Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1

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

doi:10.1002/ajmg.a.36887

Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1

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

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

485 Scopus citations

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.

Original language	English
Pages (from-to)	296-312
Number of pages	17
Journal	American Journal of Medical Genetics, Part A
Volume	167
Issue number	2
DOIs	https://doi.org/10.1002/ajmg.a.36887
State	Published - 1 Feb 2015

Funding

Funders	Funder number
National Institutes of Health
National Center for Research Resources	UL1RR025764
European Commission	309449

Keywords

Aicardi-Goutières syndrome
Bilateral striatal necrosis
Interferon signature
Spastic paraparesis
Type I interferon

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1002/ajmg.a.36887

Cite this

Crow, Y. J., Chase, D. S., Lowenstein Schmidt, J., Szynkiewicz, M., Forte, G. M. A., Gornall, H. L., Oojageer, A., Anderson, B., Pizzino, A., Helman, G., Abdel-Hamid, M. S., Abdel-Salam, G. M., Ackroyd, S., Aeby, A., Agosta, G., Albin, C., Allon-Shalev, S., Arellano, M., Ariaudo, G., ... Rice, G. I. (2015). Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. American Journal of Medical Genetics, Part A, 167(2), 296-312. https://doi.org/10.1002/ajmg.a.36887

@article{8335078fd2404b9a8cd4a83c72f1db82,

title = "Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1",

abstract = "Aicardi-Gouti{\`e}res 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-Gouti{\`e}res 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.",

keywords = "Aicardi-Gouti{\`e}res syndrome, Bilateral striatal necrosis, Interferon signature, Spastic paraparesis, Type I interferon",

author = "Crow, {Yanick J.} and Chase, {Diana S.} and {Lowenstein Schmidt}, Johanna and Marcin Szynkiewicz and Forte, {Gabriella M.A.} and Gornall, {Hannah L.} and Anthony Oojageer and Beverley Anderson and Amy Pizzino and Guy Helman and Abdel-Hamid, {Mohamed S.} and Abdel-Salam, {Ghada M.} and Sam Ackroyd and Alec Aeby and Guillermo Agosta and Catherine Albin and Stavit Allon-Shalev and Montse Arellano and Giada Ariaudo and Vijay Aswani and Riyana Babul-Hirji and Baildam, {Eileen M.} and Nadia Bahi-Buisson and Bailey, {Kathryn M.} and Christine Barnerias and Magalie Barth and Roberta Battini and Beresford, {Michael W.} and Genevi{\`e}ve Bernard and Marika Bianchi and {Billette de Villemeur}, Thierry and Blair, {Edward M.} and Miriam Bloom and Burlina, {Alberto B.} and {Luisa Carpanelli}, Maria and Carvalho, {Daniel R.} and Manuel Castro-Gago and Anna Cavallini and Cristina Cereda and Chandler, {Kate E.} and Chitayat, {David A.} and Collins, {Abigail E.} and {Sierra Corcoles}, Concepcion and Cordeiro, {Nuno J.V.} and Giovanni Crichiutti and Lyvia Dabydeen and Dale, {Russell C.} and Stefano Darrigo and {De Goede}, {Christian G.E.L.} and {De Laet}, Corinne and {De Waele}, {Liesbeth M.H.} and Ines Denzler and Isabelle Desguerre and Koenraad Devriendt and {Di Rocco}, Maja and Fahey, {Michael C.} and Elisa Fazzi and Ferrie, {Colin D.} and Ant{\'o}nio Figueiredo and Blanca Gener and Cyril Goizet and Gowrinathan, {Nirmala R.} and Kalpana Gowrishankar and Donncha Hanrahan and Bertrand Isidor and B{\"u}lent Kara and Nasaim Khan and King, {Mary D.} and Kirk, {Edwin P.} and Ram Kumar and Lieven Lagae and Pierre Landrieu and Heinz Lauffer and Vincent Laugel and Piana, {Roberta La} and Lim, {Ming J.} and Lin, {Jean Pierre S.M.} and Tarja Linnankivi and Mackay, {Mark T.} and Marom, {Daphna R.} and {Marques Louren{\c c}o}, Charles and Mckee, {Shane A.} and Isabella Moroni and Morton, {Jenny E.V.} and Moutard, {Marie Laure} and Kevin Murray and Rima Nabbout and Sheela Nampoothiri and Noemi Nunez-Enamorado and Oades, {Patrick J.} and Ivana Olivieri and Ostergaard, {John R.} and Bel{\'e}n P{\'e}rez-Due{\~n}as and Prendiville, {Julie S.} and Venkateswaran Ramesh and Magnhild Rasmussen and Luc R{\'e}gal and Federica Ricci and Marl{\`e}ne Rio and Diana Rodriguez and Agathe Roubertie and Elisabetta Salvatici and Segers, {Karin A.} and Sinha, {Gyanranjan P.} and Doriette Soler and Ronen Spiegel and St{\"o}dberg, {Tommy I.} and Rachel Straussberg and Swoboda, {Kathryn J.} and Mohnish Suri and Uta Tacke and Tan, {Tiong Y.} and {te Water Naude}, Johann and {Wee Teik}, Keng and {Mary Thomas}, Maya and Marianne Till and Davide Tonduti and {Maria Valente}, Enza and {Noel Van Coster}, Rudy and {van der Knaap}, {Marjo S.} and Grace Vassallo and Raymon Vijzelaar and Julie Vogt and Wallace, {Geoffrey B.} and Evangeline Wassmer and Webb, {Hannah J.} and Whitehouse, {William P.} and Whitney, {Robyn N.} and Zaki, {Maha S.} and Zuberi, {Sameer M.} and Livingston, {John H.} and Flore Rozenberg and Pierre Lebon and Adeline Vanderver and Simona Orcesi and Rice, {Gillian I.}",

note = "Publisher Copyright: {\textcopyright} 2015 Wiley Periodicals, Inc.",

year = "2015",

month = feb,

day = "1",

doi = "10.1002/ajmg.a.36887",

language = "אנגלית",

volume = "167",

pages = "296--312",

journal = "American Journal of Medical Genetics, Part A",

issn = "1552-4825",

publisher = "John Wiley and Sons Inc.",

number = "2",

}

Crow, YJ, Chase, DS, Lowenstein Schmidt, J, Szynkiewicz, M, Forte, GMA, Gornall, HL, Oojageer, A, Anderson, B, Pizzino, A, Helman, G, Abdel-Hamid, MS, Abdel-Salam, GM, Ackroyd, S, Aeby, A, Agosta, G, Albin, C, Allon-Shalev, S, Arellano, M, Ariaudo, G, Aswani, V, Babul-Hirji, R, Baildam, EM, Bahi-Buisson, N, Bailey, KM, Barnerias, C, Barth, M, Battini, R, Beresford, MW, Bernard, G, Bianchi, M, Billette de Villemeur, T, Blair, EM, Bloom, M, Burlina, AB, Luisa Carpanelli, M, Carvalho, DR, Castro-Gago, M, Cavallini, A, Cereda, C, Chandler, KE, Chitayat, DA, Collins, AE, Sierra Corcoles, C, Cordeiro, NJV, Crichiutti, G, Dabydeen, L, Dale, RC, Darrigo, S, De Goede, CGEL, De Laet, C, De Waele, LMH, Denzler, I, Desguerre, I, Devriendt, K, Di Rocco, M, Fahey, MC, Fazzi, E, Ferrie, CD, Figueiredo, A, Gener, B, Goizet, C, Gowrinathan, NR, Gowrishankar, K, Hanrahan, D, Isidor, B, Kara, B, Khan, N, King, MD, Kirk, EP, Kumar, R, Lagae, L, Landrieu, P, Lauffer, H, Laugel, V, Piana, RL, Lim, MJ, Lin, JPSM, Linnankivi, T, Mackay, MT, Marom, DR, Marques Lourenço, C, Mckee, SA, Moroni, I, Morton, JEV, Moutard, ML, Murray, K, Nabbout, R, Nampoothiri, S, Nunez-Enamorado, N, Oades, PJ, Olivieri, I, Ostergaard, JR, Pérez-Dueñas, B, Prendiville, JS, Ramesh, V, Rasmussen, M, Régal, L, Ricci, F, Rio, M, Rodriguez, D, Roubertie, A, Salvatici, E, Segers, KA, Sinha, GP, Soler, D, Spiegel, R, Stödberg, TI, Straussberg, R, Swoboda, KJ, Suri, M, Tacke, U, Tan, TY, te Water Naude, J, Wee Teik, K, Mary Thomas, M, Till, M, Tonduti, D, Maria Valente, E, Noel Van Coster, R, van der Knaap, MS, Vassallo, G, Vijzelaar, R, Vogt, J, Wallace, GB, Wassmer, E, Webb, HJ, Whitehouse, WP, Whitney, RN, Zaki, MS, Zuberi, SM, Livingston, JH, Rozenberg, F, Lebon, P, Vanderver, A, Orcesi, S & Rice, GI 2015, 'Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1', American Journal of Medical Genetics, Part A, vol. 167, no. 2, pp. 296-312. https://doi.org/10.1002/ajmg.a.36887

TY - JOUR

T1 - Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1

AU - Crow, Yanick J.

AU - Chase, Diana S.

AU - Lowenstein Schmidt, Johanna

AU - Szynkiewicz, Marcin

AU - Forte, Gabriella M.A.

AU - Gornall, Hannah L.

AU - Oojageer, Anthony

AU - Anderson, Beverley

AU - Pizzino, Amy

AU - Helman, Guy

AU - Abdel-Hamid, Mohamed S.

AU - Abdel-Salam, Ghada M.

AU - Ackroyd, Sam

AU - Aeby, Alec

AU - Agosta, Guillermo

AU - Albin, Catherine

AU - Allon-Shalev, Stavit

AU - Arellano, Montse

AU - Ariaudo, Giada

AU - Aswani, Vijay

AU - Babul-Hirji, Riyana

AU - Baildam, Eileen M.

AU - Bahi-Buisson, Nadia

AU - Bailey, Kathryn M.

AU - Barnerias, Christine

AU - Barth, Magalie

AU - Battini, Roberta

AU - Beresford, Michael W.

AU - Bernard, Geneviève

AU - Bianchi, Marika

AU - Billette de Villemeur, Thierry

AU - Blair, Edward M.

AU - Bloom, Miriam

AU - Burlina, Alberto B.

AU - Luisa Carpanelli, Maria

AU - Carvalho, Daniel R.

AU - Castro-Gago, Manuel

AU - Cavallini, Anna

AU - Cereda, Cristina

AU - Chandler, Kate E.

AU - Chitayat, David A.

AU - Collins, Abigail E.

AU - Sierra Corcoles, Concepcion

AU - Cordeiro, Nuno J.V.

AU - Crichiutti, Giovanni

AU - Dabydeen, Lyvia

AU - Dale, Russell C.

AU - Darrigo, Stefano

AU - De Goede, Christian G.E.L.

AU - De Laet, Corinne

AU - De Waele, Liesbeth M.H.

AU - Denzler, Ines

AU - Desguerre, Isabelle

AU - Devriendt, Koenraad

AU - Di Rocco, Maja

AU - Fahey, Michael C.

AU - Fazzi, Elisa

AU - Ferrie, Colin D.

AU - Figueiredo, António

AU - Gener, Blanca

AU - Goizet, Cyril

AU - Gowrinathan, Nirmala R.

AU - Gowrishankar, Kalpana

AU - Hanrahan, Donncha

AU - Isidor, Bertrand

AU - Kara, Bülent

AU - Khan, Nasaim

AU - King, Mary D.

AU - Kirk, Edwin P.

AU - Kumar, Ram

AU - Lagae, Lieven

AU - Landrieu, Pierre

AU - Lauffer, Heinz

AU - Laugel, Vincent

AU - Piana, Roberta La

AU - Lim, Ming J.

AU - Lin, Jean Pierre S.M.

AU - Linnankivi, Tarja

AU - Mackay, Mark T.

AU - Marom, Daphna R.

AU - Marques Lourenço, Charles

AU - Mckee, Shane A.

AU - Moroni, Isabella

AU - Morton, Jenny E.V.

AU - Moutard, Marie Laure

AU - Murray, Kevin

AU - Nabbout, Rima

AU - Nampoothiri, Sheela

AU - Nunez-Enamorado, Noemi

AU - Oades, Patrick J.

AU - Olivieri, Ivana

AU - Ostergaard, John R.

AU - Pérez-Dueñas, Belén

AU - Prendiville, Julie S.

AU - Ramesh, Venkateswaran

AU - Rasmussen, Magnhild

AU - Régal, Luc

AU - Ricci, Federica

AU - Rio, Marlène

AU - Rodriguez, Diana

AU - Roubertie, Agathe

AU - Salvatici, Elisabetta

AU - Segers, Karin A.

AU - Sinha, Gyanranjan P.

AU - Soler, Doriette

AU - Spiegel, Ronen

AU - Stödberg, Tommy I.

AU - Straussberg, Rachel

AU - Swoboda, Kathryn J.

AU - Suri, Mohnish

AU - Tacke, Uta

AU - Tan, Tiong Y.

AU - te Water Naude, Johann

AU - Wee Teik, Keng

AU - Mary Thomas, Maya

AU - Till, Marianne

AU - Tonduti, Davide

AU - Maria Valente, Enza

AU - Noel Van Coster, Rudy

AU - van der Knaap, Marjo S.

AU - Vassallo, Grace

AU - Vijzelaar, Raymon

AU - Vogt, Julie

AU - Wallace, Geoffrey B.

AU - Wassmer, Evangeline

AU - Webb, Hannah J.

AU - Whitehouse, William P.

AU - Whitney, Robyn N.

AU - Zaki, Maha S.

AU - Zuberi, Sameer M.

AU - Livingston, John H.

AU - Rozenberg, Flore

AU - Lebon, Pierre

AU - Vanderver, Adeline

AU - Orcesi, Simona

AU - Rice, Gillian I.

PY - 2015/2/1

Y1 - 2015/2/1

N2 - 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.

AB - 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.

KW - Aicardi-Goutières syndrome

KW - Bilateral striatal necrosis

KW - Interferon signature

KW - Spastic paraparesis

KW - Type I interferon

UR - http://www.scopus.com/inward/record.url?scp=84921417123&partnerID=8YFLogxK

U2 - 10.1002/ajmg.a.36887

DO - 10.1002/ajmg.a.36887

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C2 - 25604658

AN - SCOPUS:84921417123

SN - 1552-4825

VL - 167

SP - 296

EP - 312

JO - American Journal of Medical Genetics, Part A

JF - American Journal of Medical Genetics, Part A

IS - 2

ER -

Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1

Abstract

Funding

Keywords

UN SDGs

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