Quantification of vascular changes in macular telangiectasia type 2 with AngioTool software.

PURPOSE: To compare AngioTool (AT) vascular parameters (VP) between MacTel2 eyes and normal eyes. Secondary outcome measures were to correlate VP with BCVA and to analyze VP between various grades of Simple MacTel Classification. METHODS: This is a retrospective study. SD OCTA images of the superficial vascular complex (SVC) and deep capillary complex (DVC) were exported into Image J and AT. The explant area (EA), vessel area (VA), vessel percentage area (VPA), total number of junctions (TNJ), junction density (JD), total vessel length (TVL), average vessel length (AVL), total number of endpoints (TNE) and mean E lacunarity (MEL) were studied. RESULTS: Group 1 had 120 MacTel2 eyes. Group 2 had 60 age-matched normal eyes. All VP were significantly different between the two groups except EA and TNE in both complexes. None of the VP had a correlation with BCVA. Interquadrant analysis (IQA) in SVC and DVC showed statistical significance in VPA, AVL and JD and in AVL, TNE, JD, VPA respectively. Post hoc analysis in SVC and DVC showed statistical significance in TNJ, JD, TVL and AVL between grade 1 and grade 3, and in VA, VPA, TNJ, JD, TVL and MEL between grade 0 and grade 3 respectively. CONCLUSION: VP were affected in MacTel2 eyes. VP did not correlate with BCVA. Occurrence of pigmentation is an important event in the progression of disease. AT may provide quantitative markers to measure disease progression.

Anti-retinal IgG antibodies in patients with early and advanced type 2 macular telangiectasia.

Type 2 idiopathic macular telangiectasia (MacTel-2) is a progressive adult-onset macular disease associated with bilateral perifoveal vascular changes, Muller cell degeneration and increased blood-retinal barrier permeability. The pathophysiological mechanisms of MacTel-2 remain unclear, however it was previously reported that anti-retinal antibodies in MacTel-2 patients are a significant feature of the disease. In this study, we aimed to compare the prevalence of anti-retinal antibodies in patients MacTel-2, healthy controls and patients with other retinal diseases. MacTel-2 patients diagnosed with multimodal imaging were enrolled and their disease severities were graded using spectral-domain optical coherence tomography. For comparison, patients with age-related macular degeneration (AMD), inherited retinal diseases (IRDs) or no retinal disease (healthy controls) were recruited as controls. Blood serum samples were screened for immunoglobulin G anti-retinal antibodies by western blotting, followed by densitometry analysis. Odds ratios (OR) with 95% confidence intervals (CI) were calculated and p < 0.05 considered statistically significant. Overall, anti-retinal antibody-positive cases were older (64 ± 15 vs 53 ± 17 years, p < 0.001) and females were more likely to develop anti-retinal antibodies (OR: 2.41, CI: 1.12-5.18). The frequency of anti-retinal antibody detection in MacTel-2 patients (n = 42, 36%) was not significantly different from healthy controls (n = 52, 25%) or IRD patients (n = 18, 25%) and the majority of MacTel-2 patients had no anti-retinal antibodies. In contrast, the frequency of anti-retinal antibody detection was significantly higher in patients with AMD (n = 15, 73%, p < 0.001). The lack of a greater anti-retinal antibody frequency or specificity in the MacTel-2 cohort suggests that antibody mediated immunological mechanisms may play a less significant role in MacTel-2 disease pathogenesis.

Transcriptional and Distributional Profiling of Microglia in Retinal Angiomatous Proliferation.

Macular neovascularization type 3, formerly known as retinal angiomatous proliferation (RAP), is a hallmark of age-related macular degeneration and is associated with an accumulation of myeloid cells, such as microglia (MG) and infiltrating blood-derived macrophages (MAC). However, the contribution of MG and MAC to the myeloid cell pool at RAP sites and their exact functions remain unknown. In this study, we combined a microglia-specific reporter mouse line with a mouse model for RAP to identify the contribution of MG and MAC to myeloid cell accumulation at RAP and determined the transcriptional profile of MG using RNA sequencing. We found that MG are the most abundant myeloid cell population around RAP, whereas MAC are rarely, if ever, associated with late stages of RAP. RNA sequencing of RAP-associated MG showed that differentially expressed genes mainly contribute to immune-associated processes, including chemotaxis and migration in early RAP and proliferative capacity in late RAP, which was confirmed by immunohistochemistry. Interestingly, MG upregulated only a few angiomodulatory factors, suggesting a rather low angiogenic potential. In summary, we showed that MG are the dominant myeloid cell population at RAP sites. Moreover, MG significantly altered their transcriptional profile during RAP formation, activating immune-associated processes and exhibiting enhanced proliferation, however, without showing substantial upregulation of angiomodulatory factors.

Macular telangiectasia type 2 in a patient with Down syndrome: A possible association.

Purpose: Down syndrome (DS) is one of the most prevalent genetic diseases associated with a variety of ophthalmic disorders, including reported retinal abnormalities. Macular telangiectasia type 2 (MacTel 2) is a late-onset neurodegenerative retinal disease with a substantial genetic component. We hereby describe a case of a female with DS who presented with MacTel 2, and we discuss the possible pathways associating both entities. Observation: We report the case of a 49-year-old female with a medical history of DS and hydroxychloroquine (HCQ) intake. She was referred for HCQ retinal toxicity screening. The multimodal imaging revealed a temporal perifoveal gray area with crystal deposits on multicolor fundoscopy with parafoveal outer retinal atrophy and ellipsoid zone loss with inner retinal cavitations in both eyes on the optical Coherence Tomography (OCT) B scan. The corresponding swept-source OCT angiography confirmed the presence of bilateral macular telangiectasia. Conclusion and importance: Metabolic pathways including serine/glycine and sphingolipids are incriminated in both entities' pathogenesis suggesting a possible association, hence, the importance of raising awareness of this association. More cases are likely to be found since DS patients currently have a nearly normal lifespan. Additional retinal examination of DS adults is then necessary to look for signs of MacTel 2.

Unraveling the mysteries of macular telangiectasia 2: the intersection of philanthropy, multimodal imaging and molecular genetics. The 2022 founders lecture of the pan American vitreoretinal society.

PURPOSE: Offer a personal perspective on the scientific advances on macular telangiectasia type 2 (MacTel2) since the launch of the MacTel Project in 2005. DESIGN: Literature review and personal perspective. METHODS: Critical review of the peer-reviewed literature and personal perspective. RESULTS: Generous financial support from the Lowy Medical Research Institute laid the foundations of the MacTel Project. MacTel Project investigators used state of the art multimodal retinal imaging and advanced modern biological methods to unravel many of the mysteries surrounding MacTel2. Major accomplishments includes elucidation of the pathogenic role that low serine levels, elevated 1-deoxysphingolipids and other mechanisms induce mitochondrial dysfunction which lead to Müller cell and photoreceptor degeneration; the use of objective measures of retinal structures such as the area of ellipsoid zone disruption as an outcome measure in clinical trials; the demonstration that the ciliary neurotrophic factor slows down retinal degeneration and the development of a new severity scale classification based on multimodal imaging findings. CONCLUSIONS: MacTel2 is a predominantly metabolic disease characterized by defects in energy metabolism. Despite relatively good visual acuities, MacTel2 patients experience significant visual disability. The Mac Tel Project has been instrumental in advancing MacTel2 knowledge in the past two decades.

Specific Deoxyceramide Species Correlate with Expression of Macular Telangiectasia Type 2 (MacTel2) in a SPTLC2 Carrier HSAN1 Family.

Hereditary sensory and autonomic neuropathy type 1 (HSAN1/HSN1) is a peripheral neuropathy most commonly associated with pathogenic variants in the serine palmitoyltransferase complex (SPTLC1, SPTLC2) genes, which are responsible for sphingolipid biosynthesis. Recent reports have shown that some HSAN1 patients also develop macular telangiectasia type 2 (MacTel2), a retinal neurodegeneration with an enigmatic pathogenesis and complex heritability. Here, we report a novel association of a SPTLC2 c.529A>G p.(Asn177Asp) variant with MacTel2 in a single member of a family that otherwise has multiple members afflicted with HSAN1. We provide correlative data to suggest that the variable penetrance of the HSAN1/MacTel2-overlap phenotype in the proband may be explained by levels of certain deoxyceramide species, which are aberrant intermediates of sphingolipid metabolism. We provide detailed retinal imaging of the proband and his HSAN1+/MacTel2- brothers and suggest mechanisms by which deoxyceramide levels may induce retinal degeneration. This is the first report of HSAN1 vs. HSAN1/MacTel2 overlap patients to comprehensively profile sphingolipid intermediates. The biochemical data here may help shed light on the pathoetiology and molecular mechanisms of MacTel2.

Multimodal imaging of macular telangiectasia type 2 in a pediatric patient.

PURPOSE: To describe findings of multimodal imaging in non-proliferative and proliferative stages of MacTel 2 in a pediatric patient, and results of aflibercept use for treating neovascularization secondary to MacTel 2. METHODS: Retrospective case report. RESULTS: An 11-year-old girl with no history of systemic disease. BCVA was 20/200 and 20/40 in the right and left eyes, respectively. FFA, SS-OCT and SS-OCTA revealed proliferative and non-proliferative stages of MacTel 2 in the right and left eyes, respectively. Intravitreal aflibercept (2mg/0.05mL) was started (PRN) in the right eye. The patient received 5 injections that led to involution of macular neovascularization and improvement of BCVA by 5 lines. BCVA in the left eye remained stable. CONCLUSION: MacTel 2 can develop in an earlier age than previously reported. SS-OCTA is an effective alternative to conventional imaging in diagnosis and follow-up especially in pediatric patients. Intravitreal aflibercept is effective in treating proliferative MacTel 2.