Genetic, environmental and other risk factors for progression of retinitis pigmentosa

INTRODUCTION

Retinitis pigmentosa (RP) [Online Mendelian Inheritance in Man (OMIM) ID 268000] is a group of inherited retinal degeneration diseases resulting from progressive loss of rod photoreceptor cells, followed by cone photoreceptor cells. Individuals with RP often endure impaired night vision and progressive vision loss. Finally, complete blindness may occur when the visual field defect involves the macular area.The global prevalence of RP is 1/4000. Patients with RP can be divided into autosomal dominant (AD), autosomal recessive(AR) and X-linked inheritance based on their family history,as well as a large majority without family history of disease appear to be isolate cases. In addition, progression of RP can vary among different types. Also, studies have identified several genetic, environmental, phenotypic, demographic,inflammatory and other risk factors for a different RP progression. The potential benefit of discovering these risk factors is the ability to predict disease progression of RP, which can provide new ideas for the efficacy and safety evaluation of new therapies. Nowadays, diagnostic technology is developing rapidly, genetic and molecular diagnostic technologies is advanced. And new risk factors for disease progression are gradually being discovered, but there is still no comprehensive prediction model for progression of RP. Our aim is to summarize the current literature that studies the genetic,environmental, phenotypic, demographic, inflammatory and other risk factors of RP progression in the review. Moreover,we discuss the most reliable risk factors that could provide predictive models.

As RP is a slow, progressive disease, it is hard to make an accurate definition for its progression. In earlier studies, visual acuity,electroretinography (ERG), and the visual field (VF) test have been commonly used to monitor RP progression. However,there are limitation with these examinations as evaluation indicators. For example, many patients with RP still remain quite satisfactory central corrected vision in the late period of the disease. On the contrary, evaluation by ERG generally diminishes years before subjective symptoms begin. And for VF test, considerable fluctuations will have impact on the results due to its subjectivity. Therefore, in recent years, more and more researches focus on objective measurements to evaluate the severity of RP. Spectral-domain optical coherence tomography (OCT) is widely used to detect retinal structure in lots of diseases. Previous OCT studies in RP have showed that the structural changes correlated well with retinal function,measurements of ellipsoid zone (EZ) width and EZ area can serve as metrics of disease severity and progression. Retinal layer thickness measured by OCT has also been reported to coincide with the functional evaluations.

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Structural changes in the choroid will affect the progression of RP. According to the reports,compared to the control group, the choroidal blood flow in RP patients decreased by 26%, as same results as the study of choroidal capillaries density. Preliminary studies in animal models of RP had shown that loss of choroidal capillaries did exist, and decreased blood circulation in the foveal choroid caused death of cone cells. The choroidal changes that occur in RP are confirmed by the above clinical and animal experiments. In addition, the relationship between disease progression and structural changes has also been studied by Egawa. They took the choroidal area under the fovea as the observation target and set an observation range of 1500 μm.Finally, they found that the choroidal structure in RP was significantly related to the BCVA, MD, mean sensitivity(MS), EZ width, and central foveal thickness (CFT). While,another study suggested that the reduction of choroidal blood flow, rather than the change of its structure, is closely related to the structural changes and functional decline of the RP macular region.

Although there are more and more new methods to detect RP progression, the most sensitive method has not been established. A good monitor should have high sensitivity that enables to detect minor change easily and reproducibly.

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Genetic Risk Factors

Whether inheritance patterns have impact on the progression of RP is not determined, however,more and more evidence shows that inheritance pattern is an important risk factor. Patients with RP can be genetically typed by family history into different inheritance patterns, such as AD-RP, AR-RP, and X-chromosome linked forms, as well as a large group of patients appear to be isolate cases. Xusummarized during a follow-up period of up to 29y (average 12y) and found that there was no statistically significant difference in the annual VF loss rate between different genetic patterns. The annual incidence of AR inheritance is estimated to be 10.3%, X-linked inheritance is 7.2%, and AD inheritance is 2.7%. Even so, it can be seen from the results that AR-RP has tendency to lose VF more quickly than the other two genetic subtypes. The previous study by Sandbergalso testifies to this trend. It is estimated that the annual decrease in the rate of AR-RP due to the usherin () gene is 7.0%, X-link RP due to the mutations of the RP GTPase regulator () gene is the 4.7%, and AD-RP with rhodopsin () mutations is 2.6%. However, Sayocannot confirm that different genetic patterns have different rates of progression in RP because of the relatively small sample size, or maybe the shortterm follow-up.

Even if the causative gene is the same, the progression will be different due to different inheritance types. A multi-center cohort studyin Japan reported that the phenotypes of RP1 gene-associated retinal dystrophies varied with different inheritance patterns. RP1 gene has been associated with both AD-RP and AR-RP. The age at onset and clinical course of visual acuity in the two phenotypes were significantly different,the age at onset was earlier in patients with AR-RP, also visual acuity started to worsen around their 20s and reached severe visual dysfunction by their 40s instead of good visual acuity preserved in patients with AD-RP until their 50-60s. The same result applies to VF, multimodal retinal imaging, and ERG findings.

As we all know, smoking as the most common and important environmental factor always affects human health.It is not only a risk factor for many systemic diseases, but also an inducing factor for many eye conditions. Therefore,smoking may also affect the progression of RP. The way to induce those disease may be through exacerbating oxidative stress. Campochiaro and Mirreviewed the mechanism of cone cell death and proved that it was related to oxidative stress. Thus, Oishihypothesized that smoking might also affect the disease progression of RP, especially when it involves the cone-rich macular area. Finally, they discovered that smoking was an independent related factor of poor visual acuity, and might affect the course of RP, causing it to develop more rapidly in a worse direction.

Phototransduction is a biochemical process in photoreceptor neurons that converts absorption of light into electrical activity.It has been found that several gene families participate in the biochemical pathway, such as rhodopsin, transducin, and cyclic nucleotide gated ion channels. Photoreceptor viability is very sensitive to disturbation in phototransduction. Mutations in genes that encode phototransduction proteins can cause photoreceptors to degenerate, affecting the phototransduction cascade, and eventually leading to the progressive death of photoreceptors. Animal experiments verified that the RP phenotype caused by the phosphodiesterase 6B () gene mutation appeared segregated in different sexes. Female mice progressed faster than the male, and pointed out that female is potential risk factor in RP ofgene mutation. This result needs to be confirmed in future clinical studies.mutations account for 30%-40% of AD-RP, affecting the amino acidic sequence of the rod-specific protein rhodopsin. Severity and rate of progression are associated with specificmutations. For example, the argine to lysine change at codon 135 (Arg-135-Lys, or R135L) and the arginine to tryptophan change at codon 135 (Arg-135-Trp, or R135W) mutations(cytoplasmic end of the third rhodopsin transmembrane helix) result in diffuse, severe disease. And, R135W causes more severe and more rapidly progressive RP than R135L.The proline to alanine change at codon 180 (Pro-180-Ala, or P180A) and the glycine to arginine change at codon 188 (Gly-188-Arg, or G188R) mutations present a mild phenotype with regional variability and diffuse disease of moderate severity.Fascin actin-bundling protein 2 () gene encodes the initiation protein for the formation of retinal outer segment.peripherin 2 () and cadherin related family member 1 () work together to play a signal transduction role during the formation of outer segments and stabilize its morphology. There are other genes such as retinal outer segment membrane protein 1 () and prominin 1() that participate in this complex process. Changes in the number and type of mutations of any gene will cause variations in the phenotype of RP and affect its pathological process. Studies have reviewed that the more significant the changes in the protein level encoded by theandgene, the earlier the onset of the disease and the more severe the pathological changes.

Visual cycle is a complex process that requires the participation of proteins encoded by a variety of genes, such as retinoid isomerohydrolase rpe65 (), atp binding cassette subfamily A member 4 (), retinol dehydrogenase 12() and retinol binding protein 3 (). Case reports showed that, the progress of RP mediated bygene mutation was slower within two years compared with other mutation evaluated by FAF and the width of EZ. However,large sample studies need to confirm this trend subsequently.is a common causal gene of RP, coding for the transmembrane protein Usherin which is expressed in the cilia region in the photoreceptor cells.plays important roles in the development and homeostasis of the retina and inner ear. RP patients withgene mutations were divided into two groups: syndromic and non-syndromic. Comparing their average age of onset, it was found that the onset of nonsyndromic type was significantly later, and the difference between the two was close to 10y. Not only that, the rate of vision loss and change of mean defect (MD) value of non-syndromic type were also slower, and the degree of VF damage was relatively low.

Diagnosis of the molecular genetics of RP should be accompanied by analysis of number of variants.There are many genes related to RP, even if the disease-causing genes are the same, the mode of disease progression and rate of deterioration may be different. It is because many genes have different variants, which will lead to different pathogenic phenotypes. For example, Jespersgaardfound that clinical examinations of 56 RP patients caused byprotooncogene, tyrosine kinase () gene mutations showed severe phenotypes, however, the remaining phenotypes were milder, which may be due to the different number of variants in different patients. We can search hundreds of genes related to human RP in the Disgenet database (https://www.disgenet.org/search) alone, which integrates disease-related genes based on literature and multiple databases mining, and each gene has many variants, so there will be more variants affecting RP. We show the top 25 genes according to gene-disease association scores and their single nucleotide polymorphisms (SNPs) in Table 1.

Phenotypic Risk Factors

If the baseline level of the visual field is different, the disease progresses at different speeds.It can be understood that different disease stages will have different disease progression rates. In order to determine whether baseline MD would affect the deterioration rate of macular sensitivity, Sayodivided RP patients into two groups with initial MD ≥-17.9 dB and ＜-17.9 dB for the study,namely the less advanced group and the advanced group. The results showed the former progression (-0.01 dB/y) is much significantly slower than the latter (-0.67 dB/y). Since the central field of vision is still preserved in the late stage, this result is considered reasonable.

由此可見，3VT切面上MRAA-LDA-DAO與右弓優勢型DAA均表現為“/U”形環時，3VT切面上二者難以區別，但升弓部冠切切面上二者具有較明顯差異，故升弓部冠狀切面可用于二者鑒別診斷。

The progression rate of RP is slowing down when the progression of disease involves the fovea. With the advanced development of multimodal imaging, clinicians may have access to following the microstructural changes in RP patients, and the changes can be seen in a shorter time.OCT images in which the width of the ellipsoid zone line can monitor progression over time. Furthermore, the wider the EZ width, the faster the disease progresses. Sujirakulobserved that patients with narrower EZ (＜3000 μm)had a significantly lower average structural progression rate compared to wider EZ (＞3000 μm). Another studyconcluded that the longer the third high-reflectance band in OCT, the better the vision for patients with the same thickness of retina. It is the same band named as the “the second band”SD-OCT determination, which is now termed ellipsoid zone. A systematic review showed that the width of EZ was the most reliable and sensitive biomarker for detecting disease progression with outstanding reproducibility and visual function correlation.

The main pathological feature of RP is changes in photoreceptor and retinal pigment epithelium complex, structural changes will affect the corresponding functions, which refers to the visual function here. Still, the focus of many studies is to clarify the correlation between visual function and structure in RP. Sandbergconcluded that visual acuity of patients with RP who had a thinner central retina (indicating photoreceptor layer) tended to be poorer. Nguyenalso confirmed through long-term follow-up that the thickness of the photoreceptor and retinal pigment epithelial in the macula region was significantly related to best-corrected visual acuity (BCVA), even was a potential effective outcome to replace BCVA in the future.According to the research of Rangaswamy, a simple linear model can reasonably describe the relationship betweenthe product of the thickness of the outer segment (OS) and the outer nuclear layer (ONL) and the thickness of the OS versus the visual field loss. That is to say, the number of photoreceptors decreases as the sensitivity of the local retina decreases, and a linear model can be used to simulate the downward trend.

作為自然科學，高中化學雖然都是知識定