Characterisation of Aicardi-Goutières syndrome

Since its first description in 1984 by Jean Aicardi and Françoise Goutières, 1 Aicardi J Goutieres F A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann Neurol. 1984; 15: 49-54 Crossref PubMed Scopus (367) Google Scholar the progressive encephalopathy later called Aicardi-Goutières syndrome (AGS) has been recognised as a severe disease with mainly infantile onset, characterised by spastic dystonic movement disorder, calcification of the basal ganglia, acquired microcephaly, and rapid progression towards profound deterioration and often early death. Even the first description stressed that the disorder was familial and “probably genetic in origin”. Aicardi and Goutières also emphasised that there was evidence for inflammatory processes affecting the CNS, because all patients had mild but persistent lymphocytosis in CSF. 4 years later, Lebon and colleagues 2 Lebon P Badoual J Ponsot G et al. Intrathecal synthesis of interferon-alpha in infants with progressive familial encephalopathy. J Neurol Sci. 1988; 84: 201-208 Summary Full Text PDF PubMed Scopus (175) Google Scholar reported high interferon α in seven of eight patients, underlining the inflammatory nature of the disorder. Nearly 20 years later, a monogenic although heterogeneous background of AGS was verified by identification of mutations in the subunits of four genes encoding the ribonuclease TREX1 and the genes encoding subunits of the ribonuclease H2 protein complex. 3 Crow YJ Hayward BE Parmar R et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus. Nat Genet. 2006; 38: 917-920 Crossref PubMed Scopus (646) Google Scholar , 4 Rice G Newman WG Dean J et al. Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutières syndrome. Am J Human Genet. 2007; 80: 811-815 Summary Full Text Full Text PDF PubMed Scopus (296) Google Scholar With this finding, AGS was characterised as a monogenic disease in which inflammatory or autoimmune mechanisms seem to have the major pathogenetic role. AGS is thus a puzzling model for the understanding and treatment of complex autoimmune diseases. 5 Lee-Kirsch MA Wolf C Günther C Aicardi-Goutières syndrome: a model disease for systemic autoimmunity. Clin Exp Immunol. 2013; (published online June 21.)http://dx.doi.org/10.1111/cei.12160 Google Scholar Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control studyAGS 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. Full-Text PDF