Aicardi-Goutières Syndrome with Congenital Glaucoma Caused by Novel Mutation

Overview

Journal J Pers Med

Date 2023 Nov 25

PMID 38003924

Authors

Marta Swierczynska

Agnieszka Tronina

Erita Filipek

Affiliations

Soon will be listed here.

Abstract

Background: Aicardi-Goutières syndrome (AGS) is a rare genetic disorder characterized by microcephaly, white matter lesions, numerous intracranial calcifications, chilblain skin lesions and high levels of interferon-α (IFN-α) in the cerebrospinal fluid (CSF). However, ocular involvement is reported significantly less frequently.

Case Presentation: We present a case of a neonate with hypotrophy, microcephaly, frostbite-like skin lesions, thrombocytopenia, elevated liver enzymes and hepatosplenomegaly. Magnetic resonance imaging (MRI) of the brain showed multiple foci of calcification, white matter changes, cerebral atrophy, and atrophic dilatation of the ventricular system. The inflammatory parameters were not elevated, and the infectious etiology was excluded. Instead, elevated levels of IFN-α in the serum were detected. Based on the related clinical symptoms, imaging and test findings, the diagnosis of AGS was suspected. Genetic testing revealed two pathogenic mutations, c.490C>T and c.222del (novel mutation), in the three prime repair exonuclease 1 () gene, confirming AGS type 1 (AGS1). An ophthalmologic examination of the child at 10 months of age revealed an impaired pupillary response to light, a corneal haze with Haab lines in the right eye (RE), pale optic nerve discs and neuropathy in both eyes (OU). The intraocular pressure (IOP) was 51 mmHg in the RE and 49 in the left eye (LE). The flash visual evoked potential (FVEP) showed prolonged P2 latencies of up to 125% in the LE and reduced amplitudes of up to approximately 10% OU. This girl was diagnosed with congenital glaucoma, and it was managed with a trabeculectomy with a basal iridectomy of OU, resulting in a reduction and stabilization in the IOP to 12 mmHg in the RE and 10 mmHg in the LE without any hypotensive eyedrops.

Conclusions: We present the clinical characteristics, electrophysiological and imaging findings, as well as the genetic test results of a patient with AGS1. Our case contributes to the extended ophthalmic involvement of the pathogenic c.490C>T and c.222del mutations in

References

Rice G, Kasher P, Forte G, Mannion N, Greenwood S, Szynkiewicz M . Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature. Nat Genet. 2012; 44(11):1243-8. PMC: 4154508. DOI: 10.1038/ng.2414. View

Yan N . Immune Diseases Associated with TREX1 and STING Dysfunction. J Interferon Cytokine Res. 2017; 37(5):198-206. PMC: 5439420. DOI: 10.1089/jir.2016.0086. View

Wang M, Sooreshjani M, Mikek C, Opoku-Temeng C, Sintim H . Suramin potently inhibits cGAMP synthase, cGAS, in THP1 cells to modulate IFN-β levels. Future Med Chem. 2018; 10(11):1301-1317. DOI: 10.4155/fmc-2017-0322. View

Crow Y . Aicardi-Goutières syndrome. Handb Clin Neurol. 2013; 113:1629-35. DOI: 10.1016/B978-0-444-59565-2.00031-9. View

Bienias M, Bruck N, Griep C, Wolf C, Kretschmer S, Kind B . Therapeutic Approaches to Type I Interferonopathies. Curr Rheumatol Rep. 2018; 20(6):32. DOI: 10.1007/s11926-018-0743-3. View

Hemphill W, Perrino F . Measuring TREX1 and TREX2 exonuclease activities. Methods Enzymol. 2019; 625:109-133. PMC: 6893858. DOI: 10.1016/bs.mie.2019.05.004. View

Kanavi M, Yazdani S, Elahi E, Mirrahimi M, Hajizadeh M, Khodaverdi S . Prenatal diagnosis of primary congenital glaucoma and histopathological features in a fetal globe with mutations. Eur J Ophthalmol. 2021; :11206721211051235. DOI: 10.1177/11206721211051235. View

Pawlotsky J . Hepatitis C virus: standard-of-care treatment. Adv Pharmacol. 2013; 67:169-215. DOI: 10.1016/B978-0-12-405880-4.00005-6. View

Rice G, Forte G, Szynkiewicz M, Chase D, Aeby A, Abdel-Hamid M . 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):1159-69. PMC: 4349523. DOI: 10.1016/S1474-4422(13)70258-8. View

10.

Livingston J, Stivaros S, van der Knaap M, Crow Y . Recognizable phenotypes associated with intracranial calcification. Dev Med Child Neurol. 2012; 55(1):46-57. DOI: 10.1111/j.1469-8749.2012.04437.x. View

11.

Yu Z, Song H . Toward a better understanding of type I interferonopathies: a brief summary, update and beyond. World J Pediatr. 2019; 16(1):44-51. DOI: 10.1007/s12519-019-00273-z. View

12.

Rice G, Rodero M, Crow Y . Human disease phenotypes associated with mutations in TREX1. J Clin Immunol. 2015; 35(3):235-43. DOI: 10.1007/s10875-015-0147-3. View

13.

Takase H, Sugita S, Rhee D, Imai Y, Taguchi C, Sugamoto Y . The presence of macrophage migration inhibitory factor in human trabecular meshwork and its upregulatory effects on the T helper 1 cytokine. Invest Ophthalmol Vis Sci. 2002; 43(8):2691-6. View

14.

Musalem H, Dirar Q, Al-Hazzaa S, Al Zoba A, El-Mansoury J . Unusual Association of Aniridia with Aicardi-Goutières Syndrome-Related Congenital Glaucoma in a Tertiary Care Center. Am J Case Rep. 2018; 19:500-504. PMC: 5944404. DOI: 10.12659/AJCR.908036. View

15.

Rice G, Meyzer C, Bouazza N, Hully M, Boddaert N, Semeraro M . Reverse-Transcriptase Inhibitors in the Aicardi–Goutières Syndrome. N Engl J Med. 2018; 379(23):2275-7. DOI: 10.1056/NEJMc1810983. View

16.

Rice G, Patrick T, Parmar R, Taylor C, Aeby A, Aicardi J . Clinical and molecular phenotype of Aicardi-Goutieres syndrome. Am J Hum Genet. 2007; 81(4):713-25. PMC: 2227922. DOI: 10.1086/521373. View

17.

Orcesi S, La Piana R, Fazzi E . Aicardi-Goutieres syndrome. Br Med Bull. 2009; 89:183-201. DOI: 10.1093/bmb/ldn049. View

18.

dAngelo D, Di Filippo P, Breda L, Chiarelli F . Type I Interferonopathies in Children: An Overview. Front Pediatr. 2021; 9:631329. PMC: 8044321. DOI: 10.3389/fped.2021.631329. View

19.

Maccora I, Marrani E, Mastrolia M, Abu-Rumeileh S, Maniscalco V, Fusco E . Ocular involvement in monogenic autoinflammatory disease. Autoimmun Rev. 2021; 20(11):102944. DOI: 10.1016/j.autrev.2021.102944. View

20.

Lang E, Koller S, Atac D, Pfaffli O, Hanson J, Feil S . Genotype-phenotype spectrum in isolated and syndromic nanophthalmos. Acta Ophthalmol. 2020; 99(4):e594-e607. DOI: 10.1111/aos.14615. View