Current Genomics - Volume 12, Issue 4, 2011

Inherited retinal dystrophies represent the most frequent hereditary disorders of the ocular posterior segment. The chronic eye diseases included in this heterogeneous group of genetic degenerative disorders of the retina are also habitually named retinitis pigmentosa, a term coined by Donders more than 150 years ago. Taking into account all the different forms of retinitis pigmentosa (RP), among the general population, their total prevalence is variably reported in one case for each 2500-7000 persons. In view of that, RP should be labeled as rare or orphan disease even if, for several reasons, it could be considered very atypical within this category of pathologies; firstly given that a worldwide shared consensus on the definition of rare disease does not exist, but also because RP represents one of the most common causes of blindness or severe low-vision in people from 20 to 60 years old. In addition, it is not true that RP is less known or studied than other more frequent eye disorders, and the nearly 7000 references, which appear using “retinitis pigmentosa” in a PubMed search, demonstrate that RP is characterized by a high “desirability” for clinical and experimental researches. On the other hand, it is true that many clinical and welfare problems are common to all RP forms and, above all, that RP requires specific and continuative cares, the fulfillment of which is impossible without a considerable public support participation. Moreover, despite the outstanding scientific advances achieved in the knowledge of RP during the last three decades, evidencebased therapies do not exist for this terrible retinal neuro-degeneration. In other words, RPs are not sufficiently rare as to result in a low research interest, but they are so genotypically intricate and/or phenotypically severe that become very hard to face. At present, the numerous forms of RP are considered the most complex category of retinal diseases. They can be transmitted by all types of monogenic inheritance (autosomal dominant, autosomal recessive, X-linked), even if many cases are diagnosed in patients with no report of affected relatives. These genetic degenerations of the retina are sometimes associated with various non-ocular disorders (syndromic RP), and are characterized by: i) remarkable taxonomic heterogeneity; ii) frequent phenotypic inter- or intra-familial variability; iii) large genotypic multiplicity which becomes more evident examining different ethnic clusters. In fact, although more than 200 causative mutations of RP have been hitherto discovered in more than 100 different genes, the molecular defect is identifiable in just about the 50% of the affected patients. The comprehensive appraisal of these latter issues leads to a high difficulty in planning adequate clinical researches and, unfortunately, to the development of an indecorous market of vain therapeutic attempts instigating false expectations in many RP patients. An attenuation of the aforementioned trouble could rise from two main ways of acting: i) when a factual therapeutic advancement is established in animal models of RP, immediate consideration should be also given to possibly realize, within a reasonable timeline, a clinical trial based on that experimental evidence; ii) the prescriptive attitude toward this rare disease should be comprehensively based on scientific, deontological, rehabilitative and psychological aspects, also because the application of either evidence-based medicine or complementary and alternative medicine criteria may be not appropriate in the context of RP decision-making. In this manner also, even if just partly, avoid that the patient with RP must be suffering a double injury: being affected by a severe disease transmissible to own children, and being inadequately managed from a clinical point of view. Despite the good purposes to allocate considerable resources for both research and welfare of rare diseases, in several developed countries, as well as in the majority of developing countries, the denomination of RP with the adjective “rare” should be replaced by the adjective “orphan”, which deplorably means that it is still absent a broad diffuse socio-sanitary network dedicated to patients with RP and their families. The concrete carrying out of the aforementioned purposes will be not practicable without a coordinated collaboration between specialized ophthalmologists, geneticists and epidemiologists, necessary to exactly evaluate the burden of RP on both general population and Health System, and to finally facilitate the whole management of this vision-threatening disease....

Retinitis pigmentosa (RP) is a group of inherited disorders affecting 1 in 3000-7000 people and characterized by abnormalities of the photoreceptors (rods and cones) or the retinal pigment epithelium of the retina which lead to progressive visual loss. RP can be inherited in an autosomal dominant, autosomal recessive or X-linked manner. While usually limited to the eye, RP may also occur as part of a syndrome as in the Usher syndrome and Bardet-Biedl syndrome. Over 40 genes have been associated with RP so far, with the majority of them expressed in either the photoreceptors or the retinal pigment epithelium. The tremendous heterogeneity of the disease makes the genetics of RP complicated, thus rendering genotype-phenotype correlations not fully applicable yet. In addition to the multiplicity of mutations, in fact, different mutations in the same gene may cause different diseases. We will here review which genes are involved in the genesis of RP and how mutations can lead to retinal degeneration. In the future, a more thorough analysis of genetic and clinical data together with a better understanding of the genotype-phenotype correlation might allow to reveal important information with respect to the likelihood of disease development and choices of therapy.

The term retinitis pigmentosa (RP) indicates a heterogeneous group of genetic rare ocular diseases in which either rods or cones are prevalently damaged. RP represents the most common hereditary cause of blindness in people from 20 to 60 years old. In general, the different RP forms consist of progressive photo-receptorial neuro-degenerations, which are characterized by variable visual disabilities and considerable socio-sanitary burden. Sometimes, RP patients do not become visually impaired or legally blind until their 40-50 years of age and/or maintain a quite acceptable sight for all their life. Other individuals with RP become completely blind very early or in middle childhood. Although there is no treatment that can effectively cure RP, in some case-series the disease's progression seems to be reducible by specific preventive approaches. In the most part of RP patients, the quality of vision can be considerably increased by means of nanometer-controlled filters. In the present review, the main aspects of the routine clinical and rehabilitative managements for RP patients are described, particularly focusing on the importance of specific referral Centers to practice a real multidisciplinary governance of these dramatic diseases.

Inherited retinal dystrophies, such as retinitis pigmentosa (RP), include a group of relatively rare hereditary diseases caused by mutations in genes that code for proteins involved in the maintenance and function of the photoreceptor cells (cones and rods). The different forms of RP consist of progressive neurodegenerative disorders which are generally related to various and severe limitations of visual performances. In the course of typical RP (rod-cone dystrophy), the affected individuals first experience night-blindness and/or visual field constriction (secondary to rod dysfunctions), followed by variable alterations of the central vision (due to cone damages). On the other hand, during the atypical form of RP (cone-rod dystrophy), the cone's functionalities are prevalently disrupted in comparison with the rod&aposs ones. The basic diagnosis of RP relies upon the documentation of unremitting loss in photoreceptor activity by electroretinogram and/or visual field testing. The prevalence of all RP typologies is variably reported in about one case for each 3000-5000 individuals, with a total of about two millions of affected persons worldwide. The inherited retinal dystrophies are sometimes the epiphenomenon of a complex framework (syndromic RP), but more often they represent an isolated disorder (about 85-90 % of cases). Although 200 causative RP mutations have been hitherto detected in more than 100 different genes, the molecular defect is identifiable in just about the 50% of the analyzed patients with RP. Not only the RP genotypes are very heterogeneous, but also the patients with the same mutation can be affected by different phenotypic manifestations. RP can be inherited as autosomal dominant, autosomal recessive or X-linked trait, and many sporadic forms are diagnosed in patients with no affected relatives. Dissecting the clinico-genetic complexity of RP has become an attainable objective by means of large-scale research projects, in which the collaboration between ophthalmologists, geneticists, and epidemiologists becomes a crucial aspect. In the present review, the main issues regarding clinical phenotyping and epidemiologic criticisms of RP are focused, especially highlighting the importance of both standardization of the diagnostic protocols and appropriateness of the disease's registration systems.

Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal disorders. Diagnosis can be challenging as more than 40 genes are known to cause non-syndromic RP and phenotypic expression can differ significantly resulting in variations in disease severity, age of onset, rate of progression, and clinical findings. We describe the clinical manifestations of RP, the more commonly known causative gene mutations, and the genotypic-phenotypic correlation of RP.

Syndromic retinitis pigmentosa (RP) is the result of several mutations expressed in rod photoreceptors, over 40 of which have so far been identified. Enormous efforts are being made to relate the advances in unraveling the pathophysiological mechanisms to therapeutic approaches in animal models, and eventually in clinical trials on humans. This review summarizes briefly the current clinical management of RP and focuses on the new exciting treatment possibilities. To date, there is no approved therapy able to stop the evolution of RP or restore vision. The current management includes an attempt at slowing down the degenerative process by vitamin supplementation, trying to treat ocular complications and to provide psychological support to blind patients. Novel therapeutic may be tailored dependant on the stage of the disease and can be divided in three groups. In the early stages, when there are surviving photoreceptors, the first approach would be to try to halt the degeneration by correction of the underlying biochemical abnormality in the visual cycle using gene therapy or pharmacological treatment. A second approach aims to cope with photoreceptor cell death using neurotrophic growth factors or anti-apoptotic factors, reducing the production of retino-toxic molecules, and limiting oxidative damage. In advanced stages, when there are few or no functional photoreceptors, strategies that may benefit include retinal transplantation, electronic retinal implants or a newly described optogenetic technique using a light-activated channel to genetically resensitize remnant cone-photoreceptor cells.

Primary cilia are post-mitotic cellular organelles that are present in the vast majority of cell types in the human body. An extensive body of data gathered in recent years is demonstrating a crucial role for this organelle in a number of cellular processes that include mechano and chemo-sensation as well as the transduction of signaling cascades critical for the development and maintenance of different tissues and organs. Consequently, cilia are currently viewed as cellular antennae playing a critical role at the interphase between cells and their environment, integrating a range of stimuli to modulate cell fate decisions including cell proliferation, migration and differentiation. Importantly, this regulatory role is not just a consequence of their participation in signal transduction but is also the outcome of both the tight synchronization/regulation of ciliogenesis with the cell cycle and the role of individual ciliary proteins in cilia-dependent and independent processes. Here we review the role of primary cilia in the regulation of cell proliferation and differentiation and illustrate how this knowledge has provided insight to understand the phenotypic consequences of ciliary dysfunction.

Gene silencing is associated with heritable changes in gene expression which occur without changes in DNA sequence. In eukaryotes these phenomena are common and control important processes, such as development, imprinting, viral and transposon sequence silencing, as well as transgene silencing. Among the epigenetic events, paramutation occurs when a silenced allele (named paramutagenic) is able to silence another allele (paramutable) in trans and this change is heritable. The silenced paramutable allele acquires paramutagenic capacity in the next generations. In the 1950s, Alexander Brink described for the first time the phenomenon of paramutation, occurring in maize at the colored1 (r1) gene, a complex locus (encoding myc-homologous transcription factors) that regulates the anthocyanin biosynthetic pathway. Since then, paramutation and paramutation-like interactions have been discovered in other plants and animals, suggesting that they may underlie important mechanisms for gene expression. The molecular bases of these phenomena are unknown. However in some cases, the event of paramutation has been correlated with changes in DNA methylation, chromatin structure and recently several studies suggest that RNA could play a fundamental role. This last consideration is greatly supported by genetic screening for mutants inhibiting paramutation, which allowed the identification of genes involved in RNA-directed transcriptional silencing, although it is possible that proteins are also required for paramutation. The meaning of paramutation in the life cycle and in evolution remains to be determined even though we might conjecture that this phenomenon could be involved in a fast heritability of favourable epigenetic states across generations in a non- Mendelian way.