Methylation-associated pathways in Macular Telangiectasia Type 2 and ophthalmologic findings in patients with genetic methylation disorders

Abstract

Purpose: Serine (Ser) and glycine (Gly) levels were reported to differ between Macular telangiectasia type 2 (MacTel) patients compared to healthy controls. Since they are closely related to methylation metabolism, this report investigates methylation-associated metabolite (MAM) levels in MacTel patients and retinal changes in monogenetic methylation disorders. Methods: Prospective, monocentric study on MacTel patients and healthy controls the underwent a standardized protocol including a blood draw. MAM levels in plasma were determined using targeted quantitative metabolomics. Furthermore, patient records of cystathionine beta-synthase (CBS), methylenetetrahydrofolate reductase (MTHFR), and cobalamin C (MMACHC) deficiency were screened for reported retinal changes. Results: In total, 29 MacTel patients and 27 healthy controls were included. MacTel patients showed lower plasma Ser (p = 0.02 and p = 0.01) and Gly (p= 0.11 and p = 0.11) levels than controls. Principal component analyses revealed that MAM, especially homocysteine, contributed to a distinct clustering of MacTel patients. No retinal changes were seen in CBS (n=1) and MTHFR (n=2) deficiency, while two patients with MMACHC (n=4) deficiency displayed extensive macular dystrophy. Conclusions: MacTel patients show distinct clustering of MAM compared to controls. Of the three homocystinurias, only MMACHC resulted in macular dystrophy, possibly due to distinct compensatory pathways.