Charles Zucker ^1* Paul S. Bernstein ^2* Richard Schalek ¹ Jeff Lichtman ¹ John E. Dowling ^1*

• ¹ Harvard University, Cambridge, United States
• ² John A. Moran Eye Center, College of Health, University of Utah, Salt Lake City, Utah, United States

Macular Telangiectasia type 2 (MacTel), is an uncommon form of late-onset, slowly-progressive macular degeneration. Associated with regional Müller glial cell loss in the retina and the amino acid serine synthesized by Müller cells, the disease is functionally confined to a central retinal region -the MacTel zone. We have used high-throughput multi-resolution electron microscopy techniques, optimized for disease analysis, to study the retinas from two women, mother and daughter, aged 79 and 48 years respectively, suffering from MacTel. In both eyes, the principle observations made were changes specific to mitochondrial structure both outside and within the MacTel zone in all retinal cell types, with the exception of those in the retinal pigment epithelium (RPE). The lesion areas, which are a hallmark of MacTel, extend from Bruch's membrane and the choriocapillaris, through all depths of the retina, and include cells from the RPE, retinal vascular elements, and extensive hypertrophic basement membrane material. Where the Müller glial cells are lost, we have identified a significant population of microglial cells, exclusively within the Henle fiber layer, which appear to ensheath the Henle fibers, similar to that seen normally often replace the ensheathment normally provided by the Müller cells. Since Müller cells synthesize retinal serine, whereas retinal neurons do not, we propose that serine deficiency, required for normal mitochondrial function, causes may relate to mitochondrial changes that underlie the development of MacTel. With mitochondrial changes occurring retina-wide, the question remains as to why the Müller cells are uniquely susceptible within the MacTel zone.