Aicardi—Goutieres syndrome type 6 associated with a compound heterozygous variant in ADAR: a first case report in the Russian population

Close metadata

Recommended articles:

Abobotulinumtoxin A injections for the chronic sialorrhea correction in children: Russian retrospective multicenter study. S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(1):53-61

Age-related features of the gut microbiota composition of Rhesus monkeys kept in captivity. Molecular Genetics, Microbiology and Virology. 2024;(3):22-28

Aicardi-Goutieres syndrome (AGS) is a rare hereditary disorder with different types of inheritance manifested by progressive leukoencephalopathy with early onset, sharing common features with autoimmune disease. This article describes the first Russian case of AGS type 6 (AGS6) associated with compound heterozygote c.577C>G (p.Pro193Ala)+c.2304G>A (p.Trp768*) in ADAR and provides a more in-depth understanding of AGS6 by summarizing the worldwide literature and suggesting models for practitioners to diagnose patients with clinically suspected AGS.

Keywords:

Aicardi-Goutieres syndrome

cerebral palsy

ADAR gene

sequencing

Authors:

I D.V.

Khabarovsk Center for the Development of Psychology and Childhood «Psylogia»;
Far-East State Medical University

Scopus AuthorID: 57226670660
ORCID: 0000-0002-9967-0279

Seregin S.A.

Clinic Expert Khabarovsk

ORCID: 0000-0001-7495-7153

Proskokova T.N.

Far-East State Medical University

ORCID: 0000-0002-5209-2440

Received:

05.09.2024

Accepted:

26.09.2024

List of references:

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. https://doi.org/10.1002/ana.410150109
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:296-312. https://doi.org/10.1002/ajmg.a.36887
Rice G, Patrick T, Parmar R, et al. Clinical and molecular phenotype of Aicardi-Goutieres syndrome. Am J Hum Genet. 2007;81:713-725. https://doi.org/10.1086/521373
Al Mutairi F, Alfadhel M, Nashabat M, et al. Phenotypic and molecular spectrum of Aicardi-Goutieres syndrome: a study of 24 patients. Pediatr Neurol. 2018;78:35-40. https://doi.org/10.1016/j.pediatrneurol.2017.09.002
Garau J, Cavallera V, Valente M, et al. Molecular genetics and interferon signature in the Italian Aicardi Goutieres syndrome cohort: report of 12 new cases and literature review. J Clin Med. 2019;8:750. https://doi.org/10.3390/jcm8050750
Goutières F, Aicardi J, Barth PG, et al. Aicardi-Goutieres syndrome: an update and results of interferon-alpha studies. Ann Neurol. 1998;44:900-907. https://doi.org/10.1002/ana.410440608
Lanzi G, Fazzi E, D’Arrigo S. Aicardi-Goutieres syndrome: a description of 21 new cases and a comparison with the literature. Europ Paediatr Neurol. 2002;6:9-22. https://doi.org/10.1053/ejpn.2002.0568
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;46:503-509. https://doi.org/10.1038/ng.2933
Abe J, Nakamura K, Nishikomori R, et al. A nationwide survey of Aicardi-Goutieres syndrome patients identifies a strong association between dominant TREX1 mutations and chilblain lesions: Japanese cohort study. Rheumatology. 2014;53:448-458. https://doi.org/10.1093/rheumatology/ket372
Crow Y, Black D, Ali M, et al. Cree encephalitis is allelic with Aicardi-Goutieres syndrome: implications for the pathogenesis of disorders of interferon alpha metabolism. Med Genet. 2003;40:183-187. https://doi.org/10.1136/jmg.40.3.183
Al-Herz W, Bousfiha A, Casanova JL, et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2011;2:54. https://doi.org/10.3389/fimmu.2011.00054
Crow YJ, Manel N. Aicardi-Goutieres syndrome and the type I interferonopathies. Nat Rev Immunol. 2015;15:429-440. https://doi.org/10.1038/nri3850
Rice GI, Kasher PR, Forte GM, et al. Mutations in ADAR1 cause Aicardi-Goutieres syndrome associated with a type I interferon signature. Nat Genet. 2012;44:1243-1248. https://doi.org/10.1038/ng.2414
Rice GI, Bond J, Asipu A, et al. Mutations involved in Aicardi-Goutieres syndrome implicate SAMHD1 as regulator of the innate immune response. Nat Genet. 2009;41:829-832. https://doi.org/10.1038/ng.373
Uggenti C, Lepelley A, Depp M, et al. cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing. Nat Genet. 2020;52(12):1364-1372. https://doi.org/10.1038/s41588-020-00737-3
OMIM (Online Mendelian Inheritance in Man). https://www.ncbi.nlm.nih.gov/OMIM
Bryukhanova NO, Zhilina SS, Aivazyan SO, et al. Aicardi-Goutieres syndrome in children with idiopathic epilepsy. Rossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics). 2016;61(2):68-75. (In Russ.). https://doi.org/10.21508/1027-4065-2016-61-2-68-75
Livingston JH, Crow YJ. Neurologic phenotypes associated with mutations in TREX1, RNASEH2A, RNA- SEH2B, RNASEH2C, SAMHD1, ADAR1, and IFIH1: Aicardi-Goutieres syndrome and beyond. Neuropediatrics. 2016;47:355-360. https://doi.org/10.1055/s-0036-1592307
Livingston JH, Lin JP, Dale RC, et al. A type I interferon signature identifies bilateral striatal necrosis due to mutations in ADAR1. J Med Genet. 2014;51:76-82. https://doi.org/10.1136/jmedgenet-2013-102038
Crow YJ, Zaki MS, Abdel-Hamid MS, et al. Mutations in ADAR1, IFIH1, and RNASEH2B presenting as spastic paraplegia. Neuropediatrics. 2014;45:386-393. https://doi.org/10.1055/s-0034-1389161
Ramesh V, Bernardi B, Stafa A, et al. Intracerebral large artery disease in Aicardi-Goutieres syndrome implicates SAMHD1 in vascular homeostasis. Dev Med Child Neurol 2010;52:725-732. https://doi.org/10.1111/j.1469-8749.2010.03727.x
Song C, Sakurai M, Shiromoto Y, et al. Functions of the RNA editing enzyme ADAR1 and their relevance to human diseases. Genes. 2016;7:129. https://doi.org/10.3390/genes7120129
Gacem N, Kavo A, Zerad L, et al. ADAR1 mediated regulation of neural crest derived melanocytes and Schwann cell development. Nat Commun. 2020;11(1):198. https://doi.org/10.1038/s41467-019-14090-5
Rice GI, Kitabayashi N, Barth M, et al. Genetic, phenotypic, and interferon biomarker status in ADAR1-related neurological disease. Neuropediatrics. 2018;48:166-184. https://doi.org/10.1055/s-0037-1601449
Miyamura Y, Suzuki T, Kono M, et al. Mutations of the RNA-specific adenosine deaminase gene (DSRAD) are involved in dyschromatosis symmetrica hereditaria. Am J Hum Genet. 2003 Sep;73(3):693-699.
Li M, Yang L, Li C, et al. Mutational spectrum of the ADAR1 gene in dyschromatosis symmetrica hereditaria. Arch Dermatol Res. 2010;302:469-476. https://doi.org/10.1007/s00403-010-1039-2
Kondo T, Suzuki T, Ito S, et al. Dyschromatosis symmetrica hereditaria associated with neurological disorders. J Dermatol. 2008;35:662-666. https://doi.org/10.1111/j.1346-8138.2008.00540.x
Kono M, Suganuma M, Dutta A, et al. Bilateral striatal necrosis and dyschromatosis symmetrica hereditaria: A-I editing efficiency of ADAR1 mutants and phenotype expression. Br J Dermatol. 2018;179:509-511. https://doi.org/10.1111/bjd.16610
Hartner JC, Walkley CR, Lu J, et al. ADAR1 is essential for the maintenance of hematopoiesis and suppression of interferon signaling. Nat Immunol. 2009 Jan;10(1):109-115. https://doi.org/10.1038/ni.1680
Wang W, Wang W, He TY, et al. Analysis of clinical characteristics of children with Aicardi-Goutieres syndrome in China. World J Pediatr. 2022;18(7):490-497. https://doi.org/10.1007/s12519-022-00545-1
Di Lazzaro G, Graziola F, Sancesario A, et al. Movement disorders in ADAR1 disease: Insights from a comprehensive cohort. Parkinsonism Relat Disord. 2020;79:100-104. https://doi.org/10.1016/j.parkreldis.2020.08.039
Cattalini M, Galli J, Zunica F, et al. Case report: the JAK-inhibitor ruxolitinib use in Aicardi-Goutieres syndrome due to ADAR1 mutation. Front Pediatr. 2021;9:725868. https://doi.org/10.3389/fped.2021.725868
Mura E, Masnada S, Antonello C, et al. Ruxolitinib in Aicardi-Goutières syndrome. Metab Brain Dis. 2021;36:859-863. https://doi.org/10.1007/s11011-021-00716-5
Rice GI, Meyzer C, Bouazza N, et al. Reverse-transcriptase inhibitors in the Aicardi-Goutieres syndrome. N Eng J Med. 2018;379:2275-2277. https://doi.org/10.1056/NEJMc1810983
Ashrafi MR, Amanat M, Garshasbi M, et al. An update on clinical, pathological, diagnostic, and therapeutic perspectives of childhood leukodystrophies. Expert Rev Neurother. 2020;20:65-84. https://doi.org/10.1080/14737175.2020.1699060
Orcesi S, Pessagno A, Biancheri R, et al. Aicardi-Goutieres syndrome presenting atypically as a subacute leukoencephalopathy. Eur J Paediatr Neurol. 2008;12:408-411. https://doi.org/10.1016/j.ejpn.2007.10.005
D’Arrigo S, Riva D, Bulgheroni S, et al. Aicardi-Goutieres syndrome: description of a late onset case. Dev Med Child Neurol. 2008;50:631-634. https://doi.org/10.1111/j.1469-8749.2008.03033.x
Fremond ML, Rodero MP, Jeremiah N, et al. Efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in the treatment of vasculopathy associated with TMEM173-activating mutations in 3 children. J Allergy Clin Immunol. 2016;138:1752-1755. https://doi.org/10.1016/j.jaci.2016.07.015
Sanchez GAM, Reinhardt A, Ramsey S, et al. JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. J Clin Invest. 2018;128:3041-3052. https://doi.org/10.1172/JCI98814
Briand C, Fremond ML, Bessis D, et al. Efficacy of JAK1/2 inhibition in the treatment of chilblain lupus due to TREX1 deficiency. Ann Rheum Dis. 2019;78:431-433. https://doi.org/10.1136/annrheumdis-2018-214037
McLellan KE, Martin N, Davidson JE, et al. JAK 1/2 Blockade in MDA5 gain-of-function. J Clin Immunol. 2018;38:844-846. https://doi.org/10.1007/s10875-018-0563-2
Kothur K, Bandodkar S, Chu S, et al. An open-label trial of JAK 1/2 blockade in progressive IFIH1-associated neuroinflammation. Neurology. 2018;90:289-291. https://doi.org/10.1212/WNL.0000000000004921
Crow YJ, Shetty J, Livingston JH. Treatments in Aicardi-Goutières syndrome. Dev Med Child Neurol. 2020;62(1):42-47. https://doi.org/10.1111/dmcn.14268
Ramantani G, Kohlhase J, Hertzberg C, et al. Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutieres syndrome. Arthritis Rheum. 2010;62:1469-1477. https://doi.org/10.1002/art.27367
Tojo K, Sekijima Y, Suzuki T, et al. Dystonia, mental deterioration, and dyschromatosis symmetrica hereditaria in a family with ADAR1 mutation. Mov Disord. 2006;21:1510-1513. https://doi.org/10.1002/mds.21011
Sathishkumar D, Muthusamy K, Gupta A, et al. Co-occurrence of Aicardi-Goutières syndrome type 6 and dyschromatosis symmetrica hereditaria due to compound heterozygous pathogenic variants in ADAR1: a case series from India. Clin Exp Dermatol. 2021;46(4):704-709. https://doi.org/10.1111/ced.14531
Wang XP, Liu Y, Wang JM, et al. Two novel splice site mutations of the ADAR1 gene in Chinese families with dyschromatosis symmetrica hereditaria. J Dermatol. 2010;37:1051-1052. https://doi.org/10.1111/j.1346-8138.2010.00928.x
Schmelzer L, Smitka M, Wolf C, et al. Variable clinical phenotype in two siblings with Aicardi-Goutières syndrome type 6 and a novel mutation in the ADAR gene. Eur J Paediatr Neurol. 2018;22(1):186-189. https://doi.org/10.1016/j.ejpn.2017.11.003

Close metadata