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. 2013 Dec;12(12):1159-69.
doi: 10.1016/S1474-4422(13)70258-8. Epub 2013 Oct 30.

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

Gillian I Rice  1 , 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 S-M Lin, John H Livingston, Charles Marques Lourenco, Wilson Marques Jr, Patrick Oades, Pärt 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, Flore Rozenberg, Pierre Lebon, Yanick J Crow
Affiliations

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

Gillian I Rice et al. Lancet Neurol. 2013 Dec.

Abstract

Background: Aicardi-Goutières 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 CSF 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 (CSF, 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 α 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.

Funding: European Union's Seventh Framework Programme; European Research Council.

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Conflict of interest statement

Conflicts of interest

We declare that we have no conflicts of interest.

Figures

Figure 1
Figure 1. ISG transcript levels in patients and controls
(A) Quantitative reverse transcription PCR of a panel of six ISGs in whole blood measured in 82 patients with Aicardi-Goutières syndrome and 29 controls. Horizontal black bars show the median RQ value for each probe in each group. For participants with repeat samples, the mean combined measurement is shown. Analysed with one-way ANOVA with Bonferroni’s multiple comparison test. (B) ISG RQ by genotype compared with controls. Horizontal black bars show the median RQ value for each probe in each group. Analysed with one-way ANOVA with Dunnett’s multiple comparison test. ISG=interferon-stimulated gene. RQ=relative quantification.
Figure 2
Figure 2. Interferon scores in patients and controls
(A) Interferon score in all patients and controls calculated from the median fold change in relative quantification value for a panel of six interferon-stimulated genes. For participants with repeat samples, the mean combined measurement is shown. Black horizontal bars show the median interferon score in patients and controls. Negative scores are those less than 2·466 (mean of control interferon score plus two SD of mean) and positive scores are 2·466 or greater. Analysed with t test. (B) Interferon score for patients with mutations in genes related to Aicardi-Goutières syndrome versus controls. Black horizontal bars show the median interferon score for each gene. Analysed with one-way ANOVA with Dunnett’s multiple comparison test.
Figure 3
Figure 3. Interferon score plotted against age for patients and controls
Interferon scores calculated from the median fold change in relative quantification values for a panel of six interferon-stimulated genes. Spearman’s rank correlation: patients, r=0·121, p=0·28; controls, r=0·062, p=0·75.
Figure 4
Figure 4
Patients with positive or negative (below threshold) measurement of (A) CSF interferon activity or (B) serum interferon activity, by age at time of assay
See this image and copyright information in PMC

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References

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