Normal-tension glaucoma (NTG) is a type of progressive glaucomatous optic neuropathy (GON). Its main difference to primary open-angle glaucoma (POAG) is that NTG presents with normal intraocular pressure (IOP) (1). The epidemiology of NTG varies, being more prevalent among Asian populations, including Japanese and Korean populations, than among Caucasians. NTG is also considered a ‘middle-age’ disease with the mean age of patients being in the 6th decade of life. Of note, although IOP is measured within a normal range in NTG, optic disc excavation and visual field (VF) defects are detected (2). This suggests an IOP-independent multifactorial background of NTG etiology. The main factors contributing to NTG-related GON can be distinguished into two main categories, namely vascular and mechanical. These factors can lead to retinal ganglion cell (RGC) loss and axonal damage via several pathways (3). In addition, various genes have been found to be involved in NTG, thus suggesting a genetic predisposition for NTG development (4).

The aim of this review was to summarize and analyze the various pathogenetic factors which contribute to the development of NTG-related GON and to present the recent research findings on the genetics of NTG.

The keystone of the vascular pathogenesis of GON in NTG seems to be a disruption in ocular blood flow (OBF) (5). Although the measurement of OBF remains challenging, with a great variety of available methods and no gold standard method available, studies on patients with glaucoma have indicated a reduction in OBF in ocular tissues (optic nerve, retina and choroid), being more prominent in cases of progressive NTG than in POAG (5,6).

The reduction in OBF is a multifactorial phenomenon. The role of ocular perfusion pressure (OPP) is known, which is equal to arterial blood pressure (BP) minus IOP, with IOP being equal to retinal venous pressure (RVP) (7). Since IOP is within a normal range in NTG, alterations in BP or RVP can influence OPP. Low OPP, particularly if fluctuating, contributes to the progression of GON (8). Indeed, low systemic blood pressure, particularly during the night, reduces OBF via a reduction in OPP, thus being a major risk factor of NTG progression. Additionally, RVP is increased in patients with glaucoma, resulting also in a lower OPP (9,10). These facts indicate a component related to OPP reduction. As a result, structural damage and low OPP constitute a secondary element of OBF reduction.

However, a primary component may be involved. Nailfold capillaries also demonstrate a reduction in blood flow, which cannot be connected to glaucomatous damage or IOP. Moreover, a low BP does not enhance GON progression in all cases (11,12). OBF and OPP demonstrate a complex interaction in combination with local flow resistance, with a reduction in resistivity as a regulatory reaction to OPP reduction (5). There is evidence to suggest that in subjects with low BP, a reduction in OPP reduces OBF due to altered autoregulation and defective adaptation (13). OBF reduction in retrobulbar arteries with a distortion of vascular properties, concerning resistance and pulsatility, was recently reported in patients with NTG (14). In addition, OBF reduction often precedes GON, being a predictor of its progression (15). All these observations have led to the term ‘vascular dysregulation’ which, in general, describes the lack of maintaining an adequate tissue blood supply, despite alterations in perfusion pressure, embracing irregular systemic or local vasospastic/vasodilating phenomena (5). Vascular dysregulation is considered to be the key primary component of GON pathogenesis in patients with NTG (12,16).

Despite this evidence regarding OBF reduction and GON, OBF reduction in animal models through the administration of endothelin-1 (ET-1), and in patients with multiple sclerosis, has led to only mild optic nerve head (ONH) atrophy and minor excavation (17,18). Thus, it has been proposed that an OBF fluctuation initiates and promotes glaucomatous damage more effectively than baseline OBF, a fact that has been proven (5). OBF instability may be due to high IOP or low BP fluctuation exceeding normal autoregulation, or normal IOP and/or BP fluctuation in the case of altered autoregulation (19). IOP fluctuations are discussed below as a part of mechanical factors in NTG. As regards vascular factors in the case of normal autoregulation, systemic hypotension, particularly nocturnal drops, is responsible for low BP, resulting in an OPP deficit. On the other hand, improper autoregulation implies vascular dysregulation (10,16).

Hence, below, we analyze systemic hypotension with reference to nocturnal drops, and vascular dysregulation, as the major vascular factors of NTG-related GON.

BP plays a crucial role in NTG. Various studies have indicated systemic hypotension as a common risk factor in patients with NTG with ONH excavation, VF progression, and optic disc hemorrhage (10,20). Notably, Orgul et al reported that the majority of patients with NTG with systemic hypotension also present vasospasm (65%) (21), indicating an association between low BP and vasospastic disorders, possibly reflecting the additional role of vascular dysregulation (21,22). As previously mentioned, hypotension through OPP reduction creates OBF reduction/fluctuation, particularly when low BP exceeds the capacity of vascular autoregulation, resulting in perfusion deficits and ischemic injuries in optic nerve fibers (10).

These alterations are more prominent in sustained nocturnal BP drops, which are more frequent among NTG cases, almost always being observed in patients with NTG with vasospasm (10,23). A meta-analysis of the correlation between GON and the circadian rhythm of BP, including NTG cases, reported that nocturnal BP drops >10% of diurnal BP were a risk factor for VF defect progression (24). A prospective study was conducted including 85 patients with NTG, and BP was monitored over a 48-h period in 30-min intervals and during follow-up at 6 and 12 months. VF defect progression was observed in 29% of patients, with a significant predictor of it being sustained nocturnal BP drops 10 mmHg lower compared to diurnal BP (23). Consequently, systemic hypotension, particularly nocturnal BP drops, may be an important risk factor for GON and VF defect progression in NTG, although these findings are still under debate (25).

It has been suggested that vascular dysregulation is a primary step initiating glaucomatous damage in NTG via OBF instability, affecting optic nerve and retina by the enhancement of ischemic damage, as well as by promoting the apoptosis of RGCs and their axons (19). The main cause is a systemic form of vascular dysregulation, accompanied by symptoms and signs, thus constituting a ‘vascular dysregulation syndrome’. Considering its primary nature in NTG pathogenesis, the term primary vascular dysregulation syndrome or Flammer syndrome (FS) is used (26,27). Other components of vascular dysregulation include migraines, systemic vascular diseases and endothelial dysfunction (28,29). All of these are considered risk factors for GON in NTG cases (4).

The mechanical pathogenesis of NTG includes IOP and lamina cribrosa.

The role of IOP. Although an elevated IOP leads to GON through a recognized pathophysiological pathway, the normal IOP range in NTG implies that other mechanisms may coexist inducing glaucomatous damage (5).

The ‘Collaborative Normal-Tension Glaucoma Study’, which was conducted among 145 patients with NTG, reported that a 30% IOP reduction, even though favorable, did not prevent the progression of VF defects, indicating that IOP was not solely involved in GON (52). Agnifili et al observed the presence of conjunctival epithelial microcysts in NTG cases using in vivo confocal microscopy, suggesting an alteration in aqueous humor hydrodynamics concerning trans-scleral outflow in NTG (53). Epidemiological studies have demonstrated that NTG is more prevalent in Asian (52–92%) compared with Caucasian (30–39%) glaucoma cases, possibly reflecting a demographically different tolerance and/or genetic susceptibility to IOP (2,52). IOP evaluation through contact lens sensor has revealed notable IOP fluctuations, presenting nocturnal acrophase and prolonged IOP peaks in 80% of NTG individuals (54). High IOP peaks (>90 mV) have been linked to glaucomatous progression and IOP fluctuations can lead to OBF instability in view of disturbed autoregulation (55,56). Furthermore, an elevated nocturnal IOP in the supine position may contribute to ONH and/or VF damage in NTG (57). FS, the major cause of vascular dysregulation, also prevalent among Asian populations, may play an important role in IOP-induced damage in NTG. Moreover, an altered ONH morphology has been demonstrated in patients with NTG, with deeper and larger optic disc cups than POAG cases (58). Various studies have reported a thinner central corneal thickness in NTG than POAG and normal individuals which is also associated with VF defects, although these findings are considered controversial (59–61).

Thus, the above-mentioned findings create the hypothesis of a lower threshold for IOP-related damage in some patients with NTG as regards epidemiology, ocular morphology and dysregulation, where normal IOP and its fluctuations can induce mechanical stress and axonal damage in ONH.

The impact of lamina cribrosa. Lamina cribrosa (LC) is a thin mesh-like collagenous tissue containing non-myelinated RGC axons, forming a barrier between intraocular and orbital subarachnoid spaces (SAS). It has been hypothesized that the trans-laminar pressure gradient (TLPG), expressed as the difference between IOP and intracranial pressure (ICP), is associated with mechanical damage to the optic nerve fibers in NTG (62,63).

An elevated retrograde TLPG through a reduction in ICP can induce optic nerve damage, either baro-traumatically or through damage to the capillaries, resulting in a posteriorly displaced LC (64). Ren et al indicated a significantly reduced ICP using lumbar puncture in NTG regarding POAG or normal individuals, in agreement with the above-mentioned theory (65). A meta-analysis also reported a significantly reduced ICP and elevated TLPG in NTG and POAG than in normal subjects (66). Furthermore, multivariate analyses have revealed that TLPG was positively associated with perimetric VF defects and negatively with the neuroretinal rim area in both glaucoma types (65,66). Nevertheless, other studies on patients with NTG have argued that ICP is normal and that TLPG is not significantly associated with VF defects (67,68). A recent prospective study on 13 NTG cases demonstrated a normal TLPG and ICP, presenting no association with VF defects (68). Therefore, the issue of TLPG in NTG pathogenesis remains a matter of debate. Future methodological improvements may provide a more accurate assessment of TLPG, clarifying its role in NTG.

Jonas et al described a distinct difference in the appearance of optic nerve head in highly myopic eyes (refraction more than −8.00 diopters), with significantly larger discs and of a more oval configuration, which may render highly myopic eyes more susceptible to nerve fibre loss (69).

ET-1 and its receptors may also interact with LC function. Rao et al described an altered function and expression of ET_A and ET_B receptors in LC cells following prolonged stimulation by ET-1 (70,71). This implies that high ET-1 levels, a frequent observation in NTG cases, may affect LC via the remodeling of the extracellular matrix (ECM), thus causing LC deformation. An impaired LC structure and function can influence local RGC axons, astrocytes and capillaries, enhancing sensitivity to IOP-related stress in NTG (63).

There is recent evidence to suggest the involvement of obstructive sleep apnea/hypopnea syndrome (OSAHS) in NTG-related GON (72). OSAHS is characterized by upper airway obstruction during sleep. NTG is particularly prevalent among patients with OSAHS. Elevated IOP, VF disruption, glaucomatous disc alterations and thinning of the retinal nerve fiber layer have been reported in OSAHS cases (72,73). GON pathogenesis in OSAHS includes both vascular and mechanical factors (72).

Repetitive sustained upper airway obstruction leads to recurrent hypoxemia (and thus hypoxia) and hypercapnia, in addition to increased vascular resistance which derives from enhanced sympathetic stimulation. Transient hypoxia combined with increased vascular resistance can harm the vascular endothelium, thus producing endothelial dysfunction and impaired autoregulation, possibly disturbing blood flow to the optic nerve and retina (74). Such an unstable oxygen concentration can directly cause insults to the optic nerve fibers, or indirectly via reperfusion and subsequent oxidative stress and inflammation (75). A diminished cerebral perfusion pressure may also affect blood flow to the optic nerve (76). Moreover, patients with OSAHS present an IOP nocturnal acrophase, which is associated with the supine position and immoderate orbital adipose tissue due to obesity (73,77). Elastic fiber depletion in LC is also observed in patients with OSAHS, increasing the glaucomatous risk (72).

RGC cells and their axons, endothelium and glial cells, such as astrocytes, form a ‘neurovascular unit’, which contributes to the homeostasis of the microenvironment and OBF in ONH and retina, via vascular autoregulation, glial support, balance between ET-1 and NO, trophic supply, proper blood-brain barrier (BBB) and controlled immunity (19,78–80). Any disruption in these factors, mostly due to IOP-independent mechanisms, can damage the ONH and retina, resulting in NTG-related GON.

A primary pathogenetic step seems to be the OBF instability leading to RGC loss (78,81). As demonstrated above, FS, migraines, vascular diseases, OSAHS, nocturnal systemic hypotension, IOP fluctuations and LC deformation induce OPP impairment and vascular dysregulation through complex mechanisms, thus resulting in an unstable OBF, a prominent finding of NTG (9,22,25). A common characteristic of dysregulation in these conditions is an interplay between vasospasm and an ET-1-dependent endothelial dysfunction, occurring either primary or secondary to other changes, which can harm autoregulation and increase ONH susceptibility to vascular challenges (22). It should be noted that in particular, the short posterior ciliary arteries supplying the ONH and choroid are more sensitive to OPP alterations and vascular dysregulation than the central retinal artery, possibly indicating ONH as the initial location of damage (82). Although an improper OBF can directly lead to optic nerve atrophy and RGC loss through major sustained hypoxic insults, creating tissue infarction, such events rarely occur in NTG. Therefore, it is a mild, repetitive and reversible hypoxic pattern, namely an unstable oxygen tissue supply, as a result of oxygen saturation fluctuation due to impaired OBF and OSAHS, which contributes to glaucomatous damage. This phenomenon is known as ischemia-reperfusion injury (IRI) (35,36). The main effect of IRI is the induction of chronic oxidative stress, particularly in local mitochondria of RGCs and their axons (36,83).

Oxidative stress is a major factor of NTG-related GON. The reduction in the oxygen concentration impairs electron flow in mitochondrial complexes, which results in the formation of free radicals or reactive oxygen species (ROS), mainly superoxide (O₂⁻), increasing the hydrogen peroxide (H₂O₂) concentration. H₂O₂ further impairs electron flow and increases ROS production, leading to mitochondrial dysfunction. High or sustained ROS levels induce oxidative damage to the mitochondria, as well as to cellular proteins and DNA, causing insults to RGCs and their axons (84,85). The upregulated expression of proteosome 20S α subunit and numerous DNA breaks in circulating lymphocytes in glaucoma cases support the hypothesis of oxidative stress involvement in GON (86). In addition, hypoxia and oxidative stress upregulates hypoxia-inducible factor-1α (HIF-1α) in the optic nerve and retina, which stimulates p53 and caspase, leading to RGC apoptosis (87). RGC axons in ONH, particularly in the prelaminar region, are mostly non-myelinated and consequently present high density of mitochondria due to high energy demands. Thus, ONH is the major site of mitochondrial dysfunction as a result of oxidative stress creating energy deficiency (35). LC cells also demonstrate significant mitochondrial dysfunction and enhanced ROS production with impaired antioxidant capacity in glaucoma (88).

Concurrently, glial cells vigorously respond to microenvironment alterations, leading to gliosis (35). Gliosis is defined as an activation of glial cells presenting hypertrophy and proliferation. Mechanical stress (IOP fluctuations, LC deformation and increased TLPG), through the release of epidermal growth factor receptor (EGFR), elevated ET-1, IRI, ROS and oxidative stress can result in gliosis (35,85). Indeed, stimulated astrocytes and microglia have been observed in glaucoma, promoting demyelination and damage to the axons (89). Apart from ONH, gliosis also occurs in the retina through chronic stimulation of Müller cells, causing the apoptosis of RGC bodies via degenerative and inflammatory processes. Activated glial cells further disrupt the microenvironment in ONH and retina through the release of various factors being involved in neurodegeneration (90). The astrocytic release of ET-1 further impairs OBF, mediates RGC apoptosis and disrupts axonal transport (91). The glial production of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) can induce the apoptosis of RGC and axons through binding to TNF receptor and the activation of nerve factor (NF)-κB, respectively, leading to an enhanced inflammatory response (90).

Moreover, the cytokine-mediated upregulation of NO synthase-2 (NOS-2) by glial cells has been shown to elevate local NO levels (35). NO, although harmless, diffuses into RGC axons in ONH where it reacts with high levels of superoxide, due to intense local mitochondrial dysfunction and oxidative stress, creating peroxynitrite (ONOO⁻). Peroxynitrite, as well as superoxide, are able to diffuse along the RGC axons into both the retina and lateral geniculate nucleus, leading to neuronal apoptosis through oxidative DNA damage (92).

Glutamate seems to play an important role in GON. The extracellular glutamate concentration in retina is maintained below neurotoxic levels by uptake via glutamate/aspartate transporter (GLAST) into Müller glial cells. Oxidative stress could increase extracellular glutamate due to ROS-induced reuptake failure of glutamate, a fact which is evident in NTG animal studies. An impaired glial GLAST function, possibly due to genetic polymorphisms may be responsible for elevated glutamate levels, as reported in transgenic mice, although in vivo evidence in NTG is needed (84,92). Glutamate neurotoxicity is mediated through the over-stimulation of N-methyl-D-asparate (NMDA) membrane receptors by glutamate in RGCs enhancing intracellular Ca²⁺ influx, which activates various apoptotic pathways, damaging the mitochondria, endoplasmic reticulum and DNA (93). Additionally, an NMDA-related activation of NF-κB has been detected in Müller glial cells, leading to TNF-α formation and RGC apoptosis via TNFR signaling and Ca²⁺ influx (94). This glutamate-induced damage is known as ‘excitotoxicity’.

Oxidative stress, IRI and cell damage, upregulate ET-1 release in NTG, as a result of activated astrocytes and endothelial dysfunction (36,91). There are diverse mechanisms of ET-1-related GON in NTG. ET-1 induces chronic ONH ischemia through irregular vasoconstriction and enhances glutamate toxicity in retina through ET_A receptors. In addition, ET-1 promotes astrocyte activation and amplifies neuroinflammation through ET_B receptors (18,44). Combined ET_A and ET_B stimulation by increased ET-1 promotes superoxide synthesis and NOS upregulation (95), disturbs retrograde and anterograde axonal transport in optic nerve, contributes to ECM remodeling in ONH, particularly in LC (70,71), and causes RGC apoptosis (91,93,95).

Moreover, tissue remodeling triggered by activated astrocytes and mechanical stress occurs concurrently to the damage in RGC and axons, leading to the overproduction of metalloproteinases (MMPs), which enzymatically alter ECM morphology and composition (63). Upregulated MMP-2 and MMP-9 levels have been detected both locally in ONH, as well as in circulating lymphocytes in glaucoma (96). Therefore, tissue remodeling contributes to ONH excavation, as well as LC bowing and deformation (27).

BBB damage has been indicated in NTG (97). Capillaries of the retina and ONH present a complete BBB, with endothelial tight-junctions between adjacent endothelial cells. However, capillaries in prelaminar region of ONH have an improper BBB, and choroid vessels are highly fenestrated (98). Although elevated plasma ET-1 levels exert a neutral effect in retinal and ONH vessels when BBB is intact, ET-1 can diffuse from choroid capillaries into the ONH and adjacent retina, resulting in vasoconstriction, impaired ONH blood flow, increased RVP and weakening of endothelial tight-junctions. The hypoxic retina upregulates HIF-1α, stimulating the release of ET-1 in local vessels, which also leads to vasoconstriction and damage to the BBB (97). Simultaneous ET-1 and MMP-9 diffusion from the choroid into the ONH can disrupt endothelial tight-junctions and basal membrane with the subsequent leak of erythrocytes, clinically observed as optic disc hemorrhage in NTG (97,99). BBB damage also includes the extravasation of proteins, tissue deposition of toxins such as Aβ, and the release of plasma ET-1 and MMP-9 promoting BBB damage (96,100).

The aforementioned factors may be involved in RGC loss and in the synthesis of inflammatory antigens or cytokines. Moreover, interplay between oxidative stress and damage, ROS secretion and gliosis can cause an aberrant immune response due to the loss of normal immunosuppression, increased antigenity, and increased antigen presentation or exposure. All of these combined can result in immune dysregulation and possibly trigger autoimmune neurodegenerative processes (87,90). Indeed, the presence of elevated levels of anti-phosphatidylserine and anti-rhodopsin antibodies in the serum of NTG patients has been reported, pointing towards an autoimmune aspect of NTG pathogenesis (27).

Finally, mechanical and oxidative stress, astrocytes and microglia activation, ET-1, lateral geniculate nucleus (LGN) degeneration and axonal damage disrupt the signaling and bioactivity of neuronal growth factors, including brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF) and nerve growth factor (NGF), causing a diminished neurotrophic support negatively impacting axonal myelination in ONH and survival of RGC in the retina (101).

Fig. 1 summarizes the interaction of the aforementioned mechanisms in NTG pathogenesis.

NTG is a heterogeneous disease, involving multiple genes in its pathogenesis. The presence of a family history in NTG cases suggests a possible genetic predisposition to NTG (102).

Variants in genes including WD repeat-containing protein 36 (WDR36), myocilin (MYOC) and optineurin (OPTN), are considered causative for NTG, although further evidence is required (103,104). The association between OPTN gene alterations in NTG cases and families has been reported (105). OPTN plays a neuroprotective, as well as an IOP-controlling role. Studies have also revealed a possible link between OPTN, NTG and Alzheimer's disease (102,106). Mutations in the optic atrophy type 1 (OPA1) gene may be related to hereditary NTG. OPA1 is involved in mitochondrial function, protecting RGC from retinal mechanical stress. OPA1 polymorphisms in NTG have been confirmed, which can induce RGC apoptosis probably via mitochondrial dysfunction (107,108). The duplication of TANK binding kinase 1 (TBK1) gene in glaucoma 1P (GLC1P) locus on 12q14 chromosome has also been identified in familial NTG cases. TBK1 is expressed in RGC and retinal microcirculation, and can thus contribute to apoptosis and vascular impairment in NTG through a dysregulated expression (109). Polymorphisms of the endothelin receptor type A (EDNRA) gene of ET_A receptor, such as C+70G, have been related to more severe VF defects in NTG, also being revealed in a Korean NTG population study (110). Various single nucleotide polymorphisms (SNPs) in the toll-like receptor 4 (TLR4) gene have been indicated in NTG cases in Japanese contrary to Korean populations. Since TLR4 mediates immune responses, such alterations may result in aberrant immunity and autoimmune phenomena in patients with NTG (111). Human leukocyte antigen (HLA) class II variants have also been associated with NTG, contributing to autoimmunity. RAR-related orphan receptor C (RORC) gene upregulation in blood lymphocytes has been detected in patients with NTG, which can promote apoptosis and improper immunity (112). As regards oxidative stress and mitochondrial dysfunction, a variety of mitochondrial irregularities and mitochondrial DNA alterations have been determined in patients with NTG, including a Korean population, pointing towards a genetic profile of this condition (113). Concerning tissue remodeling, the upregulated gene expression of MMP-9 and MMP-14 has been detected in patients with NTG, as well as in circulating lymphocytes (96). Numerous other candidate gene variants have been reported in NTG, such as glaucoma 1B (GLC1B) (114), glaucoma 1F (GLC1F) (115), mitofusin-1 (MFN1) (116), mitofusin-2 (MFN2) (116), S1 RNA-binding domain (SRBD1) (117), presenilin-associated rhomboid-like (PARL) (116) and fatty acid elongase 5 (ELOVL5) (117).

Studies on NTG-related models of transgenic mice have helped to further elucidate NTG pathogenesis. E50K mutant transgenic mice overexpressing OPTN have demonstrated RGC loss, also reflecting the role of oxidative stress in NTG (118). WDR36-mutant mice exhibit axonal growth impairment, resulting in progressive RGC degeneration (119). Mice with the OPA1 variant exhibit RGC death and ONH atrophy (120). The endothelial overexpression of ET-1 in TET-1 mice reveals the degeneration of RGC and their axons, BBB damage and retinal gliosis, implying a vascular-related component of NTG (121). Damage to the RGCs and their axons has been reported in P301S and amyloid precursor protein/presenilin 1 (APP/PS1) mice, indicating an association between NTG and Alzheimer's disease (122,123). GLAST and excitatory carrier-1 (EAAC1) deficient mice present impulsive RGC loss and optic nerve degeneration with normal IOP. Furthermore, mice deficient with apoptosis signal-regulating kinase-1 (Ask-1) are more tolerant to ischemia, exhibit diminished RGC and axonal loss, and mild VF defects, suggesting Ask-1 as a potential target for NTG therapy (124). Table I summarizes the genes reported to be associated with NTG, to the best of the our knowledge.

All things considered, NTG is a multifactorial disease, leading to progressive GON without an elevated IOP. Vascular dysregulation may be the key of vascular pathogenesis resulting in OBF instability in ONH, retina and choroid through an interplay between retrobulbar vasospasm and endothelial dysfunction. Mechanical factors, such as increased sensitivity to IOP fluctuations, LC dysfunction and TLPG also play a significant role. OSAHS and may also be a mixed risk factor for NTG. All these factors, through oxidative stress, gliosis, excitotoxicity, ET-1 upregulation, BBB damage, abnormal immunity and deficient trophic support can promote axonal damage and RGC apoptosis via several extrinsic and intrinsic pathways. In addition, current literature indicates a strong genetic component in NTG, with genes significantly contributing to its pathogenesis. Nevertheless, NTG remains a complex disease. Further studies are warranted to focus on clarifying the mechanisms responsible for NTG-related GON and its genetic basis, aiding to the development of diagnostic and therapeutic strategies.