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INTRODUCTION

Retinitis pigmentosa (RP) is a group of rare, genetically heterogeneous and clinically generalized inherited retinal dystrophies (IRDs), characterized by progressive loss of vision. At the same time, RP is the most frequently diagnosed fundus dystrophy, with a statistical incidence rate of 1 : 2,500 to 1 : 7,000 [1], which translates into approximately 1.5 million patients worldwide. The carrier rate in the general population is about 1 in 1,000 [2, 3]. Retinitis pigmentosa is one of the leading causes of visual acuity deterioration and vision loss in patients under the age of 60 [4], carrying significant health, social, and economic consequences5. While multiple clinical studies suggest that nutritional management, including high doses of vitamin A [6, 7] or omega-3 fatty acids, may help slow down the progression of RP, the impact of these interventions appears to be rather marginal [8]. Causal treatments for RP are currently unknown and highly anticipated [9, 10], particularly for patient groups with a defined genetic background. This is attributed to the expanding understanding of metabolic pathways, the growing number of genes identified as contributors to the development of the condition, and the possibilities of gene therapy [11].

NATURAL COURSE AND INHERITANCE PATTERNS

Symptoms reported by patients include difficulty adapting to darkness, decline of vision in low-light conditions (nyctalopia – night blindness) and disturbances in peripheral vision [12], all typically occurring before deterioration in central vision. Additionally, ring-shape scotoma, photophobia and, in the late stages of the disease, tunnel vision are frequently reported. Classically, a decline in contrast sensitivity occurs before a decline in visual acuity. The triad of clinical symptoms characteristic of RP, observable on physical examination, includes narrowed retinal arteries, waxy optic nerve pallor, and bone-spicule pigmentation [13].

The inheritance pattern determines the natural course and clinical presentation of the disease, affecting in particular the rate of progression and decline in visual acuity, along with eventual total loss of vision in severe disease forms. The pattern of inheritance also influences the age at which symptoms first appear, the presence of extra-ophthalmic manifestations, and the type of visual disturbances that accompany reduced visual acuity.

To date, over 70 genes have been identified as causing various forms of RP [14]. However, when including genes linked to the development of various syndromic forms of RP, this number exceeds 100 [15]. Retinitis pigmentosa can be inherited in an autosomal dominant, autosomal recessive [16], or X-linked manner [17]. The latter is typically associated with the most severe progression and can result in complete vision loss before the age of 40 [18]. Severe disease course may also occur in types with autosomal recessive inheritance, and in both these cases the observed rapid decline in visual acuity is typically linked to the loss of function in a specific metabolic pathway. In many types of the disease, mutations in the rhodopsin gene play a key role.

Autosomal recessive forms of retinitis pigmentosa can manifest with systemic symptoms. These presentations, referred to as atypical syndromic retinitis pigmentosa, include Usher syndrome [19], Kearns-Sayre syndrome, Bassen-Korn- zweig syndrome, Bardet-Biedl syndrome, and Refsum disease [20].

Atypical forms of RP also include non-pigmented retinitis pigmentosa, where bone-spicule deposits are either completely absent or present in very small quantities [21]; retinitis punctata albescens, presenting with lesions resembling white-spotted fundus, but with a different arrangement, concentrated primarily around the equator, and co-occurrence of other RP features, or sectoral retinitis pigmentosa, characterized by the sole involvement of the inferior quadrants and slow progression [22]. Although rare, there have been reports of unilateral RP [23].

BIOCHEMISTRY OF VISION – THE VISUAL CYCLE

In vertebrates, the process of vision starts with the absorption of light by the protein rhodopsin, which is found in the outer segments of rod cells [24]. It is important to highlight that rhodopsin comprises more than 90% of the total protein content within the outer segment. It is composed of an apoprotein, opsin, and a chromophore part, 11-cis retinaldehyde, which is a derivative of vitamin A [7]. Light absorption by rhodopsin triggers the isomerization of 11-cis retinal to all-trans retinal [25], which in turn alters the configuration of opsin, thereby initiating the biochemical process of vision [26]. All-trans retinal is released from opsin and subsequently reduced to all-trans retinol which then moves to the layer of retinal pigment epithelium (RPE). Under normal circumstances, 11-cis retinal is further generated from all-trans retinol within the RPE [27, 28]. This multi-step reaction is catalyzed, among others, by 65 kDa isomerohydrolase encoded by the RPE 65 gene [29], a mutation of which is one of the leading causes of RP [30, 31]. Activated by light, rhodopsin further reacts with transducin, binding GTP, which triggers a further signaling pathway mediated, in part, by the phosphodiesterase 6 complex [32]. Disruptions at various stages of this process can lead to the development of retinitis pigmentosa manifesting as bone-spicule pigment deposits.

GENETIC BASIS OF THE BONE-SPICULE PATTERN IN RP

As outlined above, RP can present in various forms and with different clinical symptoms. Table I lists the subtypes of retinitis pigmentosa, characterized by bone-spicule pigment deposits, along with key clinical features and the degree of visual acuity deterioration.

Specifically, based on the extent and nature of pigment cell migration, RP can be categorized into three groups: RP with intense pigmentation, RP types exhibiting minimal or no pigment saturation, and pericentric pigmentary retinopathy. The distinction is illustrated in Table II.

From the data listed in Table I, it is evident that there is no correlation between the presence or distribution pattern of bone-spicule hyperpigmentation and the onset of symptoms, decline in visual acuity, narrowing of the visual field [33], or the occurrence of photopsia. Unlike the hyperpigmentation type mentioned above, a relationship between the clinical manifestation and the deterioration of visual acuity was demonstrated by Nakagawa et al. for another classic symptom of RP – the narrowing of retinal vessels [34]. This indicates that the presence of bone spicules in most types of RP is merely an additional clinical feature of the disease and does not represent the core pathophysiological process responsible for vision deterioration and loss. Furthermore, the presence of this type of pigmentation may be linked to damage in multiple cytophysiological mechanisms across different genetic types of the disease, such as impaired regulation of phagocytosis or the loss of adhesion protein function, which facilitates RPE migration. Interestingly, among the various inheritance patterns of the genes responsible for RP, this type of pigmentation is primarily associated with forms that have autosomal recessive inheritance.

CYTOPHYSIOLOGY AND HISTOPATHOLOGY OF BONE SPICULES

As shown by Li et al. [35], the formation of bone-spicule pigmentation is initiated by the death of photoreceptor cells, which are then able to detach from Bruch’s membrane and migrate into the inner layers of the retina. In these layers, they adhere to the basal laminae of epithelial cells around the blood vessels and the internal limiting lamina. As previously shown by Kolb et al. [36] and Rodrigues et al. [37], within this lamina they create structures that are cytophysiologically similar to the structure of the RPE, for example by forming analogous intercellular junctions or prompting Müller cells to generate microvilli and adherent junctions (zonulae adherentes). In the next stage, the vascular structure undergoes thinning and fenestration, allowing migrated photoreceptor cells to adhere and leading to the formation of a structure that histologically resembles normal retinal choriocapillaris [38, 39]. The specific taxic factors responsible for the aforementioned migration have not been identified. However, there is evidence suggesting the presence of markers of chronic inflammation in RP [40, 41]. These inflammatory mediators may contribute to both the migration of cells and the development of the macroscopically identifiable bone-spicule deposits characteristic of the condition [42]. The involvement of cytokine-like substances produced locally to the extracellular matrix or intravascularly is also possible [43]. Interestingly, cases of RP with bone-spicule pigmentation have been reported where defects in the immune response were identified, specifically involving impaired secretion of lymphokines and interferon-γ by lymphocytes [44]. The fenestrations mentioned above have been observed in various retinal dystrophies in rat studies, suggesting that these factors might not be unique to RP [45, 46]. Increased vascular bed permeability contributes to a higher concentration of plasma albumin in the extracellular matrix. The accumulation of albumin can then potentially constrict the blood vessel’s lumen. Additionally, significant intravitreal fluorescein leakage was observed on angiography [47]. The extracellular matrix created by migrated cells strongly resembles Bruch’s membrane at the histological level [35]. Specifically, the extracellular matrix being formed is characterized by a high content of elastin fibers, lipid deposits, and calcium. Features of neovascularization in RP [48] were identified a long time ago, however it has been hypothesized that the newly formed vessels do not produce adequate amounts of taxic factors capable of preventing the migration of pigment cells from the original site of detachment [49], while the process has only a pathological dimension, which is why anti-VEGF treatments are commonly employed in its management [50]. At the cytological level, migrated cells involved in bone-spicule pigmentation show a loss of lipofuscin and retinaldehyde-binding protein, which suggests a disruption in the phagocytosis processes in the outer segments and the biochemical cycle of vision [51, 52]. Also, disruptions in fundamental cytophysiological mechanisms, such as splicing, may contribute to the development of the condition [53]. In addition, RPE cell proliferation was commonly observed in RP-affected retinas, leading to a decrease in the unit content of melanin in the cell body. Nevertheless, due to the aforementioned cell migration, these retinas exhibit significantly higher local concentrations of pigment, especially in their perivascular regions [54]. Interestingly, melanin in bone spicules shows unusual behavior in multimodal imaging studies, notably failing to generate a signal in NIR-AF images [55]. The cause of this phenomenon remains unclear, but it has been suggested that the regrouped bone spicules may have a different pigment structure.

CONCLUSIONS

Bone-spicule hyperpigmentation is one of the triad of symptoms associated with retinitis pigmentosa. The presence and extent of the bone-spicule pattern in RP vary depending on the specific RP subtype: some exhibit a pronounced pattern, others show it minimally or only in certain sectors, and some subtypes lack it entirely. Bone-spicule pigmentation is especially characteristic of autosomal recessively inherited types of RP. Numerous genes are associated with the development of pigmentation, encoding structural proteins involved in the biochemical process of vision and phagocytosis. This implies that disruptions in various metabolic pathways could contribute to the development of the condition. At the histological level, the bone-spicule pattern is formed by the migration of numerous damaged RPE cells towards the adjacent perivascular areas, where they create structures resembling normal choriocapillaries. The presence of melanin in these cells contributes to the characteristic macroscopic appearance of the fundus. The taxic factors stimulating the migration and deposition of damaged RPE cells within the basal laminae of the vascular epithelium are not known. It is hypothesized that mediators of chronic inflammation play a role in cell migration. Neovascularization is a major problem that can complicate the natural progression of RP; it may be biochemically linked to the migration of damaged RPE cells. There is no tangible correlation between the occurrence of bone-spicule pigmentation and the deterioration of visual acuity due to RP.