Introduction
Genes play a vital role in the functioning and development of the immune system. In glaucoma, retinal ganglion cell death occurs in a specific pattern characterized by optic neuropathy. It has been classified into two categories: when the angle is open and when the angle is closed, and glaucoma when the angle has been obstructed. Innumerable risk factors have been attributed to its development, including age, sex, ethnicity, blood pressure, medications, increased intraocular pressure, and the essentially important “genetic factor.” Glaucoma remains the leading cause of permanent loss of vision worldwide due to its progressive and irreversible nature. Presently, about 60 million people are thought to be affected by it, and surprisingly, a large proportion of it remains undiagnosed. Thus, greater insight and understanding of its root causes remains vital.
What Is Glaucoma?
Glaucoma is a multifactorial disease with a mechanical linkage to elevation of intraocular pressure (IOP) factors along with progression of disease independent of IOP elevation. An increase in the intraocular pressure leads to neuronal damage. It has been serving as the leading cause of blindness worldwide. It has been categorized into four categories:
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Primary open-angle.
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Angle-closure.
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Secondary open.
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Angle-closure glaucoma.
By definition, “glaucoma” is the acquired loss of retinal ganglion cells and axons within the optic nerve or optic neuropathy, causing progressive loss of vision. Currently, the exact etiology remains unknown; by evidence, only an “elevated eye pressure “is noted in most cases.
What Is the Etiology of Glaucoma?
A gradual increase in intraocular eye pressure happens due to increased resistance to the outflow of aqueous and decreased outflow facility. A characteristic pattern occurs in the optic nerve ganglion cell nerve fiber layer. Yet there is another theory suggesting that when the intraocular pressure increases, there is a decreased blood flow reaching the optic nerve fibers. With the disease progression, there is a slow loss of peripheral vision in both eyes, with eventual loss of central vision if it is left untreated or undetected. Following this loss pattern, people affected usually fail to recognize changes in their vision until the loss is advanced, affecting the central vision.
What Are the Clinical Features of Glaucoma?
There is generally a loss of peripheral vision, and the central vision gets retained until the disease becomes progressively severe. Typically, the changes may be seen bilaterally, but the progression may not have the same rate when the optic cup disk ratio is greater than 0.5; glaucoma is suggestive. There is a loss of inferotemporal and superotemporal poles of the optic disk.
Normal tension glaucoma patients typically remain asymptomatic, and the intraocular pressure remains less than 21mm Hg. Few changes are noted in the optic disk, like increased cup-to-disk ratio. Disk hemorrhage in the nerve fiber layer may also be noted. In the acute angle closure, patients exhibit severe sudden ocular pain, redness, blurry, decreased visual acuity, headache, nausea, vomiting, and a complaint of seeing halos of light. Those with secondary glaucoma typically present with recent ophthalmic procedures, trauma, or health conditions causing neovascularization like diabetes.
How Is the Evaluation for Glaucoma Carried Out?
A fundoscopic examination, visual field testing, optic coherence tomography, tonometry, and gonioscopy determine the evaluation. Visual acuity test is mainly done to determine if the vision is affected. The corneal thickness is evaluated by pachymetry. Progressive changes in the retinal nerve fibers are evaluated using retinal scans. The basic diagnosis is made on the characteristic clinical findings. There stands no standard gold test for the same. As of today, according to the American Academy of Ophthalmology, a routine and comprehensive examination of the eye is recommended for all patients presenting with risk factors for glaucoma, the frequency of which is established on age, risk factor, family history, and race.
What Is Immunogenicity and What Are Immunogenetic Factors Related to Glaucoma?
Immunogenicity is also known as immunoreactivity; it is the ability of the cells and tissues of the body to provoke an immune response, an undesirable form of physiological response. Mendelian immunogenetic disorder belongs to the monogenic disorder class, where the immune pathway is disrupted, and autoimmunity and autoactivation are activated. The most common feature of several of these conditions is “glaucomatous optic neuropathy.” The most typical conditions include - Aicardi- Goutieres syndrome (AGS) and Singleton Merten Syndrome (SG MRT).
What Is Aicardi Goutieres Syndrome (AGS)?
AGS was first described by Jean Aicardi and Francoise Goutieres in 1984 through a case series that involved eight children from five families. It could be inherited both as autosomal recessive or dominant. It occurs due to the pathogenic variants involving various genes involved in RNA processing:
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TREX1.
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RANSHE2A.
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RNASEH2B.
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RNASEH2B.
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SAMHD1.
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ADAR.
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Innate immunity (IFIH1).
What Could Be Expected in the Most Severe Cases of AGS?
The following could be exhibited in the most severe cases:
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Microcephaly: Where the expected head size is much smaller.
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Leukodystrophy: Rare genetic disorder affecting the white matter of the brain.
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Cerebral Atrophy: There is a loss in connection between the neurons.
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Intracranial Calcification: Refers to the calcifications within the brain vasculature.
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Thrombocytopenia: Refers to low platelet counts.
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Hepatosplenomegaly: Enlarged liver beyond the normal size.
Also, elevated levels of type 1 interferon signaling of the central nervous system can be noted, leading to severe neurologic symptoms and death in early childhood. The milder features that are seen include -painful skin lesions and lupus-like and congenital glaucoma.
What Is Singleton Merten Syndrome (SG MRT)?
This condition was first described by Edward B Singleton and David Merten in 1973. It presents as an autosomal dominant condition. It occurs due to the gain of function variants in one of two RIG-I receptor-like proteins:
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DDX58.
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IFIH1.
These receptors activate innate immune pathways and the type I interferon signaling as a part of antiviral response and recognize the double-stranded RNA.
What Are the Systemic Features of SG MRT?
The systemic features include,
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Psoriatic-like Skin Rashes: Rashes such as deep bumps that are raised and inflamed.
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Vascular Calcifications: These can occur in atherosclerosis, causing calcification of arterioles.
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Skeletal Dysplasia: This causes abnormal development of the baby's bones, joints, and cartilage.
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Dental Anomalies: This may involve the maxilla, the anterior teeth, and, in the mandible, the posterior teeth.
The most prominent feature is open-angle glaucoma, mainly caused by the DDX58 variant. The median age of diagnosis is five years, with a range (two to 18 years). Those SGMRTs related to IFIH1 also feature glaucoma in small fractions, and the pathogenic variant carriers are asymptomatic. Patients may also present with failure of cornea transplant and ocular surface disease. It remains unclear if immunomodulatory therapies can be useful for managing glaucoma associated with these conditions; it remains a topic of investigation.
Conclusion:
It has become important to recognize these syndromes so that an early diagnosis can be made and a better treatment can be offered. Along with this, the management of glaucoma must be tailored to the type and severity of it. Currently, no treatments are available that can reverse the loss of vision; only it could prevent the loss of vision and further damage from happening.
