[Type 2 Macular Telangiectasia: Pathogenesis-The Interplay Between Neurodegeneration and Metabolic Changes]

Macular telangiectasia type 2 (MacTel type 2) is a rare, chronic neurodegenerative macular disease that typically occurs bilaterally in the second half of life. Patients report paracentral scotomas and reading difficulties early in the disease course. Over time, limitations in daily life progressively increase.

Although the macular vascular changes give the condition its name, MacTel type 2 is now considered a primarily neurodegenerative disease with secondary vascular changes. In a small number of patients (<5%), the disease can be causally attributed to mutations in serine metabolism. Genetic defects in serine biosynthesis should in many cases be understood more as a type of risk factor, without these genomic alterations necessarily being present in every affected individual. Furthermore, the prevalence of type 2 diabetes mellitus is significantly higher in MacTel patients than in the healthy general population.

Pathomechanistically, reduced serine levels lead to aberrant sphingolipid synthesis with the accumulation of neurotoxic deoxysphingolipids. This leads to degeneration of Müller cells, the retinal pigment epithelium, and photoreceptors, culminating in a breakdown of the blood-retinal barrier with secondary vascular changes. Neurodegeneration remains confined to a circumscribed area around the fovea, the MacTel zone.

Therapeutically, the only established treatment in Europe at present is for secondary choroidal neovascularization, using intravitreal anti-VEGF therapy. A neuroprotective therapeutic approach, in which a novel cell-based depot system continuously releases ciliary neurotrophic factor, thereby slowing down photoreceptor degeneration, is currently approved only in the U.S. Complementary strategies to slow the underlying disease progression are urgently needed. In animal models, oral serine supplementation has been shown to slow neurodegeneration. Phase 2 and 3 clinical trials in humans are already underway, although they have not yet fully completed (ClinicalTrials.gov: NCT04907084).