Clinical histopathology and pathogenesis of macular telangiectasia type 2.

Abstract

Macular telangiectasia type 2 (MacTel) is a rare neurodegenerative retinal disease defined by a unique combination of reduced macular pigment, a characteristic angiographic pattern, and a localized clinical presentation. The condition typically affects the temporal perifovea and leads to progressive visual impairment. No definitive treatment exists. Current management is limited to intravitreal anti-vascular endothelial growth factor (VEGF) injections for end-stage neovascular complications and the recently approved Encelto implant (Neurotech Pharmaceuticals, Inc.), which delivers ciliary neurotrophic factor (CNTF) for neuroprotection. To clarify the still enigmatic pathophysiology of MacTel, we conducted a comprehensive review of all human histopathology reports published in English through December 31, 2024. Findings were systematically evaluated with respect to tissue processing techniques, postmortem fixation times, disease stage at last recorded ophthalmologic evaluation, diagnostic certainty, inclusion of control specimens, and the anatomic origin of analyzed retinal sections. This approach aimed to identify histopathologic features most likely to represent core disease mechanisms. Each of the features identified as most likely to be pathophysiologically relevant was independently assessed for clinical and histopathologic specificity. These features were then further interpreted in the context of genetic, metabolic, and anatomic associations reported in the literature. Donor demographics, coexisting ocular conditions, and systemic comorbidities were also reviewed to support the development of an integrative hypothesis for MacTel pathogenesis. Drawing on this synthesis, we propose a histopathology-informed model of disease pathophysiology and outline a provisional timeline for the contribution of key factors to clinical expression. We also review current neuroprotective strategies and provide targeted recommendations for future therapeutic development and histopathologic research. The conceptual framework developed in this work -grounded in rigorous analysis of the most consistent and methodologically validated histopathologic findings, and interpretation of their mechanistic context- may serve as a model for deciphering rare retinal diseases and for generating focused, hypothesis-driven questions to guide future investigation.