{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T22:25:13Z","timestamp":1792448713785,"version":"4.5.0"},"reference-count":41,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2015,1,16]],"date-time":"2015-01-16T00:00:00Z","timestamp":1421366400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"European Union's Seventh Framework Programme","award":["GA 241779"],"award-info":[{"award-number":["GA 241779"]}]},{"name":"European Research Council","award":["GA 309449"],"award-info":[{"award-number":["GA 309449"]}]},{"name":"National Research Agency (France) under the \u201cInvestments for the Future\u201d program","award":["ANR-10-IAHU-01"],"award-info":[{"award-number":["ANR-10-IAHU-01"]}]},{"name":"Parsons Family Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2015,2]]},"abstract":"<jats:sec>\n                    <jats:label\/>\n                    <jats:p>\n                      Aicardi\u2013Gouti\u00e8res syndrome is an inflammatory disease occurring due to mutations in any of\n                      <jats:italic>TREX1<\/jats:italic>\n                      ,\n                      <jats:italic>RNASEH2A<\/jats:italic>\n                      ,\n                      <jats:italic>RNASEH2B<\/jats:italic>\n                      ,\n                      <jats:italic>RNASEH2C<\/jats:italic>\n                      ,\n                      <jats:italic>SAMHD1<\/jats:italic>\n                      ,\n                      <jats:italic>ADAR<\/jats:italic>\n                      or\n                      <jats:italic>IFIH1<\/jats:italic>\n                      . 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\u2010onset (74 patients; 22.8% of all patients where data were available), or a post\u2010natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub\u2010acute 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\u2010syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow\u2010up 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\u2010Goutieres 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\u2010stimulated 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\u2010stimulated 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\u2013Gouti\u00e8res syndrome\u2010related 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. \u00a9 2015 Wiley Periodicals, Inc.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ajmg.a.36887","type":"journal-article","created":{"date-parts":[[2015,1,16]],"date-time":"2015-01-16T02:18:17Z","timestamp":1421374697000},"page":"296-312","source":"Crossref","is-referenced-by-count":564,"title":["Characterization of human disease phenotypes associated with mutations in\n                    <i>TREX1<\/i>\n                    ,\n                    <i>RNASEH2A<\/i>\n                    ,\n                    <i>RNASEH2B<\/i>\n                    ,\n                    <i>RNASEH2C<\/i>\n                    ,\n                    <i>SAMHD1<\/i>\n                    ,\n                    <i>ADAR<\/i>\n                    , and\n                    <i>IFIH1<\/i>"],"prefix":"10.1002","volume":"167","author":[{"given":"Yanick J.","family":"Crow","sequence":"first","affiliation":[{"name":"INSERM UMR 1163 Laboratory of Neurogenetics and Neuroinflammation Paris Descartes \u2013 Sorbonne Paris Cit\u00e9 University Institut Imagine H\u00f4pital Necker Paris France"},{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana S.","family":"Chase","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Lowenstein Schmidt","sequence":"additional","affiliation":[{"name":"Department of Neurology &amp; Center for Genetic Medicine Research, George Washington University School of Medicine Children's National Health System Washington District of Columbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcin","family":"Szynkiewicz","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella M.A.","family":"Forte","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah L.","family":"Gornall","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Oojageer","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beverley","family":"Anderson","sequence":"additional","affiliation":[{"name":"Manchester Centre for Genomic Medicine Institute of Human Development, Faculty of Medical and Human Sciences Manchester Academic Health Sciences Centre University of Manchester Manchester 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