Methylation and Sulfation Research

 

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. jamesjill@uams.edu

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 hippocampus 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. ospiegelstein@ibt.tamu.edu

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. jamesjill@uams.edu

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

 
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