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

PURPOSE: Serine (Ser) and glycine (Gly) levels were reported to differ between patients with macular telangiectasia type 2 (MacTel) compared with healthy controls. Because they are closely related to methylation metabolism, this report investigates methylation-associated metabolite levels in patients with MacTel and retinal changes in monogenetic methylation disorders.

METHODS: Prospective, monocentric study on patients with MacTel and healthy controls underwent a standardized protocol including a blood draw. Methylation-associated metabolite levels in plasma were determined using targeted quantitative metabolomics. Furthermore, patient records of cystathionine beta-synthase, methylenetetrahydrofolate reductase, and methylmalonic aciduria and homocystinuria type C protein (MMACHC) deficiency were screened for reported retinal changes.

RESULTS: In total, 29 patients with MacTel and 27 healthy controls were included. Patients with MacTel 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 methylation-associated metabolite, especially homocysteine, contributed to a distinct clustering of patients with MacTel. No retinal changes were seen in cystathionine beta-synthase (n = 1) and methylenetetrahydrofolate reductase (n = 2) deficiency, while two patients with MMACHC (n = 4) deficiency displayed extensive macular dystrophy.

CONCLUSION: Patients with MacTel show distinct clustering of methylation-associated metabolite compared with controls. Of the three homocystinurias, only MMACHC resulted in macular dystrophy, possibly due to distinct compensatory pathways.