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.

Imaging techniques based on retinal autofluorescence have found broad applications in ophthalmology because they are extremely sensitive and noninvasive. Conventional fundus autofluorescence imaging measures fluorescence intensity of endogenous retinal fluorophores. It mainly derives its signal from lipofuscin at the level of the retinal pigment epithelium. Fundus autofluorescence, however, can not only be characterized by the spatial distribution of the fluorescence intensity or emission spectrum, but also by a characteristic fluorescence lifetime function. The fluorescence lifetime is the average amount of time a fluorophore remains in the excited state following excitation. Fluorescence lifetime imaging ophthalmoscopy (FLIO) is an emerging imaging modality for in vivo measurement of lifetimes of endogenous retinal fluorophores. Recent reports in this field have contributed to our understanding of the pathophysiology of various macular and retinal diseases. Within this review, the basic concept of fluorescence lifetime imaging is provided. It includes technical background information and correlation with in vitro measurements of individual retinal metabolites. In a second part, clinical applications of fluorescence lifetime imaging and fluorescence lifetime features of selected retinal diseases such as Stargardt disease, age-related macular degeneration, choroideremia, central serous chorioretinopathy, macular holes, diabetic retinopathy, and retinal artery occlusion are discussed. Potential areas of use for fluorescence lifetime imaging ophthalmoscopy will be outlined at the end of this review.

Macular pigment, which is known to have very short fluorescence decays, considerably contributes to the macular autofluorescence (AF). This study gives indirect evidence for a strong impact of MP on macular τm, although no direct measurement of MP autofluorescence lifetimes in vivo is possible at this point. Potentially, imaging the FAF lifetimes could lead to a novel methodology for the detection of macular pigment properties and pathology-induced changes in the living human retina.

PurposeTo investigate fundus autofluorescence (FAF) lifetimes in patients with nonexudative AMD.MethodsA total of 150 eyes of 110 patients (mean age: 73.2 ± 10.7 years) with nonexudative AMD, as well as a healthy group of 57 eyes in 38 subjects (mean age: 66.5 ± 8.7 years), were included. Investigations were conducted at the University Eye Clinic in Jena, Germany, as well as the Moran Eye Center in Salt Lake City, Utah, USA, using the Heidelberg Engineering Spectralis-based fluorescence lifetime imaging ophthalmoscope (FLIO). A 30° retinal field centered at the fovea was investigated. FAF decays were detected in short (498–560 nm) and long (560–720 nm, LSC) spectral channels. The mean fluorescence lifetimes (τm) were calculated. Optical coherence tomography scans and fundus photographs were also recorded.ResultsIn patients with nonexudative AMD, FLIO shows a ring-shaped pattern of prolonged τm in the LSC. This pattern occurs in all patients with AMD (including very early stages) and in one-third of the healthy controls. FAF lifetimes were longer with more advanced stages. The presence of drusen is associated with prolonged τm when compared with the healthy fundus, but drusen identification is difficult with FLIO only.ConclusionsFLIO detects a clear pattern of changes within the fundus, which appears to be AMD-associated. These changes are already visible in early AMD stages and not masked by the presence of other coexisting retinal diseases. These findings may be useful for the early diagnosis of AMD and to distinguish AMD from other retinal diseases.