Methylation & Sulfation Studies

Am J Clin Nutr. 2004 Dec;80(6):1611-7.

Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children   with autism.

James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW, Neubrander JA. Department of Pediatrics, University of Arkansas for Medical Sciences, and the Arkansas Children’s   Hospital Research Institute, Little Rock, AR 72202, USA. [email protected] BACKGROUND: Autism is a complex neurodevelopmental disorder that usually presents in early childhood and that is thought to be influenced by genetic and environmental factors. Although abnormal metabolism of methionine and homocysteine has been associated   with other neurologic diseases, these pathways have not been evaluated in persons with autism. OBJECTIVE: The purpose of this study was to evaluate plasma concentrations of metabolites in the methionine transmethylation and transsulfuration pathways in children diagnosed with autism. DESIGN: Plasma concentrations of methionine, S-adenosylmethionine (SAM), S-adenosylhomocysteine   (SAH), adenosine, homocysteine, cystathionine, cysteine, and oxidized and reduced glutathione were measured   in 20 children with autism and in 33 control children. On the basis of the abnormal metabolic profile, a targeted nutritional intervention trial with folinic acid, betaine, and methylcobalamin was initiated in a subset of the autistic children. RESULTS: Relative to the control children, the children with autism had significantly lower baseline plasma concentrations of methionine, SAM, homocysteine, cystathionine, cysteine, and total glutathione and significantly higher concentrations of SAH, adenosine, and oxidized glutathione. This metabolic profile is consistent with impaired capacity for methylation (significantly lower ratio of SAM to SAH) and increased oxidative stress (significantly lower redox ratio of reduced glutathione to oxidized glutathione) in children with autism. The intervention trial was effective in normalizing the metabolic imbalance in the autistic children. CONCLUSIONS: An increased vulnerability to oxidative stress and a decreased capacity for   methylation may contribute to the development and clinical manifestation of autism. Abstract Biol Psychiatry. 1999 Aug 1;46(3):420-4.

Sulphation deficit in “low-functioning” autistic children: a pilot study.

Alberti A, Pirrone P, Elia M, Waring RH, Romano C. Department of Pediatrics, Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Troina,   Italy. BACKGROUND: Parents of autistic children and autism support groups often report that autistic episodes   are exacerbated when the children eat certain foodstuffs such as dairy products, chocolates, wheat, corn sugar, apples, and bananas. The hypothesis that autistic behavior might be related to metabolic dysfunctions has led us to investigate in a group of “low functioning” autistic children and in an age-matched control group each made up of 20 subjects, the sulphation capacity available. METHODS: Utilizing the biochemical characteristics of paracetamol we evaluated by high performance liquid chromatography, the urine paracetamol-sulfate/paracetamol-glucuronide (PS/PG) ratio in all subjects following administration of this drug. RESULTS: The PS/PG ratio in the group of autistic subjects gave a significantly lower results than the control group with p < .00002. CONCLUSIONS:   The inability to effectively metabolize certain compounds   particularly phenolic amines, toxic for the CNS, could exacerbate the wide spectrum of autistic behavior. Abstract Biochem J. 2004 Sep 15;382(Pt 3):831-40.

Betaine rescue of an animal model with methylenetetrahydrofolate reductase deficiency.

Schwahn BC, Laryea MD, Chen Z, Melnyk S, Pogribny I, Garrow T, James SJ, Rozen R. Department of Pediatrics, Human Genetics and Biology, McGill University-Montreal Children’s Hospital, Montreal, Canada. MTHFR (methylenetetrahydrofolate reductase) catalyses the synthesis of 5-methyltetrahydrofolate, the folate   derivative utilized in homocysteine remethylation to methionine. A severe deficiency of MTHFR results in hyperhomocysteinaemia and homocystinuria. Betaine supplementation has proven effective in ameliorating the biochemical abnormalities and the clinical course   in patients with this deficiency. Mice with a complete knockout of MTHFR serve as a good animal model for   homocystinuria; early postnatal death of these mice is common, as with some neonates with low residual   MTHFR activity. We attempted to rescue Mthfr-/- mice from postnatal death by betaine supplementation to   their mothers throughout pregnancy and lactation. Betaine decreased the mortality of Mthfr-/- mice   from 83% to 26% and significantly improved somatic development from postnatal day 1, compared with Mthfr-/-   mice from unsupplemented dams. Biochemical evaluations demonstrated higher availability of betaine in suckling   pups, decreased accumulation of homocysteine, and decreased flux through the trans-sulphuration pathway in liver and brain of Mthfr-/- pups from betaine-supplemented   dams. We observed disturbances in proliferation and   differentiation in the cerebellum and hippocampu  in the knockout mice; these changes were ameliorated   by betaine supplementation. The dramatic effects of betaine on survival and growth, and the partial reversibility of the biochemical and developmental anomalies in the brains of MTHFR-deficient mice, emphasize an important role for choline and betaine depletion in the pathogenesis of homocystinuria due to MTHFR deficiency. Abstract Lancet. 1992 Jan 4;339(8784):25-6.

Abnormal sulphur oxidation in systemic lupus erythematosus.

Gordon C, Bradley H, Waring RH, Emery P. Department of Rheumatology, University of Birmingham,   UK. S-carboxy-L-methylcysteine was used to assess the   activity of the S-oxidation pathway of sulphur metabolism   in 35 patients with systemic lupus erythematosus   (SLE); 25 (71%) showed impaired sulphoxidation and   21 (60%) produced virtually no sulphoxides, compared   with 17 (36%) and 2 (4%), respectively, of 47 healthy   controls. The substrate/product ratio of cysteine   oxygenase (plasma cysteine/sulphate) was significantly   higher in SLE patients than in controls (median [interquartile   range] 362 [224-588] vs 65 [44-111]; p less than   0.00001). The alternative pathway of sulphur metabolism,   S-methylation, catalysed by thiolmethyltransferase,   was not impaired in the SLE patients. There is a   biochemical difference in sulphur metabolism between   SLE and rheumatoid arthritis, since both pathways   are impaired in the latter disorder. Abstract Toxicol Lett. 2003 Nov 30;145(2):167-74.

Effects of dietary folate intake and folate binding protein-1 (Folbp1) on urinary speciation of sodium arsenate in mice.

Spiegelstein O, Lu X, Le XC, Troen A, Selhub J, Melnyk S, James SJ, Finnell RH. Center for Environmental and Genetic Medicine, Institute   of Biosciences and Technology, Texas A&M University   System Health Science Center, 77030, Houston, TX,   USA. [email protected] In most mammalian species, arsenic biotransformation   occurs primarily by biomethylation with dimethylarsinic   acid being the predominant metabolite excreted in   the urine. Folbp1 (folate binding protein-1) mediated   intracellular folate uptake is one route by which   cells harvest folate cofactors. In light of the likely   relationship between folate biochemistry and arsenic   biotransformation, our experiments were designed   to test: (1) whether Folbp1 is an important determinant   in arsenic biotransformation, by performing urinary   arsenic speciation in Folbp1 nullizygous (Folbp1(-/-))   and wildtype control mice, and (2) whether dietary   folate deficiency alters arsenic biotransformation   in these mice. Compared to normal folate intake,   folate deficiency caused lower amounts of arsenic   to be excreted in the urine of both the wildtype   controls and Folbp1(-/-) mice. Folbp1(-/-) mice excreted   more dimethylarsinic acid than wildtype control mice   during folate deficiency, but not during normal folate   intake. The present data suggest that inadequate   folate intake may result in decreased biotransformation   and excretion of arsenic, which is likely to increase   arsenic exposure and related toxicities. Abstract Am J Clin Nutr. 2004 Dec;80(6):1611-7.

Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children     with autism.

James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW, Neubrander JA. Department of Pediatrics, University of Arkansas   for Medical Sciences, and the Arkansas Children’s   Hospital Research Institute, Little Rock, AR 72202,   USA. [email protected] BACKGROUND: Autism is a complex neurodevelopmental   disorder that usually presents in early childhood   and that is thought to be influenced by genetic and   environmental factors. Although abnormal metabolism   of methionine and homocysteine has been associated   with other neurologic diseases, these pathways have   not been evaluated in persons with autism. OBJECTIVE:   The purpose of this study was to evaluate plasma   concentrations of metabolites in the methionine transmethylation   and transsulfuration pathways in children diagnosed   with autism. DESIGN: Plasma concentrations of methionine,   S-adenosylmethionine (SAM), S-adenosylhomocysteine   (SAH), adenosine, homocysteine, cystathionine, cysteine,   and oxidized and reduced glutathione were measured   in 20 children with autism and in 33 control children.   On the basis of the abnormal metabolic profile, a   targeted nutritional intervention trial with folinic   acid, betaine, and methylcobalamin was initiated   in a subset of the autistic children. RESULTS: Relative   to the control children, the children with autism   had significantly lower baseline plasma concentrations   of methionine, SAM, homocysteine, cystathionine,   cysteine, and total glutathione and significantly   higher concentrations of SAH, adenosine, and oxidized   glutathione. This metabolic profile is consistent   with impaired capacity for methylation (significantly   lower ratio of SAM to SAH) and increased oxidative   stress (significantly lower redox ratio of reduced   glutathione to oxidized glutathione) in children   with autism. The intervention trial was effective   in normalizing the metabolic imbalance in the autistic   children. CONCLUSIONS: An increased vulnerability   to oxidative stress and a decreased capacity for   methylation may contribute to the development and   clinical manifestation of autism. Abstract