Intrathecal Interferon Signaling Genes Expression in Leukodystrophies with Calcifying Microangiopathy on Neuropathology

Objective: Characterization of interferon stimulatory genes (ISG) expression in Aicardi-Goutieres Syndrome (AGS) and Cockayne Syndrome (CS). Background: AGS and CS are leukodystrophies with similar neuropathologic features including intracranial calcifications and calcifying microangiopathy. AGS patients have a consistent intrathecal and blood interferon elevation. CS patients have been found to have an interferon-like response but intrathecal interferon production has not been confirmed. Blood expression of ISG is an outcome biomarker for therapeutic trials, but the relevance of this marker to intrathecal interferon production is unknown. Methods: A NanoString N-Counter code set was designed for expression analysis of 25 ISGs. RNA was extracted from PAX gene tubes and autopsy collected brain tissue samples of AGS and CS patients and controls. Parametric and nonparametric analyses and a two-way ANOVA model were performed on data stratified as cases and controls after the Shapiro-Wilk normality test and log transformation. An interferon signature was derived in all cases. Results: A greater than 2-fold increase in ISG activity (2.755)(p-value: u003c0.001) was seen in all AGS patients (2.015 ± 1.598) versus controls (0.115 ± 0.156)(p-value: u003c0.001). No significant elevation was seen in CS patients. There was high concordance between blood and brain tissue values in controls, AGS and CS cases, albeit with higher expression levels in brain tissue samples. Conclusions: Elevated ISG expression in AGS brains is characteristic of the disorder, consistent with previous interferon signatures in patient blood and cerebral spinal fluid. The lack of induction in CS patients does not rule out an inflammatory process and requires further work investigation. ISG expression in patient brain tissue samples is concordant with elevated ISG expression in RNA isolated from blood, suggesting that blood values closely mirror intrathecal interferon production. Our results affirm the likely utility of blood ISG levels in clinical trials as an important biomarker of disease activity in AGS. Disclosure: Dr. Helman has nothing to disclose. Dr. Brooks has nothing to disclose. Dr. Gordish-Dressman has nothing to disclose. Dr. Takanohashi has nothing to disclose. Dr. Harmon has nothing to disclose. Dr. Crow has nothing to disclose. Dr. Rice has nothing to disclose. Dr. Lebon has nothing to disclose. Dr. Van Der Knaap has nothing to disclose. Dr. Herron has nothing to disclose. Dr. Brooks has nothing to disclose. Dr. Goldbach-Mansky has nothing to disclose. Dr. Vanderver has received research support from Shire Pharmaceuticals Group and Illumina.