Characterization of Human Disease Phenotypes Associated with Mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1

被引：465

作者：

Crow, Yanick J. ^{[1
,2
]}

Chase, Diana S. ^{[2
]}

Schmidt, Johanna Lowenstein ^{[3
,4
]}

Szynkiewicz, Marcin ^{[2
]}

Forte, Gabriella M. A. ^{[2
]}

Gornall, Hannah L. ^{[2
]}

Oojageer, Anthony ^{[2
]}

Anderson, Beverley ^{[2
]}

Pizzino, Amy ^{[3
,4
]}

Helman, Guy ^{[3
,4
]}

Abdel-Hamid, Mohamed S. ^{[5
]}

Abdel-Salam, Ghada M. ^{[6
]}

Ackroyd, Sam ^{[7
]}

Aeby, Alec ^{[8
]}

Agosta, Guillermo ^{[9
]}

Albin, Catherine ^{[10
]}

Allon-Shalev, Stavit ^{[11
,12
]}

Arellano, Montse ^{[13
]}

Ariaudo, Giada ^{[14
]}

Aswani, Vijay ^{[15
]}

Babul-Hirji, Riyana ^{[16
]}

Baildam, Eileen M. ^{[17
]}

Bahi-Buisson, Nadia ^{[18
]}

Bailey, Kathryn M. ^{[19
,20
]}

Barnerias, Christine ^{[18
]}

Barth, Magalie ^{[21
]}

Battini, Roberta ^{[22
]}

Beresford, Michael W. ^{[23
]}

Bernard, Genevieve ^{[24
,25
,26
]}

Bianchi, Marika ^{[27
]}

de Villemeur, Thierry Billette ^{[28
,29
,30
]}

Blair, Edward M. ^{[31
]}

Bloom, Miriam ^{[32
]}

Burlina, Alberto B. ^{[33
]}

Carpanelli, Maria Luisa ^{[34
]}

Carvalho, Daniel R. ^{[35
]}

Castro-Gago, Manuel ^{[36
]}

Cavallini, Anna ^{[37
]}

Cereda, Cristina ^{[27
]}

Chandler, Kate E. ^{[38
]}

Chitayat, David A. ^{[39
,40
]}

Collins, Abigail E. ^{[41
]}

Sierra Corcoles, Concepcion ^{[42
]}

Cordeiro, Nuno J. V. ^{[43
]}

Crichiutti, Giovanni ^{[44
]}

Dabydeen, Lyvia ^{[45
]}

Dale, Russell C. ^{[46
]}

D'Arrigo, Stefano ^{[47
]}

De Goede, Christian G. E. L. ^{[48
]}

De Laet, Corinne ^{[49
]}

机构：

[1] Paris Descartes Sorbonne Paris Cite Univ, Lab Neurogenet & Neuroinflammat, Hop Necker, INSERM UMR 1163,Inst Imagine, Paris, France

[2] Univ Manchester, Manchester Ctr Genom Med, Inst Human Dev, Fac Med & Human Sci,Manchester Acad Hlth Sci Ctr, Manchester M13 9PT, Lancs, England

[3] George Washington Univ, Sch Med, Childrens Natl Hlth Syst, Dept Neurol, Washington, DC USA

[4] George Washington Univ, Sch Med, Childrens Natl Hlth Syst, Med Genet Res Ctr, Washington, DC USA

[5] Natl Res Ctr, Human Genet & Genome Res Div, Med Mol Genet Dept, Cairo, Egypt

[6] Natl Res Ctr, Dept Clin Genet, Human Genet & Genome Res Div, Cairo, Egypt

[7] Bradford Royal Infirm, Dept Haematol, Bradford BD9 6RJ, W Yorkshire, England

[8] Univ Libre Bruxelles, Hop Erasme, Dept Neuropediat, Brussels, Belgium

[9] Hosp Italiano Buenos Aires, Child Neurol Div, Buenos Aires, Argentina

[10] Kaiser Permanente, Dept Pediat Neurol, Santa Clara, CA USA

[11] Emek Med Ctr, Genet Inst, Afula, Israel

[12] Technion Israel Inst Technol, Rappaport Fac Med, Haifa, Israel

[13] Hosp Univ Mutua Terrassa, Dept Pediat Neurol, Barcelona, Spain

[14] Univ Pavia, Dept Brain & Behav Sci, Child Neurol & Psychiat Unit, I-27100 Pavia, Italy

[15] Marshfield Clin Fdn Med Res & Educ, Dept Internal Med & Pediat, Marshfield, MA USA

[16] Univ Toronto, Hosp Sick Children, Div Clin & Metab Genet, Dept Mol Genet, Toronto, ON M5G 1X8, Canada

[17] Alder Hey Childrens Natl Hlth Serv NHS Fdn Trust, Dept Paediat Rheumatol, Liverpool, Merseyside, England

[18] Hop Necker Enfants Malad, AP HP, Dept Paediat Neurol, Paris, France

[19] Univ Hosp Coventry, Dept Paediat, Coventry, W Midlands, England

[20] Univ Hosp Warwickshire, Dept Paediat, Coventry, W Midlands, England

[21] CHU Angers, Dept Genet, Angers, France

[22] IRCCS Stella Maris, Dept Dev Neurosci, Pisa, Italy

[23] Univ Liverpool, Inst Translat Med, Dept Womens & Childrens Hlth, Liverpool L69 3BX, Merseyside, England

[24] McGill Univ, Montreal Childrens Hosp, Ctr Hlth, Dept Pediat,Div Pediat Neurol, Montreal, PQ H3H 1P3, Canada

[25] McGill Univ, Montreal Childrens Hosp, Ctr Hlth, Dept Neurol,Div Pediat Neurol, Montreal, PQ H3H 1P3, Canada

[26] McGill Univ, Montreal Childrens Hosp, Ctr Hlth, Dept Neurosurg,Div Pediat Neurol, Montreal, PQ H3H 1P3, Canada

[27] C Mondino Natl Neurol Inst, Lab Expt Neurobiol, I-27100 Pavia, Italy

[28] Univ Paris 06, Sorbonne Univ, Paris, France

[29] Hop Trousseau, APHP, Dept Paediat Neurol, F-75571 Paris, France

[30] INSERM, U1141, Paris, France

[31] Oxford Univ Hosp NHS Trust, Dept Clin Genet, Oxford, England

[32] George Washington Univ, Sch Med, Div Hospitalist Med, Childrens Natl Hlth Syst, Washington, DC USA

[33] Univ Hosp, Div Inherited Metab Dis, Dept Pediat, Padua, Italy

[34] A Manzoni Hosp, Dept Child Neurol & Psychiat, Lecce, Italy

[35] SARAH Network Rehabil Hosp, Genet Unit, Brasilia, DF, Brazil

[36] Univ Santiago de Compostela, Hosp Clin Univ, Dept Pediat Neurol, Santiago De Compostela, Spain

[37] IRCCS Eugenio Medea, Inst Sci, Neuropsychiat & Neurorehabil Unit, Bosisio Parini, Italy

[38] St Marys Hosp, Manchester Ctr Genom Med, Manchester M13 0JH, Lancs, England

[39] Univ Toronto, Mt Sinai Hosp, Prenatal Diag & Med Genet Program, Dept Obstet & Gynecol, Toronto, ON M5G 1X5, Canada

[40] Univ Toronto, Hosp Sick Children, Dept Paediat, Div Clin & Metab Genet, Toronto, ON M5G 1X8, Canada

[41] Univ Colorado, Childrens Hosp Colorado, Dept Pediat & Neurol, Boulder, CO 80309 USA

[42] Complejo Hospitalario Jaen, Dept Paediat Neurol, Jaen, Spain

[43] NHS Ayrshire & Arran, Dept Paediat, Irvine, North Ayrshire, Scotland

[44] Azienda Osped Univ Udine, Dept Paediat, Udine, Italy

[45] Univ Hosp Leicester NHS Trust, Childrens Dept, Leicester, Leics, England

[46] Univ Sydney, Inst Neurosci & Muscle Res, Childrens Hosp Westmead, Sydney, NSW 2006, Australia

[47] IRCCS Fdn Ist Neurol C Besta, Child Neurol Dept, Milan, Italy

[48] Royal Preston Hosp, Dept Paediat Neurol, Preston, Lancs, England

[49] Hop Univ Enfants Reine Fabiola, Nutr & Metab Unit, Brussels, Belgium

[50] Ku Leuven Kulak, Dept Paediat Neurol, Univ Hosp Leuven, Kortrijk, Belgium

来源：

AMERICAN JOURNAL OF MEDICAL GENETICS PART A | 2015年 / 167卷 / 02期

基金：

欧洲研究理事会;

关键词：

Aicardi-Goutieres syndrome; bilateral striatal necrosis; spastic paraparesis; type I interferon; interferon signature; AICARDI-GOUTIERES-SYNDROME; SYSTEMIC-LUPUS-ERYTHEMATOSUS; DNA EXONUCLEASE TREX1; CLASSIFICATION-SYSTEM; INTERFERON-ALPHA; BASAL GANGLIA; GENE; ENCEPHALOPATHY; CALCIFICATIONS; VASCULOPATHY;

D O I：

10.1002/ajmg.a.36887

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Aicardi-Goutieres 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-Goutieres 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. (c) 2015 Wiley Periodicals, Inc.

引用

页码：296 / 312

页数：17

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