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Objective: Abnormal changes in metabolite levels in serum or plasma have been highlighted in several studies in age-related macular degeneration (AMD), the leading cause of irreversible vision loss. Specific changes in lipid profiles are associated with an increased risk of AMD. Metabolites could thus be used to investigate AMD disease mechanisms or incorporated into AMD risk prediction models. However, whether particular metabolites causally affect the disease has yet to be established. Design: A 3-tiered analysis of blood metabolites in the United Kingdom (UK) Biobank cohort to identify metabolites that differ in AMD patients with evidence for a putatively causal role in AMD. Participants: A total of 72 376 donors from the UK Biobank cohort including participants with AMD (N = 1353) and non-AMD controls (N = 71 023). Methods: We analyzed 325 directly measured or derived blood metabolites from the UK Biobank for 72 376 donors to identify AMD-associated metabolites. Genome-wide association studies for 325 metabolites in 98 316 European participants from the UK Biobank were performed. The causal effects of these metabolites in AMD were tested using a 2-sample Mendelian randomization approach. The predictive value of these measurements together with sex and age was assessed by developing a machine learning classifier. Main Outcome Measures: Evaluating metabolic biomarkers associated with AMD susceptibility and investigating their potential causal contribution to the development of the disease. Results: This study noted age to be the prominent risk factor associated with AMD development. While accounting for age and sex, we identified 84 metabolic markers as significantly (false discovery rate-adjusted P value < 0.05) associated with AMD. Lipoprotein subclasses comprised the majority of the AMD-associated metabolites (39%) followed by several lipoprotein to lipid ratios. Nineteen metabolites showed a likely causative role in AMD etiology. Of these, 6 lipoproteins contain very small, very low-density lipoprotein (VLDL), and phospholipids to total lipid ratio in medium VLDL. Based on this we postulate that depletion of circulating very small VLDLs is likely causal for AMD. The risk prediction model constructed from the metabolites, age and sex, identified age as the primary predictive factor with a much smaller contribution by metabolites to AMD risk prediction. Conclusions: This study underscores the pronounced role of lipids in AMD susceptibility and the likely causal contribution of particular subclasses of lipoproteins to AMD. Our study provides valuable insights into the metabopathological mechanisms of AMD disease development and progression.
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Objectives: Systemic inflammatory response syndrome (SIRS) is a frequent complication of cardiopulmonary bypass (CPB). SIRS is associated with significant morbidity and mortality, but its pathogenesis remains incompletely understood, and as a result, biomarkers are lacking and treatment remains expectant and supportive. This study aimed to understand the pathophysiological mechanisms driving SIRS induced by CPB and identify novel therapeutic targets that might reduce systemic inflammation and improve patient outcomes. Methods: Twenty-one patients undergoing cardiac surgery and CPB were recruited, and blood was sampled before, during and after surgery. SIRS was defined using the American College of Chest Physicians/Society of Critical Care Medicine criteria. We performed immune cell profiling and whole blood transcriptomics and measured individual mediators in plasma/serum to characterise SIRS induced by CPB. Results: Nineteen patients fulfilled criteria for SIRS, with a mean duration of 2.7 days. Neutrophil numbers rose rapidly with CPB and remained elevated for at least 48 h afterwards. Transcriptional signatures associated with neutrophil activation and degranulation were enriched during CPB. We identified a network of cytokines governing these transcriptional changes, including granulocyte colony-stimulating factor (G-CSF), a regulator of neutrophil production and function. Conclusions: We identified neutrophils and G-CSF as major regulators of CPB-induced systemic inflammation. Short-term targeting of G-CSF could provide a novel therapeutic strategy to limit neutrophil-mediated inflammation and tissue damage in SIRS induced by CPB.
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Importance: Deep learning image analysis often depends on large, labeled datasets, which are difficult to obtain for rare diseases. Objective: To develop a self-supervised approach for automated classification of macular telangiectasia type 2 (MacTel) on optical coherence tomography (OCT) with limited labeled data. Design, Setting, and Participants: This was a retrospective comparative study. OCT images from May 2014 to May 2019 were collected by the Lowy Medical Research Institute, La Jolla, California, and the University of Washington, Seattle, from January 2016 to October 2022. Clinical diagnoses of patients with and without MacTel were confirmed by retina specialists. Data were analyzed from January to September 2023. Exposures: Two convolutional neural networks were pretrained using the Bootstrap Your Own Latent algorithm on unlabeled training data and fine-tuned with labeled training data to predict MacTel (self-supervised method). ResNet18 and ResNet50 models were also trained using all labeled data (supervised method). Main Outcomes and Measures: The ground truth yes vs no MacTel diagnosis is determined by retinal specialists based on spectral-domain OCT. The models' predictions were compared against human graders using accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), area under precision recall curve (AUPRC), and area under the receiver operating characteristic curve (AUROC). Uniform manifold approximation and projection was performed for dimension reduction and GradCAM visualizations for supervised and self-supervised methods. Results: A total of 2636 OCT scans from 780 patients with MacTel and 131 patients without MacTel were included from the MacTel Project (mean [SD] age, 60.8 [11.7] years; 63.8% female), and another 2564 from 1769 patients without MacTel from the University of Washington (mean [SD] age, 61.2 [18.1] years; 53.4% female). The self-supervised approach fine-tuned on 100% of the labeled training data with ResNet50 as the feature extractor performed the best, achieving an AUPRC of 0.971 (95% CI, 0.969-0.972), an AUROC of 0.970 (95% CI, 0.970-0.973), accuracy of 0.898%, sensitivity of 0.898, specificity of 0.949, PPV of 0.935, and NPV of 0.919. With only 419 OCT volumes (185 MacTel patients in 10% of labeled training dataset), the ResNet18 self-supervised model achieved comparable performance, with an AUPRC of 0.958 (95% CI, 0.957-0.960), an AUROC of 0.966 (95% CI, 0.964-0.967), and accuracy, sensitivity, specificity, PPV, and NPV of 90.2%, 0.884, 0.916, 0.896, and 0.906, respectively. The self-supervised models showed better agreement with the more experienced human expert graders. Conclusions and Relevance: The findings suggest that self-supervised learning may improve the accuracy of automated MacTel vs non-MacTel binary classification on OCT with limited labeled training data, and these approaches may be applicable to other rare diseases, although further research is warranted.
Subject(s)
Deep Learning , Retinal Telangiectasis , Humans , Female , Middle Aged , Male , Tomography, Optical Coherence/methods , Retrospective Studies , Rare Diseases , Retinal Telangiectasis/diagnostic imaging , Supervised Machine LearningABSTRACT
In the retina, microglia are resident immune cells that are essential for development and function. Retinal microglia play a central role in mediating pathological degeneration in diseases such as glaucoma, retinitis pigmentosa, age-related neurodegeneration, ischemic retinopathy, and diabetic retinopathy. Current models of mature human retinal organoids (ROs) derived from iPS cell (hiPSC) do not contain resident microglia integrated into retinal layers. Increasing cellular diversity in ROs by including resident microglia would more accurately represent the native retina and better model diseases in which microglia play a key role. In this study, we develop a new 3D in vitro tissue model of microglia-containing retinal organoids by co-culturing ROs and hiPSC-derived macrophage precursor cells (MPCs). We optimized the parameters for successful integration of MPCs into retinal organoids. We show that while in the ROs, MPCs migrate to the equivalent of the outer plexiform layer where retinal microglia cells reside in healthy retinal tissue. While there, they develop a mature morphology characterized by small cell bodies and long branching processes which is only observed in vivo. During this maturation process these MPCs cycle through an activated phase followed by a stable mature microglial phase as seen by the down regulation of pro-inflammatory cytokines and upregulation of anti-inflammatory cytokines. Finally, we characterized mature ROs with integrated MPCs using RNAseq showing an enrichment of cell-type specific microglia markers. We propose that this co-culture system may be useful for understanding the pathogenesis of retinal diseases involving retinal microglia and for drug discovery directly in human tissue.
Subject(s)
Induced Pluripotent Stem Cells , Retinal Diseases , Humans , Induced Pluripotent Stem Cells/pathology , Microglia/metabolism , Reactive Oxygen Species/metabolism , Retina , Retinal Diseases/pathology , Organoids/pathology , Macrophages/pathology , Cytokines/metabolismABSTRACT
OBJECTIVES: The non-essential amino acids serine, glycine, and alanine, as well as diverse sphingolipid species, are implicated in inherited neuro-retinal disorders and are metabolically linked by serine palmitoyltransferase (SPT), a key enzyme in membrane lipid biogenesis. To gain insight into the pathophysiological mechanisms linking these pathways to neuro-retinal diseases we compared patients diagnosed with two metabolically intertwined diseases: macular telangiectasia type II (MacTel), hereditary sensory autonomic neuropathy type 1 (HSAN1), or both. METHODS: We performed targeted metabolomic analyses of amino acids and broad sphingolipids in sera from a cohort of MacTel (205), HSAN1 (25) and Control (151) participants. RESULTS: MacTel patients exhibited broad alterations of amino acids, including changes in serine, glycine, alanine, glutamate, and branched-chain amino acids reminiscent of diabetes. MacTel patients had elevated 1-deoxysphingolipids but reduced levels of complex sphingolipids in circulation. A mouse model of retinopathy indicates dietary serine and glycine restriction can drive this depletion in complex sphingolipids. HSAN1 patients exhibited elevated serine, lower alanine, and a reduction in canonical ceramides and sphingomyelins compared to controls. Those patients diagnosed with both HSAN1 and MacTel showed the most significant decrease in circulating sphingomyelins. CONCLUSIONS: These results highlight metabolic distinctions between MacTel and HSAN1, emphasize the importance of membrane lipids in the progression of MacTel, and suggest distinct therapeutic approaches for these two neurodegenerative diseases.
Subject(s)
Hereditary Sensory and Autonomic Neuropathies , Retinal Diseases , Animals , Mice , Amino Acids , Sphingomyelins , Sphingolipids/metabolism , Serine/metabolism , Alanine , GlycineABSTRACT
INTRODUCTION: The primate retina has evolved regional specialisations for specific visual functions. The macula is specialised towards high acuity vision and is an area that contains an increased density of cone photoreceptors and signal processing neurons. Different regions in the retina display unique susceptibility to pathology, with many retinal diseases primarily affecting the macula. OBJECTIVES: To better understand the properties of different retinal areas we studied the differential distribution of metabolites across the retina. METHODS: We conducted an untargeted metabolomics analysis on full-thickness punches from three different regions (macula, temporal peri-macula and periphery) of healthy primate retina. RESULTS: Nearly half of all metabolites identified showed differential abundance in at least one comparison between the three regions. Furthermore, mapping metabolomics results from macula-specific eye diseases onto our region-specific metabolite distributions revealed differential abundance defining systemic metabolic dysregulations that were region specific. CONCLUSIONS: The unique metabolic phenotype of different retinal regions is likely due to the differential distribution of different cell types in these regions reflecting the specific metabolic requirements of each cell type. Our results may help to better understand the pathobiology of retinal diseases with region specificity.
Subject(s)
Macula Lutea , Retinal Diseases , Animals , Metabolomics , Retina/metabolism , Retinal Diseases/genetics , Retinal Diseases/metabolism , Macula Lutea/metabolism , Neurons/metabolismABSTRACT
Adolescents with differences of sex development (DSD) often have complex medical, surgical, and psychological care needs and require age-appropriate resources. This cross-sectional study describes the past and current experiences of adolescents and young adults with DSD and their need for information and support. Participants aged 14−30 years with DSD diagnoses were identified, either from departmental records at the Royal Children's Hospital (RCH), Melbourne, Australia, or from the private practice of a gynecologist linked to RCH. Anonymized data were collected from a specifically designed online survey. Of the 314 successfully traced patients, 91 (28.9%) completed the survey. Amongst respondents, older age was strongly correlated with higher levels of distress at the time of disclosure (b = 0.67, p < 0.001). People who reported greater understanding of their condition (b = −0.45, p = 0.010) and higher levels of support (b = −0.40, p = 0.003) identified lower levels of current distress. Respondents preferred to receive information from a specialist doctor, GP, or websites and reported information needs being highest during adolescence. Only one in four respondents recalled ever being offered psychological support. A number of perceived barriers to accessing support were identified. Our findings indicate that young people's information and support needs may be best met by improving online resources, as well as increasing introductions to knowledgeable and appropriate primary care physicians, psychological services, and peer support groups. Further work to promote and increase engagement with psychological and peer support for those with DSD will be important.
ABSTRACT
Conversion of adenosine to inosine in RNA by ADAR enzymes, termed "RNA editing," is essential for healthy brain development. Editing is dysregulated in neuropsychiatric diseases, but has not yet been investigated at scale at the level of individual neurons. We quantified RNA editing sites in nuclear transcriptomes of 3055 neurons from six cortical regions of a neurotypical female donor, and found 41,930 sites present in at least ten nuclei. Most sites were located within Alu repeats in introns or 3' UTRs, and approximately 80% were cataloged in public RNA editing databases. We identified 9285 putative novel editing sites, 29% of which were also detectable in unrelated donors. Intersection with results from bulk RNA-seq studies provided cell-type and spatial context for 1730 sites that are differentially edited in schizophrenic brain donors, and 910 such sites in autistic donors. Autism-related genes were also enriched with editing sites predicted to modify RNA structure. Inhibitory neurons showed higher overall transcriptome editing than excitatory neurons, and the highest editing rates were observed in the frontal cortex. We used generalized linear models to identify differentially edited sites and genes between cell types. Twenty nine genes were preferentially edited in excitatory neurons, and 43 genes were edited more heavily in inhibitory neurons, including RBFOX1, its target genes, and genes in the autism-associated Prader-Willi locus (15q11). The abundance of SNORD115/116 genes from locus 15q11 was positively associated with editing activity across the transcriptome. We contend that insufficient editing of autism-related genes in inhibitory neurons may contribute to the specific perturbation of those cells in autism.
Subject(s)
Autistic Disorder/pathology , Databases, Factual/statistics & numerical data , Genome, Human , Interneurons/pathology , RNA Editing , Schizophrenia/pathology , Transcriptome , Autistic Disorder/genetics , Humans , Interneurons/metabolism , Schizophrenia/geneticsABSTRACT
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.
Subject(s)
Biosynthetic Pathways/genetics , Disease Progression , Genetic Predisposition to Disease , Retinal Telangiectasis/genetics , Retinal Telangiectasis/pathology , Serine/biosynthesis , Diabetes Mellitus, Type 2/genetics , Endophenotypes , Genetic Loci , Genome-Wide Association Study , Humans , Metabolome , Polymorphism, Single Nucleotide/genetics , Retinal Vessels/pathologyABSTRACT
Macular Telangiectasia Type 2 (MacTel) is a rare degenerative retinal disease with complex genetic architecture. We performed a genome-wide association study on 1,067 MacTel patients and 3,799 controls, which identified eight novel genome-wide significant loci (p < 5 × 10-8), and confirmed all three previously reported loci. Using MAGMA, eQTL and transcriptome-wide association analysis, we prioritised 48 genes implicated in serine-glycine biosynthesis, metabolite transport, and retinal vasculature and thickness. Mendelian randomization indicated a likely causative role of serine (FDR = 3.9 × 10-47) and glycine depletion (FDR = 0.006) as well as alanine abundance (FDR = 0.009). Polygenic risk scoring achieved an accuracy of 0.74 and was associated in UKBiobank with retinal damage (p = 0.009). This represents the largest genetic study on MacTel to date and further highlights genetically-induced systemic and tissue-specific metabolic dysregulation in MacTel patients, which impinges on retinal health.
Subject(s)
Energy Metabolism/genetics , Polymorphism, Single Nucleotide , Retina/metabolism , Retinal Telangiectasis/genetics , Aged , Aged, 80 and over , Case-Control Studies , Female , Genetic Loci , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Male , Mendelian Randomization Analysis , Middle Aged , Phenotype , Quantitative Trait Loci , Retinal Telangiectasis/diagnosis , Retinal Telangiectasis/metabolism , Risk Assessment , Risk Factors , TranscriptomeABSTRACT
PURPOSE: To define, characterize, and classify hyperreflectivity on optical coherence tomography and report its prevalence in macular telangiectasia Type 2. METHODS: In a primary cross-sectional analysis, multimodal imaging data were retrospectively analyzed. The definition of hyperreflectivity and neovascularization on optical coherence tomography followed optical coherence tomography angiography-based criteria. Eyes were graded for the presence of hyperreflectivity and neovascularization and further categorized into three classes based on position and extent of hyperreflectivity. In a secondary analysis, eyes were reviewed for ≥24 months using optical coherence tomography imaging. RESULTS: Three hundred and twenty-two eyes from 161 patients were analyzed in the cross-sectional analysis. Hyperreflectivity was found in 177 (55%) and neovascular membranes in 49 (15%) eyes. Hyperreflectivity correlated significantly with parameters indicative of disease progression. In the longitudinal analysis, 206 eyes from 103 patients were reviewed over a mean of 35.6 months. 17/86 eyes (20%) showed a de novo development of hyperreflectivity. 8/29 eyes (28%) with preexistent intraretinal hyperreflectivity developed outer retinal hyperreflectivity. A high proportion of eyes with outer retinal hyperreflectivity (17/52 [33%]) developed neovascular membranes. CONCLUSION: Hyperreflectivity represents a common finding in macular telangiectasia Type 2 but lacks a uniform definition. We propose a hyperreflectivity grading scale that may help to estimate disease progression and identify eyes at risk for developing neovascular membranes.
Subject(s)
Retinal Pigment Epithelium/diagnostic imaging , Retinal Telangiectasis/diagnosis , Tomography, Optical Coherence/methods , Visual Acuity , Aged , Cross-Sectional Studies , Disease Progression , Female , Fluorescein Angiography/methods , Fundus Oculi , Humans , Male , Middle Aged , Retinal Telangiectasis/physiopathology , Retrospective StudiesABSTRACT
In cross-platform analyses of 174 metabolites, we identify 499 associations (P < 4.9 × 10-10) characterized by pleiotropy, allelic heterogeneity, large and nonlinear effects and enrichment for nonsynonymous variation. We identify a signal at GLP2R (p.Asp470Asn) shared among higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes, with ß-arrestin signaling as the underlying mechanism. Genetically higher serine levels are shown to reduce the likelihood (by 95%) and predict development of macular telangiectasia type 2, a rare degenerative retinal disease. Integration of genomic and small molecule data across platforms enables the discovery of regulators of human metabolism and translation into clinical insights.
Subject(s)
Health , Metabolism/genetics , Diabetes Mellitus, Type 2/genetics , Eye Diseases/genetics , Gene Frequency/genetics , Genetic Loci , Genetic Pleiotropy , Genome, Human , Glucagon-Like Peptide-2 Receptor/genetics , Glycine/metabolism , Humans , Linear Models , Mendelian Randomization Analysis , Metabolism, Inborn Errors/genetics , Metabolome/genetics , Mutation, Missense/genetics , Phenotype , Polymorphism, Single Nucleotide/genetics , Retinal Telangiectasis/genetics , Sample Size , Serine/metabolismABSTRACT
Ahead of Print article withdrawn by publisher.
ABSTRACT
Macular Telangiectasia type 2 (MacTel) is an uncommon bilateral retinal disease, in which glial cell and photoreceptor degeneration leads to central vision loss. The causative disease mechanism is largely unknown, and no treatment is currently available. A previous study found variants in genes associated with glycine-serine metabolism (PSPH, PHGDH and CPS1) to be associated with MacTel, and showed low levels of glycine and serine in the serum of MacTel patients. Recently, a causative role of deoxysphingolipids in MacTel disease has been established. However, little is known about possible other metabolic dysregulation. Here we used a global metabolomics platform in a case-control study to comprehensively profile serum from 60 MacTel patients and 58 controls. Analysis of the data, using innovative computational approaches, revealed a detailed, disease-associated metabolic profile with broad changes in multiple metabolic pathways. This included alterations in the levels of several metabolites that are directly or indirectly linked to glycine-serine metabolism, further validating our previous genetic findings. We also found changes unrelated to PSPH, PHGDH and CPS1 activity. Most pronounced, levels of several lipid groups were altered, with increased phosphatidylethanolamines being the most affected lipid group. Assessing correlations between different metabolites across our samples revealed putative functional connections. Correlations between phosphatidylethanolamines and sphingomyelin, and glycine-serine and sphingomyelin, observed in controls, were reduced in MacTel patients, suggesting metabolic re-wiring of sphingomyelin metabolism in MacTel patients. Our findings provide novel insights into metabolic changes associated with MacTel and implicate altered lipid metabolism as a contributor to this retinal neurodegenerative disease.
Subject(s)
Phosphatidylethanolamines/blood , Retinal Diseases/pathology , Sphingomyelins/blood , Aged , Carbamoyl-Phosphate Synthase (Ammonia)/genetics , Carbamoyl-Phosphate Synthase (Ammonia)/metabolism , Case-Control Studies , Diabetes Mellitus, Type 2/etiology , Female , Genetic Variation , Glycine/metabolism , Humans , Male , Metabolic Networks and Pathways/genetics , Metabolome , Metabolomics/methods , Middle Aged , Phosphatidylethanolamines/metabolism , Phosphoglycerate Dehydrogenase/genetics , Phosphoglycerate Dehydrogenase/metabolism , Phosphoric Monoester Hydrolases/genetics , Phosphoric Monoester Hydrolases/metabolism , Retinal Diseases/complications , Retinal Diseases/metabolism , Risk Factors , Serine/metabolism , Sphingomyelins/metabolismABSTRACT
BACKGROUND: Identifying mechanisms of diseases with complex inheritance patterns, such as macular telangiectasia type 2, is challenging. A link between macular telangiectasia type 2 and altered serine metabolism has been established previously. METHODS: Through exome sequence analysis of a patient with macular telangiectasia type 2 and his family members, we identified a variant in SPTLC1 encoding a subunit of serine palmitoyltransferase (SPT). Because mutations affecting SPT are known to cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), we examined 10 additional persons with HSAN1 for ophthalmologic disease. We assayed serum amino acid and sphingoid base levels, including levels of deoxysphingolipids, in patients who had macular telangiectasia type 2 but did not have HSAN1 or pathogenic variants affecting SPT. We characterized mice with low serine levels and tested the effects of deoxysphingolipids on human retinal organoids. RESULTS: Two variants known to cause HSAN1 were identified as causal for macular telangiectasia type 2: of 11 patients with HSAN1, 9 also had macular telangiectasia type 2. Circulating deoxysphingolipid levels were 84.2% higher among 125 patients with macular telangiectasia type 2 who did not have pathogenic variants affecting SPT than among 94 unaffected controls. Deoxysphingolipid levels were negatively correlated with serine levels, which were 20.6% lower than among controls. Reduction of serine levels in mice led to increases in levels of retinal deoxysphingolipids and compromised visual function. Deoxysphingolipids caused photoreceptor-cell death in retinal organoids, but not in the presence of regulators of lipid metabolism. CONCLUSIONS: Elevated levels of atypical deoxysphingolipids, caused by variant SPTLC1 or SPTLC2 or by low serine levels, were risk factors for macular telangiectasia type 2, as well as for peripheral neuropathy. (Funded by the Lowy Medical Research Institute and others.).
Subject(s)
Hereditary Sensory and Autonomic Neuropathies/genetics , Mutation , Retinal Telangiectasis/genetics , Serine C-Palmitoyltransferase/genetics , Serine/metabolism , Sphingolipids/metabolism , Adult , Aged , Animals , DNA Mutational Analysis , Disease Models, Animal , Exome/genetics , Female , Hereditary Sensory and Autonomic Neuropathies/complications , Hereditary Sensory and Autonomic Neuropathies/metabolism , Humans , Lipid Metabolism , Macula Lutea/pathology , Male , Mice , Middle Aged , Pedigree , Retinal Telangiectasis/complications , Retinal Telangiectasis/metabolism , Risk Factors , Serine/blood , Sphingosine/analogs & derivatives , Sphingosine/analysis , Young AdultABSTRACT
PURPOSE: To investigate the progression characteristics of ellipsoid zone (EZ) loss in eyes with macular telangiectasia type 2 (MacTel) as reflected by area and linear measurements, and their relevance for visual acuity. METHODS: Participants were selected from the MacTel Study cohort. Linear and area measurements of EZ loss were performed in Spectral-Domain Optical Coherence Tomograph (SD-OCT) volume scans. Progression characteristics and correlations between linear and area measurements were analysed using linear mixed effects models. RESULTS: A total of 134 eyes of 70 patients were included (85 eyes with follow-up, mean 4.7 years, range: 1.4-8 years). Ellipsoid zone (EZ) loss significantly progressed at a mean annual increment of 0.057 mm2 (p = 0.005). The progression rate was non-linear and interacted significantly with initial EZ lesion size indicating an exponential growth before reaching a plateau. There was a strong heterogeneity in area sizes between fellow eyes. EZ break length had a significant linear effect on EZ break area (b = 1.06, p < 0.001) and could predict it. The location of the EZ break had a significant impact on visual acuity. CONCLUSION: Ellipsoid zone (EZ) loss in MacTel has a non-linear progression characteristic, and its rate depends on area size at baseline, which must be taken into account at sample selection in clinical trials. Our results show a good correlation of linear and area measures of EZ loss and a segregation of best-corrected visual acuity by EZ location, which may help routine clinical practice.
Subject(s)
Fluorescein Angiography/methods , Macula Lutea/pathology , Retinal Telangiectasis/diagnosis , Retinal Vessels/pathology , Tomography, Optical Coherence/methods , Visual Acuity , Adult , Aged , Aged, 80 and over , Disease Progression , Female , Follow-Up Studies , Fundus Oculi , Humans , Male , Middle Aged , Prognosis , Retinal Pigment Epithelium/pathology , Time FactorsABSTRACT
Purpose: Macular telangiectasia type 2 (MacTel) is a bilateral neurodegenerative disorder of the central macula. Previous findings indicated more functional impairment in low light conditions. We sought to further characterize retinal dysfunction using dark-adapted two-color fundus-controlled perimetry ("scotopic microperimetry"). Methods: Participants of the MacTel Natural History Observation Registry study and age-matched healthy controls underwent retinal imaging including dual wavelength autofluorescence macular pigment optical density (MPOD) measurement. Retinal sensitivity was assessed with scotopic microperimetry using cyan (505 nm) and red (627 nm). Disease was graded into classes of MPOD loss (0 to 3). For perimetry analysis, the differences of the mean sensitivities (MacTel minus controls) were compared at each test location and the results were aggregated to global indices. Results: Thirty-four eyes (19 patients, mean age 62.2 years) were compared with 25 eyes (25 controls, mean age 61.5 years). Both cyan and red sensitivity were lower in MacTel. This was more pronounced at one- and three-degree eccentricity. Eyes with MPOD class 0 did not exhibit a functional deficit. Class 1 had impaired cyan, but normal red sensitivity. Class 2 and 3 behaved similarly and had impaired cyan and red sensitivity with a relatively higher cyan impairment. Conclusions: Rods might be compromised to a greater extent than cones. Linking to previous studies, our results might also hint toward (postreceptoral) dysfunction of the cone system in very early disease stages. Macular pigment loss and global perimetry indices seemed to reflect functional impairment and might be useful as adjunct measures for disease progression.
Subject(s)
Color Vision/physiology , Dark Adaptation/physiology , Retinal Cone Photoreceptor Cells/physiology , Retinal Rod Photoreceptor Cells/physiology , Retinal Telangiectasis/physiopathology , Visual Fields/physiology , Adult , Aged , Aged, 80 and over , Female , Fundus Oculi , Humans , Macular Pigment/metabolism , Male , Middle Aged , Tomography, Optical Coherence/methods , Visual Acuity/physiology , Visual Field Tests/methodsABSTRACT
BACKGROUND/AIM: Macular pigment optical density (MPOD) is centrally depleted early on in macular telangiectasia type 2 (MacTel). Contrast sensitivity (CS) might be related to MPOD, and thus impaired in early MacTel. The effect of low luminance was assessed on both CS and best corrected visual acuity (BCVA). METHODS: This is a cross-sectional study. Pelli-Robson charts were used for CS testing at 1 m in photopic (110 lux) and mesopic (1 lux) conditions. BCVA was tested with ETDRS charts and low luminance visual acuity (LLVA) with a 2.0 log unit neutral density filter. MPOD was obtained with dual-wavelength autofluorescence. RESULTS: One hundred and three eyes of 52 patients with MacTel (mean±SD age 62.9±10.2, range 35-77) were compared with 34 healthy eyes of 17 controls (mean±SD age 65.2±7.4, range 53-78). CS was significantly lower in the eyes with MacTel. This impairment was higher in low light conditions (low light contrast sensitivity (LL-CS)). Eyes at the early stages of MacTel had significantly lower LL-CS than controls, but normal (photopic) CS. The results were similar but less pronounced for BCVA/LLVA. Decrease in CS was correlated with loss of MPOD. CONCLUSIONS: Low light conditions have a detrimental effect on visual performance in MacTel. Impaired CS might correlate with MPOD depletion as a pathognomonic finding in MacTel. Functional impairment might precede structural disintegration, indicating dysfunction at the cellular level. The applied tests might be useful as additional functional assessments in clinical routine and as outcome measures in future interventional clinical trials.
Subject(s)
Contrast Sensitivity/physiology , Light , Night Vision/physiology , Retinal Telangiectasis/physiopathology , Visual Acuity/physiology , Adult , Aged , Cross-Sectional Studies , Female , Humans , Macular Pigment/metabolism , Male , Middle Aged , Retinal Telangiectasis/metabolism , Vision Tests/instrumentationABSTRACT
PURPOSE: Pigment in the midretina is a characteristic sign in Type 2 idiopathic macular telangiectasia (MacTel) and is considered to characterize the late stage of the disease. Our aim was to investigate its incidence, and relationship with risk factors for MacTel, including outer retinal vascularization and subretinal neovascular proliferation (SRNV). METHODS: Pigment extent was measured in fundus autofluorescence images of 150 eyes of 75 MacTel probands, using the Region Finder tool of Heidelberg Eye Explorer. A linear mixed model was used to analyze the dynamics of pigment and its associations with other features of the phenotype. The relative incidence of pigment and of outer retinal outer retinal vascularization and SRNV was analyzed within the full MacTel Study cohort (1,244 probands). RESULTS: Mean pigment area at baseline was 0.157 mm (range = 0-1.295 mm, SD = 0.228 mm, n = 101). Progression demonstrated a nonlinear pattern (P < 0.001) at an overall rate of 0.0177 mm/year and was associated with the initial plaque size and with SRNV. There was a strong correlation between fellow eyes (P ≤ 0.0001). In approximately 25% of all SRNV cases, SRNV may coincide with or precede pigment. CONCLUSION: Our data may be useful for refining the current system for staging disease severity in MacTel.