视网膜色素变性伴发高度近视的临床特征和诊治研究进展

视网膜色素变性（RP）是全球最常见的致盲性眼病之一,它具有高度遗传异质性。患者因感光细胞和色素上皮细胞功能逐渐丧失,表现出夜盲、管状视野,甚至失明。但研究表明,有些RP患者还会伴发其他眼病如白内障、高度近视,其中,RP伴发高度近视因对视力损害严重而不断被关注。笔者回顾了近年来RP伴发高度近视病例的相关报道,通过总结该类患者的临床特征和诊治研究进展,旨在了解该病的基因型-表型关系,为该病的诊断和遗传咨询提供一定的理论依据。     

Estudio de densidad vascular en pacientes con retinitis pigmentosa por medio de angiografía por tomografía de coherencia óptica

AimsTo describe the changes in vessel density (VD) using optical coherence tomography angiography (OCTA) of the different sectors in the macular area between retinitis pigmentosa (RP) patients and controls.MethodsObservational case-control study. We initially included 22 patients with RP and 21 controls. We obtained 6x6 OCTA images of the macular area using Angio-OCT SS-DRI-Triton 1.22 (Topcon, Japan), together with visual acuity, biomicroscopy, visual field and optical coherence tomography examination. We compared the VD values in both groups for both superficial (SVP) and deep vascular plexus (DVP). Correlation between VD and macular thickness was also calculated.ResultsThe mean visual field index (VFI) in the RP group was 26.11% (±17.29). VD was significantly lower in the RP group compared with healthy controls in all sectors of the DVP (Superior 43.48±3.79 vs 48.86±2.62, P<.0001; Nasal 40,52±4.30 vs 46,01±3.23, P=.0002; Inferior 42.76±5.26 vs 50.10±3.36, P<.0001; Temporal 40.42±4.46 vs 46.09±2.91, P=.0001) and in all but nasal sector in the SVP (Superior 39.86±4.46 vs 46.47±2.61, P<.0001; Nasal 40.35±4.56 vs 44.09±2.87, P=.0067; Inferior 40.74±4.61 vs 46.58±3.26, P=.0002; Temporal 39.98±5.07 vs 44.78±3.28, P=.0024). Correlation between VD and macular thickness was positive and significant (RP: r=.59, P=.043; controls r=.51, P=.018).ConclusionsPatients with advanced forms of RP have less vessel density in the macular area than healthy subjects. These differences are present in all four quadrants in the DVP and three in the SVP.     

Decreased sleep quality in patients suffering from retinitis pigmentosa

The purpose of this study was to assess the prevalence of sleep disturbance in subjects diagnosed with retinitis pigmentosa (RP), as well as the influence of age and gender. Sleep quality was assessed, by means of the Pittsburgh Sleep Quality Index (PSQI), in people with RP (n=177) and gender-and age-matched normally sighted individuals (n=491). The population was divided, according to their age, in eight decade groups. People on shift-work, with affective disorders or with visual impairment other than RP, were excluded. The influence of cataracts in sleep quality was also studied in non-RP people (n=57), with cataracts significantly impairing visual acuity. Another group of healthy controls (n=190) was studied in different seasons of the year for a possible seasonality in sleep disturbance. Global sleep quality decreased in an age-dependent manner in RP-patients, especially from the second decade of life. Retinitis pigmentosa-patients showed, in relation to age-matched controls: lower subjective sleep quality and efficiency, longer sleep latency, shorter sleep duration, higher daytime dysfunction and a higher use of sleeping medication. No significant differences in sleep quality were found among RP-patients or controls depending either on their gender or on the presence of cataracts. Normal sighted individuals did not show seasonality in their sleep quality. We conclude that the sleep quality of RP-patients decreases in an age-dependent manner and points to the probably degeneration of photoreceptors mediating the photic input to the suprachiasmatic nuclei of the hypothalamus in this disease.     

Metabolic alterations in the visual pathway of retinitis pigmentosa rats: A longitudinal multimodal magnetic resonance imaging study with histopathological validation

Because retinitis pigmentosa (RP) has been shown to cause degenerative changes in the entire visual pathway, there is an urgent need to perform longitudinal assessments of RP-induced degeneration and identify imaging protocols to detect this degeneration as early as possible. In this study, we assessed a transgenic rat model of RP by using complementary noninvasive magnetic resonance imaging techniques, namely, proton magnetic resonance spectroscopy (¹H-MRS), to investigate the metabolic changes in RP. Our study demonstrated decreased concentrations and ratios to creatine (Cr) of N-acetylaspartate (NAA), glutamate (Glu), γ-aminobutyric acid (GABA), and taurine (Tau), whereas myo-inositol (Ins) and choline (Cho) were increased in the visual cortex of Royal College of Surgeons (RCS) rats compared with control rats (p < 0.05). Furthermore, with the progression of RP, the concentrations of NAA, Glu, GABA, and Tau, and the ratios of GABA/Cr and Tau/Cr significantly decreased over time, whereas the concentrations of Ins and Cho and the ratio of Ins/Cr significantly increased over time (p < 0.05). In addition, in RCS rats, NAA/Cr decreased significantly from 3 to 4 months postnatal (p < 0.001), and Cho/Cr increased significantly from 4 to 5 months postnatal (p = 0.005). Meanwhile, the ¹H-MRS indicators in 5-month postnatal RCS rats could be confirmed by immunohistochemical staining. In conclusion, with the progression of RP, the metabolic alterations in the visual cortex indicated progressive reprogramming with the decrease of neurons and axons, accompanied by the proliferation of gliocytes.     

Luteolin delays photoreceptor degeneration in a mouse model of retinitis pigmentosa

Luteolin is neuroprotective for retinal ganglion cells and retinal pigment epithelial cells after oxidative injury,whereby it can inhibit microglial neurotoxicity.Therefore,luteolin holds the potential to be useful for treatment of retinal diseases.The purpose of this study was to investigate whether luteolin exhibits neuroprotective effects on rod cells in rd10 mice,a slow photoreceptor-degenerative model of retinitis pigmentosa.Luteolin(100 mg/kg)intraperitoneally injected daily from postnatal day 14(P14)to P25 significantly enhanced the visual performance and retinal light responses of rd10 mice at P25.Moreover,it increased the survival of photoreceptors and improved retinal structure.Mechanistically,luteolin treatment attenuated increases in reactive oxygen species,photoreceptor apoptosis,and reactive gliosis;increased mRNA levels of anti-inflammatory cytokines while lowering that of pro-inflammatory and chemoattractant cytokines;and lowered the ratio of phospho-JNK/JNK.Application of the JNK inhibitor SP600125 exerted a similar protective effect to luteolin,suggesting that luteolin delays photoreceptor degeneration and functional deterioration in rd10 mice through regulation of retinal oxidation and inflammation by inhibiting the JNK pathway.Therefore,luteolin may be useful as a supplementary treatment for retinitis pigmentosa.This study was approved by the Qualified Ethics Committee of Jinan University,China(approval No.IACUC-20181217-02)on December 17,2018.     

Deletion of prominin-1 in mice results in disrupted photoreceptor outer segment protein homeostasis

AIM: To illustrate the underlying mechanism how prominin-1 (also known as Prom1) mutation contribute to progressive photoreceptor degeneration.METHODS: A CRISPR-mediated Prom1 knockout (Prom1-KO) mice model in the C57BL/6 was generated and the photoreceptor degeneration phenotypes by means of structural and functional tests were demonstrated. Immunohistochemistry and immunoblot analysis were performed to reveal the localization and quantity of related outer segment (OS) proteins.RESULTS: The Prom1-KO mice developed the photoreceptor degeneration phenotype including the decreased outer nuclear layer (ONL) thickness and compromised electroretinogram amplitude. Immunohistochemistry analysis revealed impaired trafficking of photoreceptor OS proteins. Immunoblot data demonstrated decreased photoreceptor OS proteins.CONCLUSION: Prom1 deprivation causes progressive photoreceptor degeneration. Prom1 is essential for maintaining normal trafficking and normal quantity of photoreceptor OS proteins. The new light is shed on the pathogenic mechanism underlying photoreceptor degeneration caused by Prom1 mutation.     

一个X-连锁隐性遗传视网膜色素变性家系的RPGR基因新突变

目的 研究X-连锁隐性遗传视网膜色素变性(RP)家系RPGR基因突变男性患者和女性携带者的临床表型.方法 家系调查研究.收集RP先证者及其家系资料,完善眼科检查,抽取现存77名家系成员和80名正常对照者外周静脉血,提取DNA,进行聚合酶链反应(PCR),扩增RPGR基因外显子ORF15,扩增产物纯化后直接测序.结果 RP家系中,8例RP患者均为男性,呈隔代传递,不存在男性至男性的传递,患者的母亲及女儿都是致病基因携带者而不发病,符合X-连锁隐性遗传方式.在8例男性RP患者和14例女性致病基因携带者的RPGR基因外显子ORF15+577_578位点发现一个AG缺失突变,引起阅读框架的改变,该基因缺失突变在家系中共分离.AG缺失突变导致男性患者典型的RP改变,但发病时间和进展程度不一.携带有杂合型基因突变的14例女性携带者最具特征性的临床表型是中高度近视眼(-5.00～-22.00 D).结论 该RP家系患者由RPGR 基因外显子ORF15移码突变致g.ORF15+577_578delAG位点缺失.RPGR基因外显子ORF15的新突变可导致男性患者严重的RP表型,但女性致病基因携带者仅表现为中高度近视眼.(中华眼科杂志,2011,47:516-520)

Abstract：

Objective To screen the mutation in the RPGR gene in a large Chinese family with X-linked recessive retinitis pigmentosa (RP) and to describe the phenotype in affected males and female carriers. Methods Ophthalmic examinations were performed in 77 family members of a RP pedigree to identify affected individuals. Polymerase chain reaction (PCR) and direct sequencing were used for screening of mutations in RPGR gene exon ORF15. Results Mutation screening demonstrated a novel mutation, g.ORF15+577_ 578delAG, which caused an open reading frameshift and resulted in premature truncation of the RPGR protein. This mutation was detected in 8 affected male individuals and 14 obligate female carriers in this family and was found to segregate with the phenotype in this family. This mutation led to a severe RP phenotype in male affected individuals with some variability in the age of onset of night blindness and loss of visual acuity, but was recessive in female carriers without a RP phenotype. However the most striking phenotypic feature in female carriers in this pedigree was moderate to high myopia with refractive error ranging from -5.00 D to -22.00 D in 14 female carriers. Conclusions This novel mutation in RPGR ORF15 causes serious RP phenotype in males and no RP phenotype in female carriers. Moderate to high myopia was a particular feature for female carriers in this pedigree. Our finding expands the spectrum of RPGR mutations causing RP and phenotypic spectrum of the disease in Chinese family, which is useful for further genetic consultation and genetic diagnosis.     

中医药治疗原发性视网膜色素变性的临床观察

目的观察中医药治疗原发性视网膜色素变性的临床疗效。方法采用补肾养血明目汤加减,静脉滴注舒血宁和生脉注射液,口服银杏叶片、生脉颗粒及针灸等综合治疗视网膜色素变性64例（128只眼）。结果好转63只眼,无效65只眼,有效率为49%。结论中医药治疗原发性视网膜色素变性是有效的方法。