Abnormal transmethylation/transsulfuration metabolism and DNA hypomethylation among parents of children with autism

Abstract

An integrated metabolic profile reflects the combined influence of genetic, epigenetic, and environmental factors that affect the candidate pathway of interest. Recent evidence suggests that some autistic children may have reduced detoxification capacity and may be under chronic oxidative stress. Based on reports of abnormal methionine and glutathione metabolism in autistic children, it was of interest to examine the same metabolic profile in the parents. The results indicated that parents share similar metabolic deficits in methylation capacity and glutathione-dependent antioxidant/detoxification capacity observed in many autistic children. Studies are underway to determine whether the abnormal profile in parents reflects linked genetic polymorphisms in these pathways or whether it simply reflects the chronic stress of coping with an autistic child.

Figure 1

A diagram of tetrahydrofolate (THF)-dependent methionine transmethylation and glutathione synthesis. The methionine cycle (transmethylation) involves the regeneration of methionine from homocysteine via the B12-dependent transfer of a methyl group from 5-methyl-tetrahydrofolate (5-CH₃THF) via the methionine synthase (MS) reaction. Methionine is then activated to S-adenosylmethionine (SAM), the methyl donor for multiple cellular methyltransferase (MTase) reactions and the methylation of essential molecules such as DNA, RNA, proteins, phospholipids, creatine, and neurotransmittors. The transfer of the methyl group from SAM results in the demethylated product S-adenosylhomocysteine (SAH). The reversible hydrolysis of SAH to homocysteine and adenosine by the SAH hydrolase (SAHH) reaction completes the methionine cycle. Homocysteine can then be either remethylated to methionine or irreversibly removed from the methionine cycle by cystathionine beta synthase (CBS). This is a one-way reaction that permanently removes homocysteine from the methionine cycle and initiates the transsulfuration pathway for the synthesis of cysteine and glutathione. Glutathione is shown in its active reduced form (GSH) and inactive oxidized disulfide form (GSSG).

Figure 2

A. A scatterplot showing the correlation between plasma levels of SAH and the ratio of SAM/SAH among the case parents indicating that the SAM/SAH ratio is primarily driven by the concentration of SAH. B. A scatterplot showing the strong correlation between free and total plasma glutathione levels among case parents. C. A scatterplot showing the correlation between plasma SAH levels and DNA hypomethylation (% 5-methylcytosine/total cytosine in DNA).