ABSTRACT
INTRODUCTION: The aim of this study was to evaluate the progression of atrophy as determined by spectral-domain optical coherence tomography (SD-OCT) in patients with molecularly confirmed ABCA4-associated Stargardt disease type 1 (STGD1) over a 24-month period in a multicenter prospective cohort study. METHODS: SD-OCT images from 428 eyes of 236 patients were analyzed. Change of mean thickness (MT) and intact area were estimated after semiautomated segmentation for the following individual layers in the central subfield (CS), inner ring (IR), and outer ring (OR) of the ETDRS grid: retinal pigment epithelium (RPE), outer segments (OSs), inner segments (IS), outer nuclear layer (ONL) inner retina (IR), and total retina. RESULTS: Statistically significant decreases of all outer retinal layers (RPE, OS, IS, and ONL) could be observed over a 24-month period both in decline of mean retinal thickness and intact area (p < 0.0001, respectively), whereas the IR showed an increase of retinal thickness in the CS and IR and remained unchanged in the OR. CONCLUSIONS: Significant loss could be detected in outer retinal layers by SD-OCT over a 24-month period in patients with STGD1. Loss of thickness and/or intact area of such layers may serve as potential endpoints for clinical trials that aim to slow down the disease progression of STGD1.
Subject(s)
Disease Progression , Macular Degeneration , Retinal Pigment Epithelium , Stargardt Disease , Tomography, Optical Coherence , Visual Acuity , Humans , Tomography, Optical Coherence/methods , Stargardt Disease/diagnosis , Male , Prospective Studies , Female , Adult , Young Adult , Middle Aged , Macular Degeneration/diagnosis , Macular Degeneration/congenital , Retinal Pigment Epithelium/pathology , Retinal Pigment Epithelium/diagnostic imaging , Adolescent , Follow-Up Studies , Retina/diagnostic imaging , Retina/pathology , ChildABSTRACT
PURPOSE: To assess the generalizability of a deep learning-based algorithm to segment the ellipsoid zone (EZ). METHODS: The dataset consisted of 127 spectral-domain optical coherence tomography volumes from eyes of participants with USH2A-related retinal degeneration enrolled in the RUSH2A clinical trial (NCT03146078). The EZ was segmented manually by trained readers and automatically by deep OCT atrophy detection, a deep learning-based algorithm originally developed for macular telangiectasia Type 2. Performance was evaluated using the Dice similarity coefficient between the segmentations, and the absolute difference and Pearson's correlation of measurements of interest obtained from the segmentations. RESULTS: With deep OCT atrophy detection, the average (mean ± SD, median) Dice similarity coefficient was 0.79 ± 0.27, 0.90. The average absolute difference in total EZ area was 0.62 ± 1.41, 0.22 mm2 with a correlation of 0.97. The average absolute difference in the maximum EZ length was 222 ± 288, 126 µm with a correlation of 0.97. CONCLUSION: Deep OCT atrophy detection segmented EZ in USH2A-related retinal degeneration with good performance. The algorithm is potentially generalizable to other diseases and other biomarkers of interest as well, which is an important aspect of clinical applicability.
Subject(s)
Deep Learning , Retinal Degeneration , Algorithms , Atrophy , Extracellular Matrix Proteins/genetics , Humans , Retinal Degeneration/diagnosis , Tomography, Optical Coherence/methods , Visual AcuityABSTRACT
PURPOSE: Leber congenital amaurosis due to CEP290 mutations (LCA10) is an inherited retinal disease that often results in severe visual impairment or blindness in early childhood. Currently, there are no approved treatments, highlighting the considerable unmet medical need associated with LCA10. We aimed to review the clinical characteristics of LCA10, its impact on patients and society, and the investigational treatment strategies currently in development. METHODS: Review of the current literature. RESULTS: LCA10 is an autosomal recessive ciliopathy, for which the CEP290 intronic variant c.2991+1655A>G (p.Cys998X) is the most common mutation. Usually diagnosed in early childhood, most patients with LCA10 have severe visual impairment during their first decade of life, which significantly affects the quality of life and development. LCA10 also has a significant societal burden (direct and indirect costs). RNA editing using antisense oligonucleotides or Staphylococcus aureus CRISPR-associated protein-9 nuclease is currently under investigation for treatment of p.Cys998X LCA10. Specifically, the antisense oligonucleotide therapy QR-110 (sepofarsen) has demonstrated encouraging safety and efficacy data in a first-in-human trial; a phase 3 clinical trial is ongoing. CONCLUSION: Interventions that can preserve or improve vision in patients with LCA10 have considerable potential to improve the patient quality of life and reduce burden of disease.
Subject(s)
Antigens, Neoplasm/genetics , Blindness/etiology , Cell Cycle Proteins/genetics , Cytoskeletal Proteins/genetics , DNA/genetics , Disease Management , Health Services Needs and Demand/standards , Leber Congenital Amaurosis/genetics , Antigens, Neoplasm/metabolism , Blindness/diagnosis , Blindness/therapy , Cell Cycle Proteins/metabolism , Cytoskeletal Proteins/metabolism , DNA Mutational Analysis , Humans , Leber Congenital Amaurosis/complicationsABSTRACT
Inherited retinal diseases (IRDs) are a group of rare, heterogenous eye disorders caused by gene mutations that result in degeneration of the retina. There are currently limited treatment options for IRDs; however, retinal gene therapy holds great promise for the treatment of different forms of inherited blindness. One such IRD for which gene therapy has shown positive initial results is choroideremia, a rare, X-linked degenerative disorder of the retina and choroid. Mutation of the CHM gene leads to an absence of functional Rab escort protein 1 (REP1), which causes retinal pigment epithelium cell death and photoreceptor degeneration. The condition presents in childhood as night blindness, followed by progressive constriction of visual fields, generally leading to vision loss in early adulthood and total blindness thereafter. A recently developed adeno-associated virus-2 (AAV2) vector construct encoding REP1 (AAV2-REP1) has been shown to deliver a functional version of the CHM gene into the retinal pigment epithelium and photoreceptor cells. Phase 1 and 2 studies of AAV2-REP1 in patients with choroideremia have produced encouraging results, suggesting that it is possible not only to slow or stop the decline in vision following treatment with AAV2-REP1, but also to improve visual acuity in some patients.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Choroideremia/therapy , Genetic Therapy/methods , Genetic Vectors/administration & dosage , Parvovirinae/genetics , Choroideremia/genetics , Choroideremia/pathology , Dependovirus , Humans , Mutation , Retina/pathology , Retinal Pigment Epithelium/pathology , Retinitis Pigmentosa/genetics , Retinitis Pigmentosa/pathology , Retinitis Pigmentosa/therapy , Treatment Outcome , Visual Acuity/geneticsABSTRACT
PURPOSE: Choroideremia is an incurable, X-linked, recessive retinal dystrophy caused by loss of function mutations in the CHM gene. It is estimated to affect approximately 1 in 50,000 male patients. It is characterized by progressive degeneration of the retinal pigment epithelium, choroid, and photoreceptors, resulting in visual impairment and blindness. There is an unmet need in choroideremia, because currently, there are no approved treatments available for patients with the disease. METHODS: We review the patient journey, societal impact, and emerging treatments for patients with choroideremia. RESULTS: Its relative rarity and similarities with other retinal diseases in early years mean that diagnosis of choroideremia can often be delayed. Furthermore, its impact on affected individuals, and wider society, is also likely underestimated. AAV2-mediated gene therapy is an investigational treatment that aims to replace the faulty CHM gene. Early-phase studies reported potentially important visual acuity gains and maintenance of vision in some patients, and a large Phase 3 program is now underway. CONCLUSION: Choroideremia is a disease with a significant unmet need. Interventions that can treat progression of the disease and improve visual and functional outcomes have the potential to reduce health care costs and enhance patient quality of life.
Subject(s)
Choroid/pathology , Choroideremia/diagnosis , Retinal Degeneration/etiology , Retinal Pigment Epithelium/pathology , Visual Acuity , Choroideremia/complications , Disease Progression , Humans , Retinal Degeneration/diagnosisABSTRACT
PURPOSE: To describe the study design and characteristics at first visit of participants in the longitudinal Scotopic Microperimetric Assessment of Rod Function in Stargardt Disease (SMART) study. METHODS: Scotopic microperimetry (sMP) was performed in one designated study eye in a subset of participants with molecularly proven ABCA4-associated Stargardt disease (STGD1) enrolled in a multicenter natural history study (ProgStar). Study visits were every 6 months over a period ranging from 6 to 24 months, and also included fundus autofluorescence (FAF). RESULTS: SMART enrolled 118 participants (118 eyes). At the first visit of SMART, the mean sensitivity in mesopic microperimetry was 11.48 (±5.05; range 0.00-19.88) dB and in sMP 11.25 (±5.26; 0-19.25) dB. For FAF, all eyes had a lesion of decreased autofluorescence (mean lesion size 3.62 [±3.48; 0.10-21.46] mm2), and a total of 76 eyes (65.5%) had a lesion of definitely decreased autofluorescence with a mean lesion size of 3.46 (±3.60; 0.21-21.46) mm2. CONCLUSIONS: Rod function is impaired in STGD1 and can be assessed by sMP. Testing rod function may serve as a potential outcome measure for future clinical treatment trials. This is evaluated in the SMART study.
Subject(s)
Macular Degeneration/congenital , Night Vision/physiology , Retinal Rod Photoreceptor Cells/physiology , Visual Fields/physiology , Adult , Aged , Female , Humans , Longitudinal Studies , Macular Degeneration/physiopathology , Male , Middle Aged , Research Design , Stargardt Disease , Visual Acuity/physiology , Visual Field Tests , Young AdultABSTRACT
The cyclic nucleotide-gated (CNG) channel - composed of CNGA3 and CNGB3 subunits - mediates the influx of cations in cone photoreceptors after light stimulation and thus is a key element in cone phototransduction. Mutations in CNGA3 and CNGB3 are associated with achromatopsia, a rare autosomal recessive retinal disorder. Here, we demonstrate that the presence of an early nonsense mutation in CNGA3 induces the usage of a downstream alternative translation initiation site giving rise to a short CNGA3 isoform. The expression of this short isoform was verified by Western blot analysis and DAB staining of HEK293â¯cells and cone photoreceptor-like 661W cells expressing CNGA3-GST fusion constructs. Functionality of the short isoform was confirmed by a cellular calcium influx assay. Furthermore, patients carrying an early nonsense mutation were analyzed for residual cone photoreceptor function in order to identify a potential role of the short isoform to modify the clinical outcome in achromatopsia patients. Yet the results suggest that the short isoform is not able to compensate for the loss of the long isoform leaving the biological role of this variant unclear.
Subject(s)
Codon, Nonsense/genetics , Color Vision Defects/genetics , Cyclic Nucleotide-Gated Cation Channels/genetics , Gene Expression Regulation/physiology , Peptide Chain Initiation, Translational/genetics , Protein Isoforms/genetics , Animals , Blotting, Western , Cell Line , Color Vision Defects/metabolism , Electrophoresis, Polyacrylamide Gel , HEK293 Cells/metabolism , Humans , Immunohistochemistry , Mice , Polymerase Chain Reaction , Retinal Cone Photoreceptor Cells/metabolism , TransfectionABSTRACT
PURPOSE: To explore a possible association between full-field electroretinograms with vitreomacular adhesion resolution and best-corrected visual acuity as part of the prospective, randomized, double-masked, sham-controlled Ocriplasmin for Treatment for Symptomatic Vitreomacular Adhesion Including Macular Hole (OASIS) trial studying ocriplasmin. METHODS: The ERG substudy enrolled 62 of 220 OASIS subjects (randomized 2:1) and analyzed full-field electroretinograms and their association with both vitreomacular adhesion resolution and best-corrected visual acuity from baseline through Month 24. Electroretinogram reductions were defined as acute full-field electroretinogram reductions in amplitude of ≥40% from baseline occurring at postinjection Day 7 or Day 28. RESULTS: In the ocriplasmin group, 16/40 (40%) subjects developed ERG reductions, compared to 1/21 (4.8%) in the sham group; 13/16 (81.3%) and 1/1 (100%) resolved by study end, respectively. A total of 11/16 (68.8%) ocriplasmin-treated subjects with ERG reductions achieved vitreomacular adhesion resolution, compared to those without (9/24, 37.5%). The ocriplasmin-treated subjects with ERG reductions also gained more letters on average (11.3 vs. 9.3 letters) from baseline and had a difference of 6.7 letters in mean best-corrected visual acuity by study end compared to those without ERG reductions. CONCLUSION: Ocriplasmin-treated subjects with ERG reductions had a higher rate of vitreomacular adhesion resolution and showed better visual improvement than their counterparts without ERG reductions or sham subjects by study end.
Subject(s)
Electroretinography/drug effects , Fibrinolysin/administration & dosage , Macula Lutea/pathology , Peptide Fragments/administration & dosage , Retinal Perforations/drug therapy , Visual Acuity , Vitreous Body/pathology , Vitreous Detachment/drug therapy , Adult , Aged , Aged, 80 and over , Dose-Response Relationship, Drug , Double-Blind Method , Female , Follow-Up Studies , Humans , Macula Lutea/physiopathology , Male , Middle Aged , Prospective Studies , Retinal Perforations/complications , Retinal Perforations/physiopathology , Time Factors , Tissue Adhesions/drug therapy , Tissue Adhesions/etiology , Tissue Adhesions/physiopathology , Treatment Outcome , Vitreous Body/physiopathology , Vitreous Detachment/complications , Vitreous Detachment/physiopathologyABSTRACT
Genetic testing of probands in families with an initial diagnosis of autosomal dominant retinitis pigmentosa (adRP) usually confirms the diagnosis, but there are exceptions. We report results of genetic testing in a large cohort of adRP families with an emphasis on exceptional cases including X-linked RP with affected females; homozygous affected individuals in families with heterozygous, dominant disease; and independently segregating mutations in the same family. Genetic testing was conducted in more than 700 families with a provisional or probable diagnosis of adRP. Exceptions to the proposed mode of inheritance were extracted from our comprehensive patient and family database. In a subset of 300 well-characterized families with a probable diagnosis of adRP, 195 (70%) have dominant mutations in known adRP genes but 25 (8%) have X-linked mutations, 3 (1%) have multiple segregating mutations, and 3 (1%) have dominant-acting mutations in genes previously associated with recessive disease. It is currently possible to determine the underlying disease-causing gene and mutation in approximately 80% of families with an initial diagnosis of adRP, but 10% of "adRP" families have a variant mode of inheritance. Informed genetic diagnosis requires close collaboration between clinicians, genetic counselors, and laboratory scientists.
Subject(s)
Retinitis Pigmentosa/genetics , Chromosome Mapping , Chromosomes, Human, Pair 10/genetics , Extracellular Matrix Proteins/genetics , Eye Proteins/genetics , Female , Gene Dosage , Genes, Dominant , Genes, X-Linked , Genetic Linkage , Hexokinase/genetics , Humans , Male , Pedigree , Retinitis Pigmentosa/diagnosisABSTRACT
Retinal bipolar (BP) cells mediate the earliest steps in image processing in the visual system, but the genetic pathways that regulate their development and function are incompletely known. We identified PRDI-BF1 and RIZ homology domain containing 8 (PRDM8) as a highly conserved transcription factor that is abundantly expressed in mouse retina. During development and in maturity, PRDM8 is expressed strongly in BP cells and a fraction of amacrine and ganglion cells. To determine whether Prdm8 is essential to BP cell development or physiology, we targeted the gene in mice. Prdm8(EGFP/EGFP) mice showed nonprogressive b-wave deficits on electroretinograms, consistent with compromised BP cell function or circuitry resembling the incomplete form of human congenital stationary night blindness (CSNB). BP cell specification was normal in Prdm8(EGFP/EGFP) retina as determined by VSX2(+) cell numbers and retinal morphology at postnatal day 6. BP subtype differentiation was impaired, however, as indicated by absent or diminished expression of BP subtype-specific markers, including the putative PRDM8 regulatory target PKCα (Prkca) and its protein. By adulthood, rod bipolar (RB) and type 2 OFF-cone bipolar (CB) cells were nearly absent from Prdm8-null mice. Although no change was detected in total amacrine cell (AC) numbers, increased PRKCA(+) and cholinergic ACs and decreased GABAergic ACs were seen, suggesting an alteration in amacrine subtype identity. These findings establish that PRDM8 is required for RB and type 2 OFF-CB cell survival and amacrine subtype identity, and they present PRDM8 as a candidate gene for human CSNB.
Subject(s)
Amacrine Cells/cytology , Cell Survival/physiology , Histone-Lysine N-Methyltransferase/physiology , Retinal Bipolar Cells/cytology , Amacrine Cells/metabolism , Animals , DNA-Binding Proteins , Histone Methyltransferases , Mice , Mice, Transgenic , Retinal Bipolar Cells/metabolism , Retinal Cone Photoreceptor Cells/cytology , Retinal Cone Photoreceptor Cells/metabolism , Retinal Rod Photoreceptor Cells/cytology , Retinal Rod Photoreceptor Cells/metabolismABSTRACT
The genetic heterogeneity of Mendelian disorders results in a significant proportion of patients that are unable to be assigned a confident molecular diagnosis after conventional exon sequencing and variant interpretation. Here, we evaluated how many patients with an inherited retinal disease (IRD) have variants of uncertain significance (VUS) that are disrupting splicing in a known IRD gene by means other than affecting the canonical dinucleotide splice site. Three in silico splice-affecting variant predictors were leveraged to annotate and prioritize variants for splicing functional validation. An in vitro minigene system was used to assay each variant's effect on splicing. Starting with 745 IRD patients lacking a confident molecular diagnosis, we validated 23 VUS as splicing variants that likely explain disease in 26 patients. Using our results, we optimized in silico score cutoffs to guide future variant interpretation. Variants that alter base pairs other than the canonical GT-AG dinucleotide are often not considered for their potential effect on RNA splicing but in silico tools and a minigene system can be utilized for the prioritization and validation of such splice-disrupting variants. These variants can be overlooked causes of human disease but can be identified using conventional exon sequencing with proper interpretation guidelines.
Subject(s)
Exons , Gene Expression , Genes, Reporter , Genetic Diseases, Inborn/genetics , Genetic Predisposition to Disease , Genetic Variation , RNA Splicing , Alleles , Chromosome Mapping , Computational Biology/methods , Genetic Association Studies , Genetic Diseases, Inborn/diagnosis , Genotype , High-Throughput Nucleotide Sequencing , Humans , Molecular Sequence Annotation , Pedigree , Reproducibility of ResultsABSTRACT
PURPOSE: With recent availability of next-generation sequencing (NGS), it is becoming more common to pursue disease-targeted panel testing rather than traditional sequential gene-by-gene dideoxy sequencing. In this report, we describe using NGS to identify multiple disease-causing mutations that contribute concurrently or independently to retinal dystrophy in three relatively small families. METHODS: Family members underwent comprehensive visual function evaluations, and genetic counseling including a detailed family history. A preliminary genetic inheritance pattern was assigned and updated as additional family members were tested. Family 1 (FAM1) and Family 2 (FAM2) were clinically diagnosed with retinitis pigmentosa (RP) and had a suspected autosomal dominant pedigree with non-penetrance (n.p.). Family 3 (FAM3) consisted of a large family with a diagnosis of RP and an overall dominant pedigree, but the proband had phenotypically cone-rod dystrophy. Initial genetic analysis was performed on one family member with traditional Sanger single gene sequencing and/or panel-based testing, and ultimately, retinal gene-targeted NGS was required to identify the underlying cause of disease for individuals within the three families. Results obtained in these families necessitated further genetic and clinical testing of additional family members to determine the complex genetic and phenotypic etiology of each family. RESULTS: Genetic testing of FAM1 (n = 4 affected; 1 n.p.) identified a dominant mutation in RP1 (p.Arg677Ter) that was present for two of the four affected individuals but absent in the proband and the presumed non-penetrant individual. Retinal gene-targeted NGS in the fourth affected family member revealed compound heterozygous mutations in USH2A (p. Cys419Phe, p.Glu767Serfs*21). Genetic testing of FAM2 (n = 3 affected; 1 n.p.) identified three retinal dystrophy genes (PRPH2, PRPF8, and USH2A) with disease-causing mutations in varying combinations among the affected family members. Genetic testing of FAM3 (n = 7 affected) identified a mutation in PRPH2 (p.Pro216Leu) tracking with disease in six of the seven affected individuals. Additional retinal gene-targeted NGS testing determined that the proband also harbored a multiple exon deletion in the CRX gene likely accounting for her cone-rod phenotype; her son harbored only the mutation in CRX, not the familial mutation in PRPH2. CONCLUSIONS: Multiple genes contributing to the retinal dystrophy genotypes within a family were discovered using retinal gene-targeted NGS. Families with noted examples of phenotypic variation or apparent non-penetrant individuals may offer a clue to suspect complex inheritance. Furthermore, this finding underscores that caution should be taken when attributing a single gene disease-causing mutation (or inheritance pattern) to a family as a whole. Identification of a disease-causing mutation in a proband, even with a clear inheritance pattern in hand, may not be sufficient for targeted, known mutation analysis in other family members.
Subject(s)
Extracellular Matrix Proteins/genetics , High-Throughput Nucleotide Sequencing , Mutation , Peripherins/genetics , RNA-Binding Proteins/genetics , Retinitis Pigmentosa/genetics , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , DNA Mutational Analysis , Eye Proteins/genetics , Female , Genetic Testing , Homeodomain Proteins/genetics , Humans , Inheritance Patterns , Male , Microtubule-Associated Proteins , Middle Aged , Pedigree , Trans-Activators/genetics , Young AdultABSTRACT
BACKGROUND: The purpose of this study is to determine the maximum tolerated dose of a single intravitreal injection of aminoguanidine and 1400W, 2 inhibitors of inducible nitric oxide synthase, in rabbit eyes. Inhibition of inducible nitric oxide synthase has already been shown to be beneficial in various animal models of diabetic eye disease. METHODS: Groups of 4 New Zealand white rabbits were injected with balanced salt solution in the right eye and a single dose of either aminoguanidine (5, 1, 0.25 mg) or 1400W (2 mg and 0.4 mg) in the left eye. Toxicity was assessed by slit-lamp and fundus examination, intraocular pressure and pachymetric measurements, and electrophysiologic and histologic analysis. RESULTS: Eyes injected with high doses of aminoguanidine (5 mg) or 1400W (2 mg) demonstrated severe retinal vascular attenuation and infarction. Lower doses of intravitreal aminoguanidine (1 mg) and 1400W (0.4 mg) caused no significant toxic ocular effects in rabbit eyes. CONCLUSION: If the difference in vitreal volume between rabbit eyes and human eyes is taken into account, aminoguanidine (2.7 mg) and 1400W (1 mg) would be reasonable intravitreal doses to test for safety and efficacy in early clinical trials.
Subject(s)
Amidines/toxicity , Benzylamines/toxicity , Diabetic Retinopathy/drug therapy , Enzyme Inhibitors/toxicity , Guanidines/toxicity , Nitric Oxide Synthase Type II/antagonists & inhibitors , Retina/drug effects , Amidines/administration & dosage , Amidines/therapeutic use , Animals , Aqueous Humor/metabolism , Benzylamines/administration & dosage , Benzylamines/therapeutic use , Diabetic Retinopathy/pathology , Disease Models, Animal , Electroretinography/drug effects , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/therapeutic use , Guanidines/administration & dosage , Guanidines/therapeutic use , Intraocular Pressure/drug effects , Intravitreal Injections/adverse effects , Male , Nitric Oxide/metabolism , Rabbits , Retina/pathology , Vitreous Body/drug effects , Vitreous Body/metabolismABSTRACT
PURPOSE: To identify the underlying cause of disease in a large family with North Carolina macular dystrophy (NCMD). METHODS: A large four-generation family (RFS355) with an autosomal dominant form of NCMD was ascertained. Family members underwent comprehensive visual function evaluations. Blood or saliva from six affected family members and three unaffected spouses was collected and DNA tested for linkage to the MCDR1 locus on chromosome 6q12. Three affected family members and two unaffected spouses underwent whole exome sequencing (WES) and subsequently, custom capture of the linkage region followed by next-generation sequencing (NGS). Standard PCR and dideoxy sequencing were used to further characterize the mutation. RESULTS: Of the 12 eyes examined in six affected individuals, all but two had Gass grade 3 macular degeneration features. Large central excavation of the retinal and choroid layers, referred to as a macular caldera, was seen in an age-independent manner in the grade 3 eyes. The calderas are unique to affected individuals with MCDR1. Genome-wide linkage mapping and haplotype analysis of markers from the chromosome 6q region were consistent with linkage to the MCDR1 locus. Whole exome sequencing and custom-capture NGS failed to reveal any rare coding variants segregating with the phenotype. Analysis of the custom-capture NGS sequencing data for copy number variants uncovered a tandem duplication of approximately 60 kb on chromosome 6q. This region contains two genes, CCNC and PRDM13. The duplication creates a partial copy of CCNC and a complete copy of PRDM13. The duplication was found in all affected members of the family and is not present in any unaffected members. The duplication was not seen in 200 ethnically matched normal chromosomes. CONCLUSIONS: The cause of disease in the original family with MCDR1 and several others has been recently reported to be dysregulation of the PRDM13 gene, caused by either single base substitutions in a DNase 1 hypersensitive site upstream of the CCNC and PRDM13 genes or a tandem duplication of the PRDM13 gene. The duplication found in the RFS355 family is distinct from the previously reported duplication and provides additional support that dysregulation of PRDM13, not CCNC, is the cause of NCMD mapped to the MCDR1 locus.
Subject(s)
Corneal Dystrophies, Hereditary/genetics , Eye Proteins/genetics , Histone-Lysine N-Methyltransferase/genetics , Mutation , Tandem Repeat Sequences/genetics , Transcription Factors/genetics , Adult , Aged , Child , Child, Preschool , Chromosome Mapping , Corneal Dystrophies, Hereditary/diagnosis , Female , Genetic Linkage , Humans , Male , Pedigree , Polymerase Chain Reaction , Polymorphism, Single Nucleotide , Tomography, Optical Coherence , Visual Acuity/physiologyABSTRACT
PURPOSE: To describe the design and baseline characteristics of patients enrolled into 2 natural history studies of Stargardt disease (STGD1). DESIGN: Multicenter retrospective and prospective cohort studies. PARTICIPANTS: Three hundred sixty-five unique patients aged 6 years and older at baseline harboring disease-causing variants in the ABCA4 gene and with specified ocular lesions were enrolled from 9 centers in the United States and Europe. METHODS: In the retrospective study, patients contributed medical record data from at least 2 and up to 4 visits for at least 1 examination modality: fundus autofluorescence (FAF), spectral-domain (SD) optical coherence tomography (SD OCT), and/or microperimetry (MP). The total observational period was at least 2 years and up to 5 years between single visits. Demographic and visual acuity (VA) data also were obtained. In the prospective study, eligible patients were examined at baseline using a standard protocol, with 6-month follow-up visits planned for a 2-year period for serial Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected VA, SD OCT, FAF, and MP. MAIN OUTCOME MEASURES: Design and rationale of a multicenter study to determine the progression of STGD1 in 2 large retrospective and prospective international cohorts. Detailed baseline characteristics of both cohorts are presented, including demographics, and structural and functional retinal metrics. RESULTS: Into the retrospective study, 251 patients (458 eyes) were enrolled; mean follow-up ± standard deviation was 3.9±1.6 years. At baseline, 36% had no or mild VA loss, and 47% of the study eyes had areas of definitely decreased autofluorescence (DDAF) with an average lesion area of 2.5±2.9 mm(2) (range, 0.02-16.03 mm(2)). Two hundred fifty-nine patients (489 eyes) were enrolled in the prospective study. At baseline, 20% had no or mild VA loss, and 64% had areas of DDAF with an average lesion area of 4.0±4.4 mm(2) (range, 0.03-24.24 mm(2)). The mean retinal sensitivity with MP was 10.8±5.0 dB. CONCLUSIONS: The ProgStar cohorts have baseline characteristics that encompass a wide range of disease severity and are expected to provide valuable data on progression based on serial quantitative measurements derived from multiple methods, which will be critical to the design of planned clinical trials.
Subject(s)
Geographic Atrophy/diagnosis , Macular Degeneration/congenital , Retinal Pigment Epithelium/pathology , ATP-Binding Cassette Transporters/genetics , Adolescent , Adult , Child , Disease Progression , Female , Fluorescein Angiography , Follow-Up Studies , Geographic Atrophy/etiology , Geographic Atrophy/genetics , Geographic Atrophy/physiopathology , Humans , Macular Degeneration/complications , Macular Degeneration/diagnosis , Macular Degeneration/genetics , Macular Degeneration/physiopathology , Male , Middle Aged , Mutation/genetics , Optical Imaging , Prospective Studies , Research Design , Retina/physiology , Retrospective Studies , Stargardt Disease , Tomography, Optical Coherence , Visual Acuity/physiology , Visual Field Tests , Visual Fields/physiology , Young AdultABSTRACT
PURPOSE: To summarize the recent literature describing the application of modern technologies in the study of patients with geographic atrophy (GA) secondary to age-related macular degeneration. METHODS: Review of the literature describing the terms and definitions used to describe GA, imaging modalities used to capture and measure GA, and the tests of visual function and functional deficits that occur in patients with GA. RESULTS: In this paper, we describe the evolution of the definitions used to describe GA. We compare imaging modalities used in the characterization of GA, report on the sensitivity and specificity of the techniques where data exist, and describe the correlations between these various modes of capturing the presence of GA. We review the functional tests that have been used in patients with GA, and critically examine their ability to detect and quantify visual deficits. CONCLUSION: Ophthalmologists and retina specialists now have a wide range of assessments available for the functional and anatomic characterization of GA in patients with age-related macular degeneration. To date, studies have been limited by their unimodal approach, and we recommend that future studies of GA use multimodal imaging. We also suggest strategies for the optimal functional testing of patients with GA.
Subject(s)
Geographic Atrophy/diagnosis , Geographic Atrophy/etiology , Macular Degeneration/complications , Contrast Sensitivity/physiology , Electroretinography , Endpoint Determination , Fluorescein Angiography , Geographic Atrophy/physiopathology , Humans , Macular Degeneration/physiopathology , Quality of Life , Tomography, Optical Coherence , Visual Acuity/physiology , Visual Field TestsABSTRACT
BACKGROUND: A position paper based on the collective experiences of Argus II Retinal Prosthesis System investigators to review strategies to optimize outcomes in patients with retinitis pigmentosa undergoing retinal prosthesis implantation. METHODS: Retinal surgeons, device programmers, and rehabilitation specialists from Europe, Canada, Middle East, and the United States were convened to the first international Argus II Investigator Meeting held in Ann Arbor, MI in March 2015. The recommendations from the collective experiences were collected. Factors associated with successful outcomes were determined. RESULTS: Factors leading to successful outcomes begin with appropriate patient selection, expectation counseling, and preoperative retinal assessment. Challenges to surgical implantation include presence of staphyloma and inadequate Tenon's capsule or conjunctiva. Modified surgical technique may reduce risks of complications such as hypotony and conjunctival erosion. Rehabilitation efforts and correlation with validated outcome measures following implantation are critical. CONCLUSIONS: Bringing together Argus II investigators allowed the identification of strategies to optimize patient outcomes. Establishing an on-line collaborative network will foster coordinated research efforts to advance outcome assessment and rehabilitation strategies.
Subject(s)
Electrodes, Implanted , Retinitis Pigmentosa/surgery , Visual Prosthesis , Blindness/etiology , Blindness/rehabilitation , Humans , Outcome Assessment, Health Care , Patient Selection , Prosthesis Implantation/methodsABSTRACT
Whole-genome linkage mapping identified a region on chromosome 10q21.3-q22.1 with a maximum LOD score of 3.0 at 0 % recombination in a six-generation family with autosomal dominant retinitis pigmentosa (adRP). All known adRP genes and X-linked RP genes were excluded in the family by a combination of methods. Whole-exome next-generation sequencing revealed a missense mutation in hexokinase 1, HK1 c.2539G > A, p.Glu847Lys, tracking with disease in all affected family members. One severely-affected male is homozygous for this region by linkage analysis and has two copies of the mutation. No other potential mutations were detected in the linkage region nor were any candidates identified elsewhere in the genome. Subsequent testing detected the same mutation in four additional, unrelated adRP families, for a total of five mutations in 404 probands tested (1.2 %). Of the five families, three are from the Acadian population in Louisiana, one is French Canadian and one is Sicilian. Haplotype analysis of the affected chromosome in each family and the homozygous individual revealed a rare, shared haplotype of 450 kb, suggesting an ancient founder mutation. HK1 is a widely-expressed gene, with multiple, abundant retinal transcripts, coding for hexokinase 1. Hexokinase catalyzes phosphorylation of glucose to glusose-6-phospate, the first step in glycolysis. The Glu847Lys mutation is in a highly-conserved site, outside of the active site or known functional sites.
Subject(s)
Chromosomes, Human, Pair 10/genetics , Genetic Predisposition to Disease/genetics , Hexokinase/genetics , Mutation, Missense , Retinitis Pigmentosa/genetics , Base Sequence , DNA Mutational Analysis , Exome/genetics , Family Health , Female , Genes, Dominant , Genotype , Haplotypes , High-Throughput Nucleotide Sequencing , Humans , Male , Pedigree , Retinitis Pigmentosa/diagnosis , Sequence Homology, Nucleic AcidABSTRACT
Complete congenital stationary night blindness (cCSNB) is a clinically and genetically heterogeneous group of retinal disorders characterized by nonprogressive impairment of night vision, absence of the electroretinogram (ERG) b-wave, and variable degrees of involvement of other visual functions. We report here that mutations in GPR179, encoding an orphan G protein receptor, underlie a form of autosomal-recessive cCSNB. The Gpr179(nob5/nob5) mouse model was initially discovered by the absence of the ERG b-wave, a component that reflects depolarizing bipolar cell (DBC) function. We performed genetic mapping, followed by next-generation sequencing of the critical region and detected a large transposon-like DNA insertion in Gpr179. The involvement of GPR179 in DBC function was confirmed in zebrafish and humans. Functional knockdown of gpr179 in zebrafish led to a marked reduction in the amplitude of the ERG b-wave. Candidate gene analysis of GPR179 in DNA extracted from patients with cCSNB identified GPR179-inactivating mutations in two patients. We developed an antibody against mouse GPR179, which robustly labeled DBC dendritic terminals in wild-type mice. This labeling colocalized with the expression of GRM6 and was absent in Gpr179(nob5/nob5) mutant mice. Our results demonstrate that GPR179 plays a critical role in DBC signal transduction and expands our understanding of the mechanisms that mediate normal rod vision.
Subject(s)
Mutation , Myopia/genetics , Myopia/physiopathology , Night Blindness/genetics , Night Blindness/physiopathology , Receptors, G-Protein-Coupled/genetics , Retinal Bipolar Cells/metabolism , Retinal Bipolar Cells/physiology , Animals , Chromosome Mapping/methods , Dark Adaptation/genetics , Electroretinography/methods , Eye Diseases, Hereditary , Gene Knockdown Techniques/methods , Genetic Diseases, X-Linked , Heterozygote , Humans , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Myopia/metabolism , Night Blindness/metabolism , Pedigree , Receptors, Metabotropic Glutamate/genetics , Retinal Rod Photoreceptor Cells/metabolism , Retinal Rod Photoreceptor Cells/physiology , Signal Transduction , ZebrafishABSTRACT
PURPOSE: To determine whether annual decline in visual field sensitivity is greater in the transition zone at the edge of the frequency-domain optical coherence tomography (fdOCT) inner segment ellipsoid zone (EZ) than at other locations in the visual field. DESIGN: Prospective, longitudinal, observational study. PARTICIPANTS: Forty-four patients with X-linked retinitis pigmentosa (XLRP) resulting from a mutation in the RPGR gene. METHODS: Static perimetric fields (Humphrey 30-2; Carl Zeiss Meditec, Dublin, CA) were obtained annually for 4 years. Beginning with year 2, fdOCT scans were obtained annually with a Heidelberg Spectralis HRA + OCT (Heidelberg Engineering, Heidelberg, Germany). MAIN OUTCOME MEASURES: The rate of visual field decline at locations near the edge of the EZ compared with the rates for the macula and in the mid periphery. RESULTS: Sensitivity just inside and outside the edge of the EZ declined at rates of 0.84 and 0.92 dB/year, respectively. By comparison, average sensitivity in the macula and mid periphery declined by 0.38 and 0.61 dB/year, respectively. CONCLUSIONS: The edge of the EZ in each patient with XLRP indicates a transition zone between relatively healthy and relatively degenerate retina. The annual loss of sensitivity in the transition zone is more rapid than it is elsewhere in the retina.