Congratulations on your New England Journal of Medicine - Dr. Christian Metallo
Indentifying 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 matabolism has been established previously. Through exome aequewnce 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 ophtalmologic 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 rentinal organoids.
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. https://www.nejm.org/