J Int Med Res. 2026 Aug;54(8):3000605261473180. doi: 10.1177/03000605261473180. Epub 2026 Aug 4.
ABSTRACT
Macular telangiectasia type 2 is a genetically complex disorder with variable penetrance and expressivity. Although several causative genes have been identified, the genetic basis remains unknown in most affected individuals. Genetic and metabolomic studies have implicated dysregulated serine and lipid metabolism in disease pathogenesis. Serine deficiency promotes the accumulation of cytotoxic 1-deoxysphingolipids, which damage Müller cells, photoreceptors, and retinal pigment epithelium. Emerging evidence suggests that the retinal pigment epithelium plays a more important role in disease development than previously recognized. Macular telangiectasia type 2 has traditionally been considered a primary neurodegenerative disorder with secondary vascular abnormalities. However, optical coherence tomography angiography findings have indicated that vascular changes may occur earlier than previously appreciated and may develop in parallel with neurodegeneration rather than as a secondary consequence. Furthermore, there is a strong structure-function correlation between ellipsoid zone loss on optical coherence tomography and retinal sensitivity measured using microperimetry. This relationship supported the acceptance by the US Food and Drug Administration of ellipsoid zone loss area, a structural surrogate endpoint, for the approval of the ciliary neurotrophic factor implant (revakinagene taroretcel-Lwey) in macular telangiectasia type 2 patients. Several therapeutic strategies targeting the underlying metabolic abnormalities are also under investigation. These include serine supplementation, fenofibrate to reduce 1-deoxysphingolipid production, and gene replacement therapy. In addition, growing evidence suggests that mitochondrial dysfunction and impaired cellular energy metabolism contribute to disease pathogenesis and warrant further investigation as potential therapeutic targets.
PMID:42551495 | DOI:10.1177/03000605261473180