebon Pierre , Vanderver Adeline , Orcesi Simona , Rice Gillian I. 
Published: January 2015

Aicardi–Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease‐onset (74 patients; 22.8% of all patients where data were available), or a post‐natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub‐acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non‐syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow‐up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi‐Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon‐stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon‐stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi–Goutières syndrome‐related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials. © 2015 Wiley Periodicals, Inc.