Assessment of interferon-related biomarkers in Aicardi-Goutieres syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study

Gillian I. Rice; Gabriella M. A. Forte; Marcin Szynkiewicz; Diana S. Chase; Alec Aeby; Mohamed S. Abdel-Hamid; Sam Ackroyd; Rebecca Allcock; Kathryn M. Bailey; Umberto Balottin; Christine Barnerias; Genevieve Bernard; Christine Bodemer; Maria P. Botella; Cristina Cereda; Kate E. Chandler; Lyvia Dabydeen; Russell C. Dale; Corinne De Laet; Christian G. E. L. De Goede; Mireia del Toro; Laila Effat; Noemi Nunez Enamorado; Elisa Fazzi; Blanca Gener; Madli Haldre; Jean-Pierre Lin; John H. Livingston; Charles Marques Lourenco; Wilson Marques; Patrick Oades; Paert Peterson; Magnhild Rasmussen; Agathe Roubertie; Johanna Loewenstein Schmidt; Stavit A. Shalev; Rogelio Simon; Ronen Spiegel; Kathryn J. Swoboda; Samia A. Temtamy; Grace Vassallo; Catheline N. Vilain; Julie Vogt; Vanessa Wermenbol; William P. Whitehouse; Doriette Soler; Ivana Olivieri; Simona Orcesi; Mona S. Aglan; Maha S. Zaki; Ghada M. H. Abdel-Salam; Adeline Vanderver; Kai Kisand; Fiore Rozenberg; Pierre Lebon; Yanick J. Crow

doi:10.1016/S1474-4422(13)70258-8

Assessment of interferon-related biomarkers in Aicardi-Goutieres syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study

Gillian I. Rice, Gabriella M. A. Forte, Marcin Szynkiewicz, Diana S. Chase, Alec Aeby, Mohamed S. Abdel-Hamid, Sam Ackroyd, Rebecca Allcock, Kathryn M. Bailey, Umberto Balottin, Christine Barnerias, Genevieve Bernard, Christine Bodemer, Maria P. Botella, Cristina Cereda, Kate E. Chandler, Lyvia Dabydeen, Russell C. Dale, Corinne De Laet, Christian G. E. L. De GoedeMireia del Toro, Laila Effat, Noemi Nunez Enamorado, Elisa Fazzi, Blanca Gener, Madli Haldre, Jean-Pierre Lin, John H. Livingston, Charles Marques Lourenco, Wilson Marques, Patrick Oades, Paert Peterson, Magnhild Rasmussen, Agathe Roubertie, Johanna Loewenstein Schmidt, Stavit A. Shalev, Rogelio Simon, Ronen Spiegel, Kathryn J. Swoboda, Samia A. Temtamy, Grace Vassallo, Catheline N. Vilain, Julie Vogt, Vanessa Wermenbol, William P. Whitehouse, Doriette Soler, Ivana Olivieri, Simona Orcesi, Mona S. Aglan, Maha S. Zaki, Ghada M. H. Abdel-Salam, Adeline Vanderver, Kai Kisand, Fiore Rozenberg, Pierre Lebon, Yanick J. Crow^*

^*Corresponding author for this work

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

343 Citations (Scopus)

Abstract

Background
Aicardi-Goutieres syndrome (AGS) is an inflammatory disorder caused by mutations in any of six genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR). The disease is severe and effective treatments are urgently needed. We investigated the status of interferon-related biomarkers in patients with AGS with a view to future use in diagnosis and clinical trials.

Methods
In this case-control study, samples were collected prospectively from patients with mutation-proven AGS. The expression of six interferon-stimulated genes (ISGs) was measured by quantitative PCR, and the median fold change, when compared with the median of healthy controls, was used to create an interferon score for each patient. Scores higher than the mean of controls plus two SD (>2.466) were designated as positive. Additionally, we collated historical data for interferon activity, measured with a viral cytopathic assay, in C SF and serum from mutation-positive patients with AGS. We also undertook neutralisation assays of interferon activity in serum, and looked for the presence of autoantibodies against a panel of interferon proteins.

Findings
74 (90%) of 82 patients had a positive interferon score (median 12.90, IQR 6.14-20-41) compared with two (7%) of 29 controls (median 0.93, IQR 0.57-1.30). Of the eight patients with a negative interferon score, seven had mutations in RNASEH2B (seven [27%] of all 26 patients with mutations in this gene). Repeat sampling in 16 patients was consistent for the presence or absence of an interferon signature on 39 of 41 occasions. Interferon activity (tested in 147 patients) was negatively correlated with age (C SF, r=-0.604; serum, r=-0.289), and was higher in CSF than in serum in 104 of 136 paired samples. Neutralisation assays suggested that measurable antiviral activity was related to interferon a production. We did not record significantly increased concentrations of autoantibodies to interferon subtypes in patients with AGS, or an association between the presence of autoantibodies and interferon score or serum interferon activity.

Interpretation
AGS is consistently associated with an interferon signature, which is apparently sustained over time and can thus be used to differentiate patients with AGS from controls. If future studies show that interferon status is a reactive biomarker, the measurement of an interferon score might prove useful in the assessment of treatment efficacy in clinical trials.

Original language	English
Pages (from-to)	1159-1169
Number of pages	11
Journal	Lancet Neurology
Volume	12
Issue number	12
DOIs	https://doi.org/10.1016/S1474-4422(13)70258-8
Publication status	Published - Dec 2013

Keywords

SYSTEMIC-LUPUS-ERYTHEMATOSUS
PROGRESSIVE FAMILIAL ENCEPHALOPATHY
CEREBROSPINAL-FLUID LYMPHOCYTOSIS
INDUCIBLE GENE-EXPRESSION
INTRATHECAL SYNTHESIS
RHEUMATOID-ARTHRITIS
DOSE-ESCALATION
BASAL GANGLIA
PHASE-I
DISEASE

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Rice, G. I., Forte, G. M. A., Szynkiewicz, M., Chase, D. S., Aeby, A., Abdel-Hamid, M. S., Ackroyd, S., Allcock, R., Bailey, K. M., Balottin, U., Barnerias, C., Bernard, G., Bodemer, C., Botella, M. P., Cereda, C., Chandler, K. E., Dabydeen, L., Dale, R. C., De Laet, C., ... Crow, Y. J. (2013). Assessment of interferon-related biomarkers in Aicardi-Goutieres syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study. Lancet Neurology, 12(12), 1159-1169. https://doi.org/10.1016/S1474-4422(13)70258-8

@article{6841b68b823b4b238bde644e44d2a1da,

title = "Assessment of interferon-related biomarkers in Aicardi-Goutieres syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study",

abstract = "Background Aicardi-Goutieres syndrome (AGS) is an inflammatory disorder caused by mutations in any of six genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR). The disease is severe and effective treatments are urgently needed. We investigated the status of interferon-related biomarkers in patients with AGS with a view to future use in diagnosis and clinical trials. Methods In this case-control study, samples were collected prospectively from patients with mutation-proven AGS. The expression of six interferon-stimulated genes (ISGs) was measured by quantitative PCR, and the median fold change, when compared with the median of healthy controls, was used to create an interferon score for each patient. Scores higher than the mean of controls plus two SD (>2.466) were designated as positive. Additionally, we collated historical data for interferon activity, measured with a viral cytopathic assay, in C SF and serum from mutation-positive patients with AGS. We also undertook neutralisation assays of interferon activity in serum, and looked for the presence of autoantibodies against a panel of interferon proteins. Findings 74 (90%) of 82 patients had a positive interferon score (median 12.90, IQR 6.14-20-41) compared with two (7%) of 29 controls (median 0.93, IQR 0.57-1.30). Of the eight patients with a negative interferon score, seven had mutations in RNASEH2B (seven [27%] of all 26 patients with mutations in this gene). Repeat sampling in 16 patients was consistent for the presence or absence of an interferon signature on 39 of 41 occasions. Interferon activity (tested in 147 patients) was negatively correlated with age (C SF, r=-0.604; serum, r=-0.289), and was higher in CSF than in serum in 104 of 136 paired samples. Neutralisation assays suggested that measurable antiviral activity was related to interferon a production. We did not record significantly increased concentrations of autoantibodies to interferon subtypes in patients with AGS, or an association between the presence of autoantibodies and interferon score or serum interferon activity. Interpretation AGS is consistently associated with an interferon signature, which is apparently sustained over time and can thus be used to differentiate patients with AGS from controls. If future studies show that interferon status is a reactive biomarker, the measurement of an interferon score might prove useful in the assessment of treatment efficacy in clinical trials.",

keywords = "SYSTEMIC-LUPUS-ERYTHEMATOSUS, PROGRESSIVE FAMILIAL ENCEPHALOPATHY, CEREBROSPINAL-FLUID LYMPHOCYTOSIS, INDUCIBLE GENE-EXPRESSION, INTRATHECAL SYNTHESIS, RHEUMATOID-ARTHRITIS, DOSE-ESCALATION, BASAL GANGLIA, PHASE-I, DISEASE",

author = "Rice, {Gillian I.} and Forte, {Gabriella M. A.} and Marcin Szynkiewicz and Chase, {Diana S.} and Alec Aeby and Abdel-Hamid, {Mohamed S.} and Sam Ackroyd and Rebecca Allcock and Bailey, {Kathryn M.} and Umberto Balottin and Christine Barnerias and Genevieve Bernard and Christine Bodemer and Botella, {Maria P.} and Cristina Cereda and Chandler, {Kate E.} and Lyvia Dabydeen and Dale, {Russell C.} and {De Laet}, Corinne and {De Goede}, {Christian G. E. L.} and {del Toro}, Mireia and Laila Effat and {Nunez Enamorado}, Noemi and Elisa Fazzi and Blanca Gener and Madli Haldre and Jean-Pierre Lin and Livingston, {John H.} and Lourenco, {Charles Marques} and Wilson Marques and Patrick Oades and Paert Peterson and Magnhild Rasmussen and Agathe Roubertie and Schmidt, {Johanna Loewenstein} and Shalev, {Stavit A.} and Rogelio Simon and Ronen Spiegel and Swoboda, {Kathryn J.} and Temtamy, {Samia A.} and Grace Vassallo and Vilain, {Catheline N.} and Julie Vogt and Vanessa Wermenbol and Whitehouse, {William P.} and Doriette Soler and Ivana Olivieri and Simona Orcesi and Aglan, {Mona S.} and Zaki, {Maha S.} and Abdel-Salam, {Ghada M. H.} and Adeline Vanderver and Kai Kisand and Fiore Rozenberg and Pierre Lebon and Crow, {Yanick J.}",

year = "2013",

month = dec,

doi = "10.1016/S1474-4422(13)70258-8",

language = "English",

volume = "12",

pages = "1159--1169",

journal = "Lancet Neurology",

issn = "1474-4422",

publisher = "Elsevier",

number = "12",

}

Rice, GI, Forte, GMA, Szynkiewicz, M, Chase, DS, Aeby, A, Abdel-Hamid, MS, Ackroyd, S, Allcock, R, Bailey, KM, Balottin, U, Barnerias, C, Bernard, G, Bodemer, C, Botella, MP, Cereda, C, Chandler, KE, Dabydeen, L, Dale, RC, De Laet, C, De Goede, CGEL, del Toro, M, Effat, L, Nunez Enamorado, N, Fazzi, E, Gener, B, Haldre, M, Lin, J-P, Livingston, JH, Lourenco, CM, Marques, W, Oades, P, Peterson, P, Rasmussen, M, Roubertie, A, Schmidt, JL, Shalev, SA, Simon, R, Spiegel, R, Swoboda, KJ, Temtamy, SA, Vassallo, G, Vilain, CN, Vogt, J, Wermenbol, V, Whitehouse, WP, Soler, D, Olivieri, I, Orcesi, S, Aglan, MS, Zaki, MS, Abdel-Salam, GMH, Vanderver, A, Kisand, K, Rozenberg, F, Lebon, P & Crow, YJ 2013, 'Assessment of interferon-related biomarkers in Aicardi-Goutieres syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study', Lancet Neurology, vol. 12, no. 12, pp. 1159-1169. https://doi.org/10.1016/S1474-4422(13)70258-8

Assessment of interferon-related biomarkers in Aicardi-Goutieres syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study. / Rice, Gillian I.; Forte, Gabriella M. A.; Szynkiewicz, Marcin et al.
In: Lancet Neurology, Vol. 12, No. 12, 12.2013, p. 1159-1169.

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

TY - JOUR

T1 - Assessment of interferon-related biomarkers in Aicardi-Goutieres syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR

T2 - a case-control study

AU - Rice, Gillian I.

AU - Forte, Gabriella M. A.

AU - Szynkiewicz, Marcin

AU - Chase, Diana S.

AU - Aeby, Alec

AU - Abdel-Hamid, Mohamed S.

AU - Ackroyd, Sam

AU - Allcock, Rebecca

AU - Bailey, Kathryn M.

AU - Balottin, Umberto

AU - Barnerias, Christine

AU - Bernard, Genevieve

AU - Bodemer, Christine

AU - Botella, Maria P.

AU - Cereda, Cristina

AU - Chandler, Kate E.

AU - Dabydeen, Lyvia

AU - Dale, Russell C.

AU - De Laet, Corinne

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

AU - del Toro, Mireia

AU - Effat, Laila

AU - Nunez Enamorado, Noemi

AU - Fazzi, Elisa

AU - Gener, Blanca

AU - Haldre, Madli

AU - Lin, Jean-Pierre

AU - Livingston, John H.

AU - Lourenco, Charles Marques

AU - Marques, Wilson

AU - Oades, Patrick

AU - Peterson, Paert

AU - Rasmussen, Magnhild

AU - Roubertie, Agathe

AU - Schmidt, Johanna Loewenstein

AU - Shalev, Stavit A.

AU - Simon, Rogelio

AU - Spiegel, Ronen

AU - Swoboda, Kathryn J.

AU - Temtamy, Samia A.

AU - Vassallo, Grace

AU - Vilain, Catheline N.

AU - Vogt, Julie

AU - Wermenbol, Vanessa

AU - Whitehouse, William P.

AU - Soler, Doriette

AU - Olivieri, Ivana

AU - Orcesi, Simona

AU - Aglan, Mona S.

AU - Zaki, Maha S.

AU - Abdel-Salam, Ghada M. H.

AU - Vanderver, Adeline

AU - Kisand, Kai

AU - Rozenberg, Fiore

AU - Lebon, Pierre

AU - Crow, Yanick J.

PY - 2013/12

Y1 - 2013/12

N2 - Background Aicardi-Goutieres syndrome (AGS) is an inflammatory disorder caused by mutations in any of six genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR). The disease is severe and effective treatments are urgently needed. We investigated the status of interferon-related biomarkers in patients with AGS with a view to future use in diagnosis and clinical trials. Methods In this case-control study, samples were collected prospectively from patients with mutation-proven AGS. The expression of six interferon-stimulated genes (ISGs) was measured by quantitative PCR, and the median fold change, when compared with the median of healthy controls, was used to create an interferon score for each patient. Scores higher than the mean of controls plus two SD (>2.466) were designated as positive. Additionally, we collated historical data for interferon activity, measured with a viral cytopathic assay, in C SF and serum from mutation-positive patients with AGS. We also undertook neutralisation assays of interferon activity in serum, and looked for the presence of autoantibodies against a panel of interferon proteins. Findings 74 (90%) of 82 patients had a positive interferon score (median 12.90, IQR 6.14-20-41) compared with two (7%) of 29 controls (median 0.93, IQR 0.57-1.30). Of the eight patients with a negative interferon score, seven had mutations in RNASEH2B (seven [27%] of all 26 patients with mutations in this gene). Repeat sampling in 16 patients was consistent for the presence or absence of an interferon signature on 39 of 41 occasions. Interferon activity (tested in 147 patients) was negatively correlated with age (C SF, r=-0.604; serum, r=-0.289), and was higher in CSF than in serum in 104 of 136 paired samples. Neutralisation assays suggested that measurable antiviral activity was related to interferon a production. We did not record significantly increased concentrations of autoantibodies to interferon subtypes in patients with AGS, or an association between the presence of autoantibodies and interferon score or serum interferon activity. Interpretation AGS is consistently associated with an interferon signature, which is apparently sustained over time and can thus be used to differentiate patients with AGS from controls. If future studies show that interferon status is a reactive biomarker, the measurement of an interferon score might prove useful in the assessment of treatment efficacy in clinical trials.

AB - Background Aicardi-Goutieres syndrome (AGS) is an inflammatory disorder caused by mutations in any of six genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR). The disease is severe and effective treatments are urgently needed. We investigated the status of interferon-related biomarkers in patients with AGS with a view to future use in diagnosis and clinical trials. Methods In this case-control study, samples were collected prospectively from patients with mutation-proven AGS. The expression of six interferon-stimulated genes (ISGs) was measured by quantitative PCR, and the median fold change, when compared with the median of healthy controls, was used to create an interferon score for each patient. Scores higher than the mean of controls plus two SD (>2.466) were designated as positive. Additionally, we collated historical data for interferon activity, measured with a viral cytopathic assay, in C SF and serum from mutation-positive patients with AGS. We also undertook neutralisation assays of interferon activity in serum, and looked for the presence of autoantibodies against a panel of interferon proteins. Findings 74 (90%) of 82 patients had a positive interferon score (median 12.90, IQR 6.14-20-41) compared with two (7%) of 29 controls (median 0.93, IQR 0.57-1.30). Of the eight patients with a negative interferon score, seven had mutations in RNASEH2B (seven [27%] of all 26 patients with mutations in this gene). Repeat sampling in 16 patients was consistent for the presence or absence of an interferon signature on 39 of 41 occasions. Interferon activity (tested in 147 patients) was negatively correlated with age (C SF, r=-0.604; serum, r=-0.289), and was higher in CSF than in serum in 104 of 136 paired samples. Neutralisation assays suggested that measurable antiviral activity was related to interferon a production. We did not record significantly increased concentrations of autoantibodies to interferon subtypes in patients with AGS, or an association between the presence of autoantibodies and interferon score or serum interferon activity. Interpretation AGS is consistently associated with an interferon signature, which is apparently sustained over time and can thus be used to differentiate patients with AGS from controls. If future studies show that interferon status is a reactive biomarker, the measurement of an interferon score might prove useful in the assessment of treatment efficacy in clinical trials.

KW - SYSTEMIC-LUPUS-ERYTHEMATOSUS

KW - PROGRESSIVE FAMILIAL ENCEPHALOPATHY

KW - CEREBROSPINAL-FLUID LYMPHOCYTOSIS

KW - INDUCIBLE GENE-EXPRESSION

KW - INTRATHECAL SYNTHESIS

KW - RHEUMATOID-ARTHRITIS

KW - DOSE-ESCALATION

KW - BASAL GANGLIA

KW - PHASE-I

KW - DISEASE

U2 - 10.1016/S1474-4422(13)70258-8

DO - 10.1016/S1474-4422(13)70258-8

M3 - Article

SN - 1474-4422

VL - 12

SP - 1159

EP - 1169

JO - Lancet Neurology

JF - Lancet Neurology

IS - 12

ER -

Assessment of interferon-related biomarkers in Aicardi-Goutieres syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study

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