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PubMed1997

[Increased cataract rate and characteristics of Nd:YAG laser capsulotomy in retinitis pigmentosa].

BACKGROUND: Retinitis pigmentosa (RP) is associated with the development of a posterior subcapsular cataract (PSC). The development of posterior capsule opacification (PCO) after cataract surgery and a decrease of central visual acuity is sometimes misinterpreted by the patients as natural course of RP. Therefore, therapeutic intervention is often delayed. PATIENTS AND METHODS: In a retrospective study (part 1) the incidence of PCO was evaluated in a group of 26 RP patients who underwent cataract surgery and IOL implantation. In a prospective analyse (part 2) PCO was quantified in 13 RP patients using the standardized photographic technique and image analysis system introduced by Tetz et al. Matched pairs were formed with a control group of 13 patients without retinal disease who matched the RP group in terms of age distribution and postoperative follow-up time. In part 3 the parameters of Nd:YAG laser capsulotomy in 12 RP patients and 14 controls were evaluated. RESULTS: Part 1: The cumulative PCO rate in RP at the end of the first postoperative year was 14.6%, 26.8% in the second, 53.7% in the third and 70.7% after the third year. Nd:YAG laser capsulotomy was performed in 70% of eyes (after 18.4 +/- 14.7 months). In eyes with significant PCO development 70% had PSC preoperatively, while in eyes without PCO formation only 41.7% showed PSC. Part 2: The matched pairs analysis showed a significantly higher PCO value for RP patients (2.11 +/- 1.42) than for the control group (0.89 +/- 0.72) (P = 0.038). Part 3: Average Nd:YAG laser energy levels were 12.8 +/- 11.2 MJ (RP) and 7.6 +/- 6.7 MJ (control). Some 25% of RP patients required further laser treatment of regrown secondary cataract. CONCLUSIONS: Patients with RP showed a significantly higher incidence and density of PCO. Whether RP-specific pathomechanisms are responsible for this needs further investigation.

Adult↗
PubMed1999

Mutations in a novel retina-specific gene cause autosomal dominant retinitis pigmentosa.

Inherited retinal diseases are a common cause of visual impairment in children and young adults, often resulting in severe loss of vision in later life. The most frequent form of inherited retinopathy is retinitis pigmentosa (RP), with an approximate incidence of 1 in 3,500 individuals worldwide. RP is characterized by night blindness and progressive degeneration of the midperipheral retina, accompanied by bone spicule-like pigmentary deposits and a reduced or absent electroretinogram (ERG). The disease process culminates in severe reduction of visual fields or blindness. RP is genetically heterogeneous, with autosomal dominant, autosomal recessive and X-linked forms. Here we have identified two mutations in a novel retina-specific gene from chromosome 8q that cause the RP1 form of autosomal dominant RP in three unrelated families. The protein encoded by this gene is 2,156 amino acids and its function is currently unknown, although the amino terminus has similarity to that of the doublecortin protein, whose gene (DCX) has been implicated in lissencephaly in humans. Two families have a nonsense mutation in codon 677 of this gene (Arg677stop), whereas the third family has a nonsense mutation in codon 679 (Gln679stop). In one family, two individuals homozygous for the mutant gene have more severe retinal disease compared with heterozygotes.

Adult↗
PubMed2001

Mutations in the pre-mRNA splicing factor gene PRPC8 in autosomal dominant retinitis pigmentosa (RP13).

Retinitis pigmentosa (RP) is a genetically heterogeneous disorder characterized by progressive degeneration of the peripheral retina leading to night blindness and loss of visual fields. With an incidence of approximately 1 in 4000, RP can be inherited in X-linked, autosomal dominant or autosomal recessive modes. The RP13 locus for autosomal dominant RP (adRP) was placed on chromosome 17p13.3 by linkage mapping in a large South African adRP family. Using a positional cloning and candidate gene strategy, we have identified seven different missense mutations in the splicing factor gene PRPC8 in adRP families. Three of the mutations cosegregate within three RP13 linked families including the original large South African pedigree, and four additional mutations have been identified in other unrelated adRP families. The seven mutations are clustered within a 14 codon stretch within the last exon of this large 7 kb transcript. The altered amino acid residues at the C-terminus exhibit a high degree of conservation across species as diverse as humans, Arabidopsis and trypanosome, suggesting that some functional significance is associated with this part of the protein. These mutations in this ubiquitous and highly conserved splicing factor offer compelling evidence for a novel pathway to retinal degeneration.

Animals↗
PubMed2003

Mutation of CERKL, a novel human ceramide kinase gene, causes autosomal recessive retinitis pigmentosa (RP26).

Retinitis pigmentosa (RP), the main cause of adult blindness, is a genetically heterogeneous disorder characterized by progressive loss of photoreceptors through apoptosis. Up to now, 39 genes and loci have been implicated in nonsyndromic RP, yet the genetic bases of >50% of the cases, particularly of the recessive forms, remain unknown. Previous linkage analysis in a Spanish consanguineous family allowed us to define a novel autosomal recessive RP (arRP) locus, RP26, within an 11-cM interval (17.4 Mb) on 2q31.2-q32.3. In the present study, we further refine the RP26 locus down to 2.5 Mb, by microsatellite and single-nucleotide polymorphism (SNP) homozygosity mapping. After unsuccessful mutational analysis of the nine genes initially reported in this region, a detailed gene search based on expressed-sequence-tag data was undertaken. We finally identified a novel gene encoding a ceramide kinase (CERKL), which encompassed 13 exons. All of the patients from the RP26 family bear a homozygous mutation in exon 5, which generates a premature termination codon. The same mutation was also characterized in another, unrelated, Spanish pedigree with arRP. Human CERKL is expressed in the retina, among other adult and fetal tissues. A more detailed analysis by in situ hybridization on adult murine retina sections shows expression of Cerkl in the ganglion cell layer. Ceramide kinases convert the sphingolipid metabolite ceramide into ceramide-1-phosphate, both key mediators of cellular apoptosis and survival. Ceramide metabolism plays an essential role in the viability of neuronal cells, the membranes of which are particularly rich in sphingolipids. Therefore, CERKL deficiency could shift the relative levels of the signaling sphingolipid metabolites and increase sensitivity of photoreceptor and other retinal cells to apoptotic stimuli. This is the first genetic report suggesting a direct link between retinal neurodegeneration in RP and sphingolipid-mediated apoptosis.

Amino Acid Sequence↗
PubMed2002

[Molecular pathology of retinitis pigmentosa].

BACKGROUND: Retinitis pigmentosa (RP) is primary, chronic, and hereditary chorioretinal degeneration characterized by photopsia, progressive visual loss with ring scotoma, and impairment of dark adaptation. Although modern molecular biology and molecular genetics have identified many causative genes, the molecular pathophysiology of RP is not fully understood, and no effective treatments have been found yet. In recent studies using animal models of RP, new treatments have been devised and their clinical use is being considered. METHOD: In terms of the molecular pathophysiology of RP, we summarized previous studies of genetic impairment of proteins involved in the phototransduction pathway and introduced new possible therapies for RP. RESULTS: We found that most abnormalities of the genes related with the photoxcitation and its inhibition process in the photoreceptor cells caused a variety of clinical manifestations of RP. CONCLUSION: So far, a variety of abnormalities of the genes causing RP have been identified. However, further studies of the relationship between the abnormalities and clinical expression are needed for better understanding of the pathophysiology of RP.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1998

[Identification of 2 allelic mutations of the gene of the phosphodiesterase beta subunit in a Spanish family with recessive autosomic retinitis pigmentosa].

BACKGROUND: Retinitis pigmentosa (RP) is a group of inherited eye disorders that affect photoreceptor and pigment epithelial function. Mutations in different genes involved in the phototransduction process have been described in patients with autosomal recessive RP. PATIENTS AND METHODS: We examined the gene coding the beta subunit of the phosphodiesterase (PDEB) in a ARRP family with two affected sisters. SSCP (single stand conformational polymorphism) analysis of the coding region of the gene showed abnormal bands in two different exons. PCR products showing SSCP aberrant patterns were subsequently sequenced. RESULTS: The two affected sisters had inherited from their father a PDEB gene with a known mutation (Gln298X) and a rare variant and from their mother a PDEB gene with a new mutation: Asp600Asn. CONCLUSIONS: The nature of the mutations in the PDEB gene and their pattern of inheritance indicate that the lack of activity of the phosphodiesterase (PDE), a key enzyme in the visual phototransduction process, account for the RP phenotype in these patients.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2006

A novel locus for X-linked retinitis pigmentosa.

INTRODUCTION: Retinitis pigmentosa (RP) is the most prevalent group of inherited retinopathies and demonstrates considerable clinical and genetic heterogeneity, with wide variations in disease severity, progression, and gene involvement. We studied a large family with RP to determine the pattern of inheritance and to identify the disease-causing gene/locus. MATERIALS AND METHODS: Ophthalmic examination was performed on 35 family members to identify affected individuals and carriers and to characterise the disease phenotype. Genetic linkage analysis was performed using short tandem repeat (STR) polymorphic markers encompassing the known loci for Xlinked RP (xlRP) including RP2, RP3, RP6, RP23, and RP24. Mutation screening was performed by direct sequencing of PCR-amplified genomic DNA of the RP2 and RPGR genes of the affected individuals. RESULTS: A highly penetrant, X-linked form of RP was observed in this family. Age of onset was from 5 to 8 years and visual acuity ranged from 20/25 in children to light perception in older adults. Linkage analysis and direct sequencing showed that no known loci/genes were associated with the phenotype in this kindred. CONCLUSION: A novel disease gene locus/loci is responsible for the xlRP phenotype in this family.

Adolescent↗
PubMed1997

[Development of a standardized evaluation system for cataracta complicata in retinitis pigmentosa].

INTRODUCTION: Retinitis pigmentosa (RP) is associated with the formation of a posterior subcapsular cataract (PSC). As only a small part of the crystalline lens is usually affected, it is sometimes difficult to determine to what extent the visual loss is caused by the PSC alone. PATIENTS AND METHODS: The methodology was developed in analogy to a scoring system for posterior capsule opacification by Tetz et al. Following dilation of the pupil, standardized photographs of the anterior segments were obtained utilizing a Zeiss photoslitlamp model 40 SL/P. The PSC was scored by evaluating retroillumination photographs. The individual PSC index was calculated by multiplying the density of the opacification (graded from 0 to 4) by the area involved in the central 4 mm zone of the pupil (calculated between 0 and 1). For testing the reliability of the evaluation system in part 1 of this study, 11 RP patients with different grades of PSC were examined by three independent observers. In part 2 of this study 37 eyes of 24 RP patients, aged 47.2 +/- 11.8 years, were evaluated and the PSC index was correlated with different parameters (visual acuity, age, visual fields, eletroretinography). RESULTS PART 1: The cataract-density grades were between 1 and 4 in the 11 patients. In relation to the central 4-mm pupillary zone between 13 and 100% of the area were opacified. Cataract indices (density x area) were between 0.13 and 4.0 (Mean values: Examiner 1:1.41 +/- 1.49; Examiner 2:1.28 +/- 1.46; Examiner 3:1.22 +/- 1.44; differences not significant: P = 0.77). PART 2: After an average duration of RP of 23 years, the average cataract index of the 24 patients was 1.72 +/- 1.35. There was no correlation between cataract index and ERG or visual fields (r < 0.2; P > 0.4); however, there was a good correlation to visual acuity (r = -0.72; P = 0.0001). Patients with early onset of RP (before 20th year of life) presented on average with an higher cataract index (2.06 +/- 1.67) compared to patients with late manifestation (0.61 +/- 0.44), but equivalent duration of RP. CONCLUSIONS: The evaluation system offers a reliable and reproducible method for measuring PSC density and extension in RP patients. The method can serve as a useful tool for documenting PSC development and help to define the indications for cataract surgery in RP.

Adult↗
PubMed1994

Autosomal recessive retinitis pigmentosa with preserved para-arteriolar retinal pigment epithelium.

Retinitis pigmentosa with preserved para-arteriolar retinal pigment epithelium is a rare form of retinitis pigmentosa that starts early in life with preservation of retinal pigment epithelium adjacent to and under the retinal arterioles and that has hitherto been described as an isolated form. We examined 22 patients from one large family, together with two isolated patients, and confirmed the presumed autosomal recessive mode of inheritance in this type of retinitis pigmentosa. New findings associated with retinitis pigmentosa with preserved para-arteriolar retinal pigment epithelium were asteroid hyalosis in four (17%) of 24 patients, tortuosity of retinal arterioles in 11 (46%) of 24 patients, peripheral regions of opacified vessels in eight (33%) of 24 patients, and preservation not only of the para-arteriolar pigment epithelium, but also of the peripheral retinal pigment epithelium in 13 (54%) of 24 patients. Previously reported signs present in these patients were nystagmus in six (25%) of 24 patients, hypermetropia in 23 (96%) of 24 patients, optic nerve head drusen in nine (38%) of 24 patients, vascular sheathing in 11 (46%) of 24 patients, maculopathy in all 24 patients (100%), yellow round deposits in the posterior pole in nine (38%) of 24 patients, exudates resembling those in Coats' disease in two (8%) of 24 patients, visual field defects in all 24 patients (100%), and nondeductible electroretinograms in 21 (91%) of 23 patients. Linkage analysis carried out in the large family resulted in the assignment of a gene for retinitis pigmentosa with preserved para-arteriolar retinal pigment epithelium to chromosome 1q31-q32.1.

Adolescent↗
PubMed2003

Activated microglia in human retinitis pigmentosa, late-onset retinal degeneration, and age-related macular degeneration.

Many gaps exist in our knowledge of human retinal microglia in health and disease. We address the hypothesis that primary death of rod photoreceptors leads to activation of resident microglia in human retinas with retinitis pigmentosa (RP), late-onset retinal degeneration (L-ORD), or age-related macular degeneration (AMD). Regions of ongoing photoreceptor cell death were studied by immunocytochemistry with microglia- and other retinal cell-specific markers. In normal human retinas, quiescent microglia were small, stellate cells associated with inner retinal blood vessels. In retinas with RP, L-ORD, or AMD, numerous activated microglia were present in the outer nuclear layer in regions of ongoing rod cell death. These microglia were enlarged, amoeboid cells that contained rhodopsin-positive cytoplasmic inclusions. We conclude that activated microglia migrate to the outer nuclear layer and remove rod cell debris. In other central nervous system diseases such as stroke, activated microglia phagocytose debris from the primary injury and also secrete molecules that kill nearby normal neurons. By analogy with these diseases, we suggest that microglia activated by primary rod cell death may kill adjacent photoreceptors. Activated microglia may be a missing link in understanding why initial rod cell death in the human diseases RP, L-ORD, and AMD leads to death of the cones that are critical for high acuity daytime vision.

Adult↗
PubMed1987

[Peripheral retinal telangiectasis in retinitis pigmentosa].

The association between retinitis pigmentosa and retinal telangiectasis has been rarely reported. The case of a young woman affected with retinitis pigmentosa and telangiectasis involving bilaterally and symmetrically the inferior retinal periphery is described. Moreover, the patient showed a high degree edema of the retina produced by the permeabilization of the retinal capillaries (especially foveal capillaries) and by the passage of fluid from the choroid through the damaged retinal pigment epithelium. The telangiectasis were successfully treated with cryotherapy. The telangiectasis found in patients with retinitis pigmentosa have to be distinguished from other forms of telangiectasis, as those found in young males or those of the temporal retinal periphery of adults, in which respect they have particular characteristics. The cause of the telangiectasis and of the breakdown of the blood-retinal barrier in retinitis pigmentosa is not know. It is probable that they are produced by a toxic or inflammatory action on the vessels mediated by retinal antigens.

Adult↗
PubMed1985

Class II antigen expression and gamma interferon modulation of monocytes and retinal pigment epithelial cells from patients with retinitis pigmentosa.

Monocytes from retinitis pigmentosa patients express diminished amounts of class II (HLA-DR) antigens in comparison to normal individuals, normal siblings of retinitis pigmentosa patients, glaucoma patients, and macular degeneration patients. This observation is correlated with a subnormal production of IFN-gamma, a potent regulator of class II antigen expression. When monocytes from retinitis pigmentosa patients are treated with IFN-gamma, the decreased expression of HLA-DR on the cell surface is restored to levels found on monocytes from normal individuals. HLA-DR antigens were detected on the surfaces of human retinal pigment epithelial cells grown in vitro and the expression of these antigens can be enhanced following IFN-gamma treatment. These data demonstrate an altered expression and regulation of class II, HLA-DR, antigens in a human eye disease. Since class II antigens and IFN-gamma are currently known to be necessary regulating proteins for efficient immune reactivity, these findings may indicate an immune disturbance in retinitis pigmentosa patients. Alternatively, this alteration may have nonimmune implications. For example, these studies may demonstrate an imbalance in systemic regulatory control systems and hence raise the possibility that these or related regulatory proteins and cell surface receptors may be instrumental in maintaining retinal integrity.

Cells, Cultured↗
PubMed1988

EB-virus transformed human lymphocytes from uveitis and retinitis pigmentosa patients secrete antibodies to retinal antigens.

Autoimmunity to retinal antigens has been implicated in the pathogenesis of both endogenous posterior uveitis and retinitis pigmentosa. Recent studies, however, suggest that low levels of antibodies to retinal antigens occur generally in the population. We have attempted to maximize antibody secretion by peripheral blood lymphocytes from patients and normal healthy controls using the polyclonal activator, Epstein-Barr virus, to stimulate lymphocytes in vitro. Whereas cells from controls and uveitis patients showed a level of anti-retinal antibody secretion which corresponded with their serum titres of antibodies, patients with retinitis pigmentosa showed a greater tendency to produce high secretor lymphocytes after EB-virus stimulation despite having low serum titres of antibody. This strategy for studying antibody secretion may be of value in unmasking low levels of autoimmune responsiveness in conditions such as retinitis pigmentosa where low grade tissue damage occurs over many years and antigen release is correspondingly too low to initiate a measurable autoimmune reaction.

Autoantibodies↗
PubMed1991

Mutations in the human retinal degeneration slow gene in autosomal dominant retinitis pigmentosa.

The murine retinal degeneration slow (rds) gene is a semidominant mutation with a phenotype having rod and cone photoreceptors that develop abnormally and then slowly degenerate. The phenotype is a possible model for retinitis pigmentosa, one of the scores of hereditary human retinal degenerations, which is also characterized by photoreceptor degeneration. We report here three mutations of the human homologue of the rds gene (RDS) that cosegregate with autosomal dominant retinitis pigmentosa in separate families. Our results indicate that some cases of autosomal dominant retinitis pigmentosa are due to mutations at the RDS locus.

Adult↗