11-cis-retinal and Syndrome

Retinitis pigmentosa (RP) is an inherited retinal dystrophy caused by the loss of photoreceptors and characterized by retinal pigment deposits visible on fundus examination. Prevalence of non syndromic RP is approximately 1/4,000. The most common form of RP is a rod-cone dystrophy, in which the first symptom is night blindness, followed by the progressive loss in the peripheral visual field in daylight, and eventually leading to blindness after several decades. Some extreme cases may have a rapid evolution over two decades or a slow progression that never leads to blindness. In some cases, the clinical presentation is a cone-rod dystrophy, in which the decrease in visual acuity predominates over the visual field loss. RP is usually non syndromic but there are also many syndromic forms, the most frequent being Usher syndrome. To date, 45 causative genes/loci have been identified in non syndromic RP (for the autosomal dominant, autosomal recessive, X-linked, and digenic forms). Clinical diagnosis is based on the presence of night blindness and peripheral visual field defects, lesions in the fundus, hypovolted electroretinogram traces, and progressive worsening of these signs. Molecular diagnosis can be made for some genes, but is not usually performed due to the tremendous genetic heterogeneity of the disease. Genetic counseling is always advised. Currently, there is no therapy that stops the evolution of the disease or restores the vision, so the visual prognosis is poor. The therapeutic approach is restricted to slowing down the degenerative process by sunlight protection and vitaminotherapy, treating the complications (cataract and macular edema), and helping patients to cope with the social and psychological impact of blindness. However, new therapeutic strategies are emerging from intensive research (gene therapy, neuroprotection, retinal prosthesis).

Topics: Adolescent; Child; Child, Preschool; Diagnosis, Differential; Female; Humans; Infant; Metabolic Diseases; Nervous System Diseases; Night Blindness; Pregnancy; Prenatal Diagnosis; Prognosis; Retinal Rod Photoreceptor Cells; Retinitis Pigmentosa; Rhodopsin; Sensation Disorders; Syndrome

Retinitis pigmentosa (RP), the group of hereditary conditions involving death of retinal photoreceptors, represents the most prevalent cause of visual handicap among working populations in developed countries. Here we provide an overview of the molecular pathologies associated with such disorders, from which it becomes clearly apparent that RP is one of the most genetically heterogeneous of hereditary conditions for which molecular pathologies have so far been elucidated. While heterogeneity of such magnitude would appear to represent a major impediment to the development of therapeutics, mutation-independent approaches to therapy are being developed to effectively by-pass such diversity in genetic aetiology. The implications of such technologies in terms of therapeutic intervention in RP, and indeed other genetically heterogeneous conditions, will be addressed.

Topics: 3' Untranslated Regions; 5' Untranslated Regions; Animals; Apoptosis; Disease Progression; Eye Proteins; Genes, Dominant; Genes, Recessive; Genetic Heterogeneity; Genetic Linkage; Genetic Therapy; Humans; Mammals; Mice; Mice, Knockout; Models, Animal; Nerve Growth Factors; Optic Atrophy, Hereditary, Leber; Retina; Retinal Rod Photoreceptor Cells; Retinitis Pigmentosa; Rhodopsin; RNA, Catalytic; RNA, Messenger; Syndrome; Transcription Factors; X Chromosome

Mutations in more than 60 different genes have been associated with non-syndromic and syndromic retinitis pigmentosa (RP), a heterogeneous group of inherited retinal dystrophies. To increase the understanding of the molecular epidemiology of the disease in Italy, we analyzed 56 patients with syndromic and non-syndromic forms of RP attending the Retinitis Pigmentosa Center of San Paolo Hospital (Milan, Italy). Patients underwent detailed clinical examination. Genomic DNA isolated from peripheral blood samples was screened for mutations in different genes according to RP form by direct sequencing analysis. The impact of novel missense mutations on protein functions was predicted by in silico analysis and protein sequence alignment. Cosegregation analysis was performed between available family members. Forty-one of the 56 probands analyzed had non-syndromic and 15 had syndromic RP forms. Putative disease-causing mutations were identified in 19 of 56 unrelated RP probands. Mutation screening identified a total of 22 different heterozygous variants. Notably, 12 of these putative pathogenic mutations have not been previously reported. New variants were found to be located on the USH2A, RPGR, EYS, and RHO genes. All 3 new variants detected in X-linked RP probands were confirmed in other affected family members. We found a positivity rate of 24.4% and 60% for probands with non-syndromic and syndromic RP, respectively. This is the first report of RPGR X-linked RP proband-ORF15 mutations in Italian patients with X-linked (XL)-RP. In addition, this is the first report of data regarding the association between EYS mutations and non-syndromic RP forms in the Italian population.

Topics: Adult; Aged; Amino Acid Sequence; Base Sequence; DNA Mutational Analysis; Extracellular Matrix Proteins; Eye Proteins; Family Health; Female; Genetic Predisposition to Disease; Humans; Italy; Male; Middle Aged; Molecular Sequence Data; Mutation; Pedigree; Retinitis Pigmentosa; Rhodopsin; Sequence Homology, Amino Acid; Syndrome; Young Adult

To define the retinal pathology in an 88-year-old male affected with Goldmann-Favre syndrome with a 2 bp 5' A>C splice site mutation in the NR2E3 gene.. Retinal tissue from the macula and periphery was processed for immunohistochemistry. Perimacular retina was processed for transmission electron microscopy. Cryosections were studied by indirect immunofluorescence, using well-characterized antibodies to rhodopsin, cone cytoplasm, and cone opsins. The affected donor eye was compared to a postmortem matched normal eye.. The retina was highly disorganized without laminar organization. The RPE was discontinuous in some perimacular regions. Large (>1 mm) spherical electrondense melanosomes were observed in the RPE and choroid by TEM. Rods were virtually absent in the affected retina. Cones were present in the macula, but were mostly absent from the retinal periphery. In addition, cone rosettes were observed in the perimacular area. Both red/green and blue cone opsins were distributed along the entire cellular expanse of the cone photoreceptors in the affected eye, but were restricted to the cone outer segments in the control retina.. The histological data obtained from the retina of an elderly male patient with Goldmann-Favre syndrome showed an absence of rods and abnormal distribution of red/green and blue cone opsins.

Topics: Aged; Aged, 80 and over; Arrestin; Fluorescent Antibody Technique, Indirect; Humans; Male; Night Blindness; Opsins; Orphan Nuclear Receptors; Retina; Retinal Degeneration; Retinal Pigment Epithelium; Rhodopsin; Syndrome

Several ophthalmic conditions manifest a flecked retina. Developing an understanding of their clinical presentations will enable the practitioner to most appropriately manage these conditions.. A 27-year-old Middle Eastern woman manifested flecked retinas and nyctalopia. She had been given a diagnosis of retinitis punctata albescens, an inherited, progressive, night blindness; however, the medical history and clinical findings were not consistent with this disorder. Rather, they were consistent with fundus albipunctatus, an autosomal recessive, stationary, night blindness. The clinical presentation of fundus albipunctatus is characterized by discrete, white dots at the level of the retinal pigment epithelium and stable night blindness. A prolonged time for dark adaptation is required to produce normal amplitude electroretinograms in fundus albipunctatus as the result of a delay in the regeneration of rhodopsin. An electroretinogram administered after a prolonged dark adaptation time confirmed the diagnosis of stationary night blindness.. In order to ensure an accurate diagnosis for fundus albipunctatus, it is important to be aware of the clinical characteristics and appropriate electroretinogram protocol for this disorder.

Topics: Adult; Dark Adaptation; Diagnosis, Differential; Electroretinography; Eye Diseases, Hereditary; Female; Fundus Oculi; Humans; Night Blindness; Retinal Diseases; Retinal Rod Photoreceptor Cells; Rhodopsin; Syndrome