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, Carpanelli Maria Luisa, 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, La Piana Roberta, 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, Thomas Maya Mary, Till Marianne, Tonduti Davide, Valente Enza Maria, Van Coster Rudy Noel, 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
INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris Descartes - Sorbonne Paris Cité University, Institut Imagine, Hôpital Necker, Paris, France; Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK.
Am J Med Genet A. 2015 Feb;167A(2):296-312. doi: 10.1002/ajmg.a.36887. Epub 2015 Jan 16.
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.
艾卡迪 - 古铁雷斯综合征是一种炎症性疾病，由TREX1、RNASEH2A、RNASEH2B、RNASEH2C、SAMHD1、ADAR或IFI1H基因中的任何一个发生突变引起。我们报告了来自299个家庭的374例这七个基因发生突变的患者。大多数患者符合两种相当典型的临床特征之一；要么在子宫内发病（74例患者；在可获得数据的所有患者中占22.8%），要么在出生后发病，通常在生命的第一年（223例患者；68.6%），其特征为亚急性脑病和丧失先前获得的技能。还观察到其他临床上不同的表型；特别是双侧纹状体坏死（13例患者；3.6%）和非综合征性痉挛性截瘫（12例患者；3.4%）。我们记录了69例死亡（占随访数据患者的19.3%）。在285例可获得数据的患者中，210例（73.7%）严重残疾，没有有用的运动、言语和智力功能。冻疮、青光眼、甲状腺功能减退、心肌病、脑内血管炎、周围神经病变、肠道炎症和系统性红斑狼疮的出现频率足以证实与艾卡迪 - 古铁雷斯综合征表型存在真正关联。我们观察到所有七个基因的突变与脑脊液和血清中I型干扰素活性增加以及外周血中干扰素刺激基因转录本表达增加之间存在密切关系。我们记录到在疾病出现后一年内检测的脑脊液干扰素活性水平与随后的残疾程度之间存在正相关。大多数患者的干扰素刺激基因转录本仍然很高，表明疾病过程持续存在。基于严重的发病率和死亡率，我们的数据突出了迫切需要为与艾卡迪 - 古铁雷斯综合征相关基因的突变相关的表型确定连贯的治疗策略。我们的发现还清楚地表明，对于大多数受影响的患者存在一个治疗机会窗口，并表明I型干扰素活性的评估可能在未来的临床试验中作为一种有用的生物标志物。
