Title: 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 LMH, Liesbeth
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
RĂ©gal, 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 #
Issue Date: Feb-2015
Publisher: Wiley-Liss
Series Title: American Journal of Medical Genetics A vol:167 issue:2 pages:296-312
Article number: 10.1002/ajmg.a.36887
Abstract: 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.
ISSN: 1552-4825
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Organ Systems (+)
Laboratory for Biochemical Neuroendocrinology
Development and Regeneration, Campus Kulak Kortrijk
Department of Development and Regeneration - miscellaneous (+)
× corresponding author
# (joint) last author

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