Download PDF
Neuropediatrics 2016; 47(06): 355-360
DOI: 10.1055/s-0036-1592307
Review Article
Georg Thieme Verlag KG Stuttgart · New York

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

John H. Livingston
1   Department of Paediatric Neurology, Leeds Teaching Hospitals NHS Trust, Leeds General Infirmary, Leeds, United Kingdom
,
Yanick J. Crow
2   Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, Paris Descartes–Sorbonne Paris Cité University, Paris, France
3   Manchester Centre for Genomic Medicine, Institute of Human Development, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom
› Author Affiliations
Further Information

Publication History

10 June 2016

21 July 2016

Publication Date:
19 September 2016 (online)

   Permissions and Reprints

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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 4 Goutières F. Aicardi-Goutières syndrome. Brain Dev 2005; 27 (3) 201-206
    CrossrefPubMedGoogle Scholar
  • 5 Crow YJ, Livingston JH. Aicardi-Goutières syndrome: an important Mendelian mimic of congenital infection. Dev Med Child Neurol 2008; 50 (6) 410-416
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 8 Dale RC, Tang SP, Heckmatt JZ, Tatnall FM. Familial systemic lupus erythematosus and congenital infection-like syndrome. Neuropediatrics 2000; 31 (3) 155-158
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 15 Crow YJ, Manel N. Aicardi-Goutières syndrome and the type I interferonopathies. Nat Rev Immunol 2015; 15 (7) 429-440
    CrossrefPubMedGoogle Scholar
  • 16 Crow YJ. Type I interferonopathies: a novel set of inborn errors of immunity. Ann N Y Acad Sci 2011; 1238: 91-98
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar