Neurologic Phenotypes Associated with Mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, and IFIH1: Aicardi–Goutières Syndrome and Beyond

Abstract

The Aicardi–Goutières syndrome (AGS) was first described in 1984, and over the following years was defined by the clinical and radiological features of an early onset, severe, neurologic disorder with intracranial calcification, leukoencephalopathy, and cerebral atrophy, usually associated with a cerebrospinal fluid (CSF) pleocytosis and elevated CSF interferon α activity. It is now recognized that mutations in any of the following seven genes may result in the classical AGS phenotype: TREX1 (AGS1), RNASEH2A (AGS2), RNASEH2B (AGS3), RNASEH2C (AGS4), SAMHD1 (AGS5), ADAR1 (AGS6), and IFIH1 (AGS7). All of these genes encode proteins involved in nucleotide metabolism and/or sensing. Mutations in these genes result in the induction of type 1 interferon production and an upregulation of interferon stimulated genes. As more patients harboring mutations in these genes have been described, in particular facilitated by the advent of whole exome sequencing, a remarkably broad spectrum of associated neurologic phenotypes has been revealed, which we summarize here. We propose that the term AGS has continued clinical utility in the designation of a characteristic phenotype, which suggests relevant diagnostic investigations and can inform outcome predictions. However, we also suggest that the use of the term “type 1 interferonopathy” is appropriate for the wider spectrum of disease consequent upon dysfunction of these genes and proteins since it implies the possibility of a common “anti-interferon” approach to therapy as such treatments become available.

Keywords

Aicardi–Goutières syndrome - type 1 interferonopathies - interferon signature

• References

• 1 Aicardi J, Goutières F. A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann Neurol 1984; 15 (1) 49-54
• 2 Lebon P, Badoual J, Ponsot G, Goutières F, Hémeury-Cukier F, Aicardi J. Intrathecal synthesis of interferon-alpha in infants with progressive familial encephalopathy. J Neurol Sci 1988; 84 (2–3) 201-208
• 3 Lanzi G, Fazzi E, D'Arrigo S. Aicardi-Goutières syndrome: a description of 21 new cases and a comparison with the literature. Eur J Paediatr Neurol 2002; 6 (Suppl A): A9-A22 , discussion A23–A25, A77–A86
• 4 Goutières F. Aicardi-Goutières syndrome. Brain Dev 2005; 27 (3) 201-206
• 5 Crow YJ, Livingston JH. Aicardi-Goutières syndrome: an important Mendelian mimic of congenital infection. Dev Med Child Neurol 2008; 50 (6) 410-416
• 6 Rice G, Patrick T, Parmar R , et al. Clinical and molecular phenotype of Aicardi-Goutières syndrome. Am J Hum Genet 2007; 81 (4) 713-725
• 7 Tolmie JL, Shillito P, Hughes-Benzie R, Stephenson JBP. The Aicardi-Goutières syndrome (familial, early onset encephalopathy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis). J Med Genet 1995; 32: 881-884
• 8 Dale RC, Tang SP, Heckmatt JZ, Tatnall FM. Familial systemic lupus erythematosus and congenital infection-like syndrome. Neuropediatrics 2000; 31 (3) 155-158
• 9 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 (8) 917-920
• 10 Crow YJ, Leitch A, Hayward BE , et al. Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection. Nat Genet 2006; 38 (8) 910-916
• 11 Rice GI, Bond J, Asipu A , et al. Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response. Nat Genet 2009; 41 (7) 829-832
• 12 Rice GI, Kasher PR, Forte GM , et al. Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature. Nat Genet 2012; 44 (11) 1243-1248
• 13 Rice GI, del Toro Duany Y, Jenkinson EM , et al. Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nat Genet 2014; 46 (5) 503-509
• 14 Vogt J, Agrawal S, Ibrahim Z , et al. Striking intrafamilial phenotypic variability in Aicardi-Goutières syndrome associated with the recurrent Asian founder mutation in RNASEH2C. Am J Med Genet A 2013; 161A (2) 338-342
• 15 Crow YJ, Manel N. Aicardi-Goutières syndrome and the type I interferonopathies. Nat Rev Immunol 2015; 15 (7) 429-440
• 16 Crow YJ. Type I interferonopathies: a novel set of inborn errors of immunity. Ann N Y Acad Sci 2011; 1238: 91-98
• 17 Crow YJ, Chase DS, Lowenstein Schmidt J , et al. Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. Am J Med Genet A 2015; 167A (2) 296-312
• 18 Uggetti C, La Piana R, Orcesi S, Egitto MG, Crow YJ, Fazzi E. Aicardi-Goutières syndrome: neuroradiologic findings and follow-up. AJNR Am J Neuroradiol 2009; 30 (10) 1971-1976
• 19 Livingston JH, Stivaros S, van der Knaap MS, Crow YJ. Recognizable phenotypes associated with intracranial calcification. Dev Med Child Neurol 2013; 55 (1) 46-57
• 20 La Piana R, Uggetti C, Roncarolo F , et al. Neuroradiologic patterns and novel imaging findings in Aicardi-Goutières syndrome. Neurology 2016; 86 (1) 28-35
• 21 Vanderver A, Prust M, Kadom N , et al. Early onset Aicardi-Goutières syndrome: magnetic resonance imaging (MRI) pattern recognition. J Child Neurol 2015; 30 (10) 1343-1348
• 22 D'Arrigo S, Riva D, Bulgheroni S , et al. Aicardi-Goutières syndrome: description of a late onset case. Dev Med Child Neurol 2008; 50 (8) 631-634
• 23 Orcesi S, Pessagno A, Biancheri R , et al. Aicardi-Goutières syndrome presenting atypically as a sub-acute leukoencephalopathy. Eur J Paediatr Neurol 2008; 12 (5) 408-411
• 24 La Piana R, Uggetti C, Olivieri I , et al. Bilateral striatal necrosis in two subjects with Aicardi-Goutières syndrome due to mutations in ADAR1 (AGS6). Am J Med Genet A 2014; 164A (3) 815-819
• 25 Livingston JH, Lin J-P, Dale RC , et al. A type I interferon signature identifies bilateral striatal necrosis due to mutations in ADAR1. J Med Genet 2014; 51 (2) 76-82
• 26 Crow YJ, Zaki MS, Abdel-Hamid MS , et al. Mutations in ADAR1, IFIH1, and RNASEH2B presenting as spastic paraplegia. Neuropediatrics 2014; 45 (6) 386-393
• 27 Ramesh V, Bernardi B, Stafa A , et al. Intracerebral large artery disease in Aicardi-Goutières syndrome implicates SAMHD1 in vascular homeostasis. Dev Med Child Neurol 2010; 52 (8) 725-732
• 28 Olivieri I, Cattalini M, Tonduti D , et al. Dysregulation of the immune system in Aicardi-Goutières syndrome: another example in a TREX1-mutated patient. Lupus 2013; 22 (10) 1064-1069
• 29 Crow YJ, Massey RF, Innes JR , et al. Congenital glaucoma and brain stem atrophy as features of Aicardi-Goutières syndrome. Am J Med Genet A 2004; 129A (3) 303-307
• 30 Rice GI, Forte GMA, Szynkiewicz M , et al. Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study. Lancet Neurol 2013; 12 (12) 1159-1169
• 31 Bursztejn AC, Briggs TA, del Toro Duany Y , et al. Unusual cutaneous features associated with a heterozygous gain-of-function mutation in IFIH1: overlap between Aicardi-Goutières and Singleton-Merten syndromes. Br J Dermatol 2015; 173 (6) 1505-1513