Autosomal dominant retinitis pigmentosa with apparent incomplete penetrance: a clinical, electrophysiological, psychophysical, and molecular genetic study

7 páginas, 7 figuras, 4 tablas.-- Licence Creative Commons, attribution, Non-commercial licence.-- et al.Twenty five symptomatic individuals and six asymptomatic obligate gene carriers from four families with autosomal dominant retinitis pigmentosa (adRP) showing apparent incomplete penetrance have been studied. Symptomatic individuals from three families showed early onset of night blindness, non-recordable rod electroretinograms, and marked elevation of both rod and cone thresholds in all subjects tested. In the fourth family, there was more variation in the age of onset of night blindness and some symptomatic individuals showed well preserved rod and cone function in some retinal areas. All asymptomatic individuals tested had evidence of mild abnormalities of rod and cone function, indicating that these families show marked variation in expressivity rather than true non-penetrance of the adRP gene. No mutations of the rhodopsin or RDS genes were found in these families and the precise genetic mutation(s) remain to be identified.This study was supported by the Medical Research Council (UK), The Weilcome Trust, British Retinitis Pigmentosa Society, and the National Retinitis Pigmentosa Society, Fighting Blindness, USA.Peer reviewe

Combined central serous chorioretinopathy, hypermetropia, short axial length, chorioretinal folds, enlarged/thickened ocular coats, with varying association of scleral changes (CHAFES)

Purpose: To describe a condition with the following features: chronic central serous chorioretinopathy (CCSC), chorioretinal folds, scleral changes (including any of the following flattened or ‘squared off’ posterior pole, ‘T sign’, or thickened ocular coats), accompanied by a short axial length and hypermetropia in a series of 7 patients. Methods: The case notes of 7 patients presenting with a combination of CSC, choroidal folds scleral changes and hypermetropia were reviewed as part of a retrospective case series. Corrected visual acuities, serial refraction, colour imaging, fluorescein and indocyanine green angiography findings, together with B-ultrasound scan features were recorded, with axial length measurements as available ( Results: The study included 14 eyes of 7 subjects (2 females and 5 males) with a primary presentation of central vision disturbance. All patients showed signs of previous or current episodes of the following features in at least one eye: CSC (5/7 bilateral); choroidal folds (6/7 bilateral), thickening of ocular coats in the 5 in whom this was measured, at least one scleral abnormality on ultrasound in at least one eye. A short axial length at final appointment was recorded in 13/14 eyes. Conclusions and relevance: The combination of CCSC with choroidal folds, hypermetropia with apparent shortening of the eyeball associated with one or more scleral abnormalities such as a flattened or ‘squared off ‘appearance of the B ultrasound may be a specific ocular condition. The aetiology of this particular combination of posterior segment manifestations is unknown; the choroid could be the primary focus of disease with secondary involvement of the sclera. Alternatively, the features observed may result from a chronic inflammatory process affecting the sclera with secondary effects on the choroid, retinal pigment epithelium and retina. In our case series, the final vision was not significantly different from vision at presentation

Close genetic linkage between X linked retinitis pigmentosa and a restriction fragment length polymorphism identified by recombinant DNA probe L1.28

Retinitis pigmentosa (RP) is a group of retinal degeneration characterized by progressive visual field loss, night blindness and pigmentary retinopathy. Its prevalence is in the region of 1-2 in 5,000 of the general population, making it one of the commoner causes of blindness in early and middle life. Although 36-48% of RP patients are isolated cases, the remainder show autosomal dominant, autosomal recessive or X-linked modes of inheritance. The X-linked variety ( XLRP ) is found in 14-22% of RP families in the UK. In the present study, X chromosome-specific recombinant DNA probes which can detect restriction fragment length polymorphisms have been used to localize the XLRP gene(s) to a subregion of the X chromosome using linkage analysis. One of the probes, L1.28, has been shown to be closely linked to XLRP in five kindreds, with 95% confidence limits of 0-15 centimorgans (maximum LOD score of 7.89 at a distance of 3 centimorgans). This suggests that the XLRP locus lies on the proximal part of the short arm of the X chromosome. This probe is potentially useful for carrier detection and early diagnosis in about 40% of cases, provided that genetic heterogeneity can be excluded by analysis of further families

Functional characteristics of patients with retinal dystrophy that manifest abnormal parafoveal annuli of high density fundus autofluorescence; a review and update

Purpose To examine the presence and functional significance of annular fundus autofluorescence abnormalities in patients with different retinal dystrophies. Methods Eighty one patients were ascertained who had a parafoveal ring of high density on fundus autofluorescence imaging. Sixty two had had a clinical diagnosis of retinitis pigmentosa (RP) or Usher syndrome with normal visual acuity. Others included a case of Leber congenital amaurosis and genetically confirmed cases of cone or cone-rod dystrophy (GUCA1A, RPGR, RIMS1), “cone dystrophy with supernormal rod ERG” (KCNV2) and X-linked retinoschisis (RS1). International-standard full-field and pattern electroretinography (ERG; PERG) were performed. Some patients with rod-cone or cone-rod dystrophy underwent multifocal ERG (mfERG) testing and photopic and scotopic fine matrix mapping (FMM). Results In patients with RP, the radius of the parafoveal ring of high density correlated with PERG P50 (R = 0.83, P < 0.0005, N = 62) and encircled areas of preserved photopic function. In the other patients, AF rings either resembled those seen in RP or encircled an area of central atrophy. Ring radius was inversely related to the PERG P50 component in 4 of 18 cases with a detectable response. FMM showed that arcs of high density were associated with a gradient of sensitivity change. Conclusions Parafoveal rings of high density autofluorescence are a non-specific manifestation of retinal dysfunction that can occur in different retinal dystrophies. Electrophysiology remains essential for accurate diagnosis. The high correlation of autofluorescence with PERG, mfERG and FMM demonstrates that AF abnormalities have functional significance and may help identify suitable patients and retinal areas amenable to future therapeutic intervention

Peripheral Retinal Imaging Biomarkers for Alzheimer’s Disease: A Pilot Study

Purpose: To examine whether ultra-widefield (UWF) retinal imaging can identify biomarkers for Alzheimer's disease (AD) and its progression. Methods: Images were taken using a UWF scanning laser ophthalmoscope (Optos P200C AF) to determine phenotypic variations in 59 patients with AD and 48 healthy controls at baseline (BL). All living participants were invited for a follow-up (FU) after 2 years and imaged again (if still able to participate). All participants had blood taken for genotyping at BL. Images were graded for the prevalence of age-related macular degeneration-like pathologies and retinal vascular parameters. Comparison between AD patients and controls was made using the Student t test and the χ2 test. Results: Analysis at BL revealed a significantly higher prevalence of a hard drusen phenotype in the periphery of AD patients (14/55; 25.4%) compared to controls (2/48; 4.2%) [χ2 = 9.9, df = 4, p = 0.04]. A markedly increased drusen number was observed at the 2-year FU in patients with AD compared to controls. There was a significant increase in venular width gradient at BL (zone C: 8.425 × 10-3 ± 2.865 × 10-3 vs. 6.375 × 10-3 ± 1.532 × 10-3, p = 0.008; entire image: 8.235 × 10-3 ± 2.839 × 10-3 vs. 6.050 × 10-3 ± 1.414 × 10-3, p = 0.004) and a significant decrease in arterial fractal dimension in AD at BL (entire image: 1.250 ± 0.086 vs. 1.304 ± 0.089, p = 0.049) with a trend for both at FU. Conclusions: UWF retinal imaging revealed a significant association between AD and peripheral hard drusen formation and changes to the vasculature beyond the posterior pole, at BL and after clinical progression over 2 years, suggesting that monitoring pathological changes in the peripheral retina might become a valuable tool in AD monitoring

Genetic disruption of serine biosynthesis is a key driver of macular telangiectasia type 2 aetiology and progression.

BACKGROUND: Macular telangiectasia type 2 (MacTel) is a rare, heritable and largely untreatable retinal disorder, often comorbid with diabetes. Genetic risk loci subtend retinal vascular calibre and glycine/serine/threonine metabolism genes. Serine deficiency may contribute to MacTel via neurotoxic deoxysphingolipid production; however, an independent vascular contribution is also suspected. Here, we use statistical genetics to dissect the causal mechanisms underpinning this complex disease. METHODS: We integrated genetic markers for MacTel, vascular and metabolic traits, and applied Mendelian randomisation and conditional and interaction genome-wide association analyses to discover the causal contributors to both disease and spatial retinal imaging sub-phenotypes. RESULTS: Genetically induced serine deficiency is the primary causal metabolic driver of disease occurrence and progression, with a lesser, but significant, causal contribution of type 2 diabetes genetic risk. Conversely, glycine, threonine and retinal vascular traits are unlikely to be causal for MacTel. Conditional regression analysis identified three novel disease loci independent of endogenous serine biosynthetic capacity. By aggregating spatial retinal phenotypes into endophenotypes, we demonstrate that SNPs constituting independent risk loci act via related endophenotypes. CONCLUSIONS: Follow-up studies after GWAS integrating publicly available data with deep phenotyping are still rare. Here, we describe such analysis, where we integrated retinal imaging data with MacTel and other traits genomics data to identify biochemical mechanisms likely causing this disorder. Our findings will aid in early diagnosis and accurate prognosis of MacTel and improve prospects for effective therapeutic intervention. Our integrative genetics approach also serves as a useful template for post-GWAS analyses in other disorders

The USNO-B Catalog

USNO-B is an all-sky catalog that presents positions, proper motions, magnitudes in various optical passbands, and star/galaxy estimators for 1,042,618,261 objects derived from 3,643,201,733 separate observations. The data were obtained from scans of 7,435 Schmidt plates taken for the various sky surveys during the last 50 years. USNO-B1.0 is believed to provide all-sky coverage, completeness down to V = 21, 0.2 arcsecond astrometric accuracy at J2000, 0.3 magnitude photometric accuracy in up to five colors, and 85% accuracy for distinguishing stars from non-stellar objects. A brief discussion of various issues is given here, but the actual data are available from http://www.nofs.navy.mil and other sites.Comment: Accepted by Astronomical Journa

Analysis of candidate genes for macular telangiectasia type 2

Purpose: To find the gene(s) responsible for macular telangiectasia type 2 (MacTel) by a candidate-gene screening approach.Methods: Candidate genes were selected based on the following criteria: those known to cause or be associated with diseases with phenotypes similar to MacTel, genes with known function in the retinal vasculature or macular pigment transport, genes that emerged from expression microarray data from mouse models designed to mimic MacTel phenotype characteristics, and genes expressed in the retina that are also related to diabetes or hypertension, which have increased prevalence in MacTel patients. Probands from eight families with at least two affected individuals were screened by direct sequencing of 27 candidate genes. Identified nonsynonymous variants were analyzed to determine whether they cosegregate with the disease in families. Allele frequencies were determined by TaqMan analysis of the large MacTel and control cohorts.Results: We identified 23 nonsynonymous variants in 27 candidate genes in at least one proband. Of these, eight were known single nucleotide polymorphisms (SNPs) with allele frequencies of >0.05; these variants were excluded from further analyses. Three previously unidentified missense variants, three missense variants with reported disease association, and five rare variants were analyzed for segregation and/or allele frequencies. No variant fulfilled the criteria of being causal for MacTel. A missense mutation, p.Pro33Ser in frizzled homolog (Drosophila) 4 (FZD4), previously suggested as a disease-causing variant in familial exudative vitreoretinopathy, was determined to be a rare benign polymorphism.Conclusions: We have ruled out the exons and flanking intronic regions in 27 candidate genes as harboring causal mutations for MacTel