• Marin L Gantner, Kevin Eade, Martina Wallace, Michal K Handzlik, Regis Fallon, Jennifer Trombley, Roberto Bonelli, Sarah Giles, Sarah Harkins-Perry, Tjebo F C Heeren, Lydia Sauer, Yoichiro Ideguchi, Michelle Baldini, Lea Scheppke, Michael I Dorrell, Maki Kitano, Barbara J Hart, Carolyn Cai, Takayuki Nagasaki, Mehmet G Badur, Mali Okada, Sasha M Woods, Catherine Egan, Mark Gillies, Robyn Guymer, Florian Eichler, Melanie Bahlo, Marcus Fruttiger, Rando Allikmets, Paul S Bernstein, Christian M Metallo, and Martin Friedlander.
• From the Lowy Medical Research Institute (M.L.G., K.E., R.F., J.T., S.G., S.H.-P., Y.I., L. Scheppke, M.I.D., M.K., M. Friedlander), University of California, San Diego (M.W., M.K.H., M. Baldini, M.G.B., C.M.M.), Scripps Research Institute (S.H.-P., Y.I., M.K., M. Friedlander), and Scripps Clinic Medical Group (M. Friedlander), La Jolla, and Point Loma Nazarene University, San Diego (M.I.D.) - all in California; Moran Eye Center, University of Utah, Salt Lake City (L. Sauer, B.J.H., P.S.B.); Moorfields Eye Hospital (T.F.C.H., C.E.) and University College London Institute of Ophthalmology (S.M.W., M. Fruttiger), London; Columbia University, New York (C.C., T.N., R.A.); Walter and Eliza Hall Institute of Medical Research, Parkville, VIC (R.B., M. Bahlo), Royal Victorian Eye and Ear Hospital (M.O.) and University of Melbourne Centre for Eye Research (R.G.), Melbourne, VIC, and the Save Sight Institute, University of Sydney, Sydney (M.G.) - all in Australia; and Massachusetts General Hospital, Boston (F.E.).
• N. Engl. J. Med. 2019 Oct 10; 381 (15): 1422-1433.

BackgroundIdentifying 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.MethodsThrough 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.ResultsTwo 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.ConclusionsElevated 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.).Copyright © 2019 Massachusetts Medical Society.

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