Glaucoma and Immunogenetic Disorders
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Introduction
Immunogenetic disorders are diseases characterized by a genetic mutation that results in a primary immunodeficiency. There are many different systemic and ocular manifestations of these diseases. Immunogenetic disorders associated with glaucoma include Aicardi-Goutières Syndrome (AGS) and Singleton-Merten Syndrome (SGMRT).[1]
Aicardi-Goutieres Syndrome
Aicardi-Goutières Syndrome (AGS) is a rare immunogenetic disorder that usually presents within the first year of life and most commonly follows an autosomal recessive inheritance pattern but can also develop rarely from autosomal dominant inheritance or from a de novo gene mutation[1]. First described in 1984 by Jean Aicadi and Françoise Goutières, there are currently seven known genes associated with the development of AGS. Mutations in the genes TREX 1, RNASESH2A, RNASESH2B, RNASESH2C, SAMHD1, and ADAR are inherited in an autosomal recessive inheritance pattern. Mutations in the gene IFIH1, which is involved in innate immunity, can be associated with an autosomal dominant inheritance pattern.
There are a variety of systemic features and symptoms associated with AGS. These include progressive encephalopathy, microcephaly, leukodystrophy, cerebral atrophy, intracranial calcifications of the basal ganglia, chronic CSF lymphocytosis, hepatosplenomegaly, thrombocytopenia, and lupus-like syndrome. AGS is often mistaken for TORCH (Toxoplasmosis, Others, Rubella, Cytomegalovirus, Herpes) infections[2]. Ocular manifestations include glaucoma (congenital or later onset), optic atrophy, and cortical blindness. Most cases of glaucoma are diagnosed within the first 6 months of life[3]. Studies have shown that the risk of glaucoma development differs depending on the specific genetic mutation. SAMHD1 mutation was found to be most associated with glaucoma with one study showing that over 20% of patients with this mutation have congenital glaucoma. The ADAR and IFIH1 mutations were found to be the least associated with glaucoma.[4][5]
Singleton-Merten Syndrome
Singleton-Merten Syndrome (SGMRT) is an uncommon autosomal dominant immunogenetic disorder that was first described in 1973 by Edward B Singleton and David Merten. It is associated with mutations in the genes DDX58[6] and IFIH1[7], which are involved in innate immunity. Systemic features associated with SGMRT include psoriasiform rash, aortic and valvular calcifications, osteopenia and osteoporosis, tendon rupture, arthritis, and dental anomalies. Glaucoma (congenital or juvenile open-angle) is the most penetrant feature of SGMRT, and the median age at diagnosis is 5 years old.[8] Studies have shown that 94% of individuals with a mutation in DDX58 and 40% of individuals with a mutation in IFIH1 have glaucoma[4][9]. The mutation in DDX58 leads to dysfunction in the retinoic acid-inducible gene I (RIG-I) receptor, which is found in trabecular meshwork cells, resulting in the death of trabecular meshwork cells and decreased ability to drain aqueous fluid.[10] RIG-I receptors are also found in the cornea. Due to the dysfunction of corneal RIG-I receptors, patients with SGMRT have a high rate of corneal transplant failure.[11]
Treatment
Glaucoma treatment in AGS and SGMRT consists of medical therapy followed by surgical intervention as needed. The visual prognosis of patients with AGS and SGMRT is poor and affected individuals may require multiple glaucoma surgical interventions[8]. Systemic therapies, such as inhibition of Janus kinase (JAK), have demonstrated promise in treating SGMRT and may demonstrate efficacy in treating ocular manifestations of this condition[12].
- ↑ 1.0 1.1 Crow Y. Aicardi-Goutières Syndrome. 2005 Jun 29 [Updated 2016 Nov 22]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1475
- ↑ Rice G, Patrick T, Parmar R, et al. Clinical and molecular phenotype of Aicardi Goutieres syndrome. Am J Hum Genet. 2007;81:P713-25. doi:10.1086/52137
- ↑ Crow Y, Massey R, Innes J, et al. Congenital glaucoma and brain stem atrophy as features of Aicardi-Goutières syndrome. Am J Med Genet A. 2004;129A(3):303-7. doi: 10.1002/ajmg.a.30250
- ↑ 4.0 4.1 Balikov D, Jacobson A, Prasov L. Glaucoma syndromes: Insights into glaucoma genetics and pathogenesis from monogenic syndromic disorders. Genes (Basel). 2021;12(9):1403. doi:10.3390/genes12091403
- ↑ Crow Y. Aicardi-Goutieres syndrome. Handb Clin Neurol. 2013;113:1629-1635. doi:10.1016/B978-0-444-59565-2.00031-9
- ↑ Jang MA, Kim EK, Nguyen NT, Kim WJ, Yoo JY, Lee J, Jeong YM, Kim CH, Kim OH, Sohn S, Nam SH. Mutations in DDX58, which encodes RIG-I, cause atypical Singleton-Merten syndrome. Am J Hum Genet. 2015 Feb 5;96(2):266-74.
- ↑ Rutsch F, MacDougall M, Lu C, Buers I, Mamaeva O, Nitschke Y, Rice GI, Erlandsen H, Kehl HG, Thiele H, Nürnberg P. A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome. Am J Hum Genet. 2015 Feb 5;96(2):275-82.
- ↑ 8.0 8.1 Serpen J, Armenti S, Prasov L. Immunogenetics of the Ocular Anterior Segment: Lessons from Inherited Diseases. J Ophthalmol. 2021:6691291. doi: 10.1155/2021/6691291
- ↑ Feigenbaum A, Müller C, Yale C, et al. Singleton-Merten syndrome: An autosomal dominant disorder with variable expression. Am J Med Genet A. 2013;161A(2):360-370. doi:10.1002/ajmg/a/35732
- ↑ Changmin L, MacDougall M. RIG-I-Like Receptor Signaling in Singleton-Merten Syndrome. Front Genet. 2017;8:118. doi:10.3389/fgene.2017.00118
- ↑ Prasov L, Bohnsack B, El Husny A, et al. DDX58(RIG-I)-related disease is associated with tissue-specific interferon pathway activation. J. Med. Genet. 2022;59:294-304. doi: 10.1136/jmedgenet-2020-1074471
- ↑ Broser P, von Mengershausen U, Heldt K, Bartholdi D, Braun D, Wolf C, Lee-Kirsch MA. Precision treatment of Singleton Merten syndrome with ruxolitinib: a case report. Pediatr Rheumatol Online J. 2022;20(1):24. doi: 10.1186/s12969-022-00686-7. PMID: 35410415; PMCID: PMC8995680.
