Skip to main content
Top
Published in: BMC Pediatrics 1/2020

Open Access 01-12-2020 | Autism Spectrum Disorder | Research article

Altered metabolism of mothers of young children with Autism Spectrum Disorder: a case control study

Authors: Kathryn Hollowood-Jones, James B. Adams, Devon M. Coleman, Sivapriya Ramamoorthy, Stepan Melnyk, S. Jill James, Bryan K. Woodruff, Elena L. Pollard, Christine L. Snozek, Uwe Kruger, Joshua Chuah, Juergen Hahn

Published in: BMC Pediatrics | Issue 1/2020

Login to get access

Abstract

Background

Previous research studies have demonstrated abnormalities in the metabolism of mothers of young children with autism.

Methods

Metabolic analysis was performed on blood samples from 30 mothers of young children with Autism Spectrum Disorder (ASD-M) and from 29 mothers of young typically-developing children (TD-M). Targeted metabolic analysis focusing on the folate one-carbon metabolism (FOCM) and the transsulfuration pathway (TS) as well as broad metabolic analysis were performed. Statistical analysis of the data involved both univariate and multivariate statistical methods.

Results

Univariate analysis revealed significant differences in 5 metabolites from the folate one-carbon metabolism and the transsulfuration pathway and differences in an additional 48 metabolites identified by broad metabolic analysis, including lower levels of many carnitine-conjugated molecules.
Multivariate analysis with leave-one-out cross-validation allowed classification of samples as belonging to one of the two groups of mothers with 93% sensitivity and 97% specificity with five metabolites. Furthermore, each of these five metabolites correlated with 8–15 other metabolites indicating that there are five clusters of correlated metabolites. In fact, all but 5 of the 50 metabolites with the highest area under the receiver operating characteristic curve were associated with the five identified groups. Many of the abnormalities appear linked to low levels of folate, vitamin B12, and carnitine-conjugated molecules.

Conclusions

Mothers of children with ASD have many significantly different metabolite levels compared to mothers of typically developing children at 2–5 years after birth.
Appendix
Available only for authorised users
Literature
1.
go back to reference American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Washington, D.C.: American Psychiatric Association; 2013.CrossRef American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Washington, D.C.: American Psychiatric Association; 2013.CrossRef
2.
go back to reference James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW, et al. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr. 2004;80(6):1611–7.CrossRef James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW, et al. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr. 2004;80(6):1611–7.CrossRef
3.
go back to reference Adams JB, Audhya T, McDonough-Means S, Rubin RA, Quig D, Geis E, et al. Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autism severity. Nutr Metab (Lond). 2011;8:34.CrossRef Adams JB, Audhya T, McDonough-Means S, Rubin RA, Quig D, Geis E, et al. Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autism severity. Nutr Metab (Lond). 2011;8:34.CrossRef
4.
go back to reference Howsmon DP, Kruger U, Melnyk S, James SJ, Hahn J. Classification and adaptive behavior prediction of children with autism spectrum disorder based upon multivariate data analysis of markers of oxidative stress and DNA methylation. PLoS Comput Biol. 2017;13(3):e1005385.CrossRef Howsmon DP, Kruger U, Melnyk S, James SJ, Hahn J. Classification and adaptive behavior prediction of children with autism spectrum disorder based upon multivariate data analysis of markers of oxidative stress and DNA methylation. PLoS Comput Biol. 2017;13(3):e1005385.CrossRef
5.
go back to reference Howsmon DP, Vargason T, Rubin RA, Delhey L, Tippett M, Rose S, et al. Multivariate techniques enable a biochemical classification of children with autism spectrum disorder versus typically-developing peers: a comparison and validation study. Bioeng Transl Med. 2018;3(2):156–65.CrossRef Howsmon DP, Vargason T, Rubin RA, Delhey L, Tippett M, Rose S, et al. Multivariate techniques enable a biochemical classification of children with autism spectrum disorder versus typically-developing peers: a comparison and validation study. Bioeng Transl Med. 2018;3(2):156–65.CrossRef
6.
go back to reference James SJ, Melnyk S, Jernigan S, Hubanks A, Rose S, Gaylor DW. Abnormal Transmethylation/transsulfuration metabolism and DNA Hypomethylation among parents of children with autism. J Autism Dev Disord. 2008;38(10):1966–75.CrossRef James SJ, Melnyk S, Jernigan S, Hubanks A, Rose S, Gaylor DW. Abnormal Transmethylation/transsulfuration metabolism and DNA Hypomethylation among parents of children with autism. J Autism Dev Disord. 2008;38(10):1966–75.CrossRef
7.
go back to reference James SJ, Melnyk S, Jernigan S, Pavliv O, Trusty T, Lehman S, et al. A functional polymorphism in the reduced FolateCarrier gene and DNA Hypomethylation in mothers ofChildren with autism. Am J Med Genet. 2010;153B(6):1209–20.PubMed James SJ, Melnyk S, Jernigan S, Pavliv O, Trusty T, Lehman S, et al. A functional polymorphism in the reduced FolateCarrier gene and DNA Hypomethylation in mothers ofChildren with autism. Am J Med Genet. 2010;153B(6):1209–20.PubMed
8.
go back to reference Hollowood K, Melnyk S, Pavliv O, Evans T, Sides A, Schmidt RJ, et al. Maternal metabolic profile predicts high or low risk of an autism pregnancy outcome. Res Autism Spectr Disord. 2018;56:72–82.CrossRef Hollowood K, Melnyk S, Pavliv O, Evans T, Sides A, Schmidt RJ, et al. Maternal metabolic profile predicts high or low risk of an autism pregnancy outcome. Res Autism Spectr Disord. 2018;56:72–82.CrossRef
9.
go back to reference Boris M, Galanko J. Association of MTHFR Gene Variants with Autism 2004;9(4):3. Boris M, Galanko J. Association of MTHFR Gene Variants with Autism 2004;9(4):3.
10.
11.
go back to reference Raghavan R, Riley AW, Volk H, Caruso D, Hironaka L, Sices L, et al. Maternal multivitamin intake, plasma Folate and vitamin B12 levels and autism Spectrum disorder risk in offspring. Paediatr Perinat Epidemiol. 2018;32(1):100–11.CrossRef Raghavan R, Riley AW, Volk H, Caruso D, Hironaka L, Sices L, et al. Maternal multivitamin intake, plasma Folate and vitamin B12 levels and autism Spectrum disorder risk in offspring. Paediatr Perinat Epidemiol. 2018;32(1):100–11.CrossRef
13.
go back to reference Schmidt RJ, Hansen RL, Hartiala J, Allayee H, Schmidt LC, Tancredi DJ, et al. Prenatal vitamins, one-carbon metabolism gene variants, and risk for autism. Epidemiology. 2011;22(4):476–85.CrossRef Schmidt RJ, Hansen RL, Hartiala J, Allayee H, Schmidt LC, Tancredi DJ, et al. Prenatal vitamins, one-carbon metabolism gene variants, and risk for autism. Epidemiology. 2011;22(4):476–85.CrossRef
14.
go back to reference Schmidt RJ, Tancredi DJ, Ozonoff S, Hansen RL, Hartiala J, Allayee H, et al. Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood autism risks from genetics and environment) case-control study123. Am J Clin Nutr. 2012;96(1):80–9.CrossRef Schmidt RJ, Tancredi DJ, Ozonoff S, Hansen RL, Hartiala J, Allayee H, et al. Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood autism risks from genetics and environment) case-control study123. Am J Clin Nutr. 2012;96(1):80–9.CrossRef
16.
go back to reference Ozonoff S, Young GS, Carter A, Messinger D, Yirmiya N, Zwaigenbaum L, et al. Recurrence risk for autism Spectrum disorders: a baby siblings research consortium study. Pediatrics. 2011;128(3):e488–95.PubMedPubMedCentral Ozonoff S, Young GS, Carter A, Messinger D, Yirmiya N, Zwaigenbaum L, et al. Recurrence risk for autism Spectrum disorders: a baby siblings research consortium study. Pediatrics. 2011;128(3):e488–95.PubMedPubMedCentral
17.
go back to reference Lord C, Rutter M, Le Couteur A. Autism diagnostic interview-revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord. 1994;24(5):659–85.CrossRef Lord C, Rutter M, Le Couteur A. Autism diagnostic interview-revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord. 1994;24(5):659–85.CrossRef
18.
go back to reference Melnyk S, Pogribna M, Pogribny IP, Yi P, James SJ. Measurement of plasma and intracellular S-adenosylmethionine and S-adenosylhomocysteine utilizing coulometric electrochemical detection: alterations with plasma homocysteine and pyridoxal 5′-phosphate concentrations. Clin Chem. 2000;46(2):265–72.CrossRef Melnyk S, Pogribna M, Pogribny IP, Yi P, James SJ. Measurement of plasma and intracellular S-adenosylmethionine and S-adenosylhomocysteine utilizing coulometric electrochemical detection: alterations with plasma homocysteine and pyridoxal 5′-phosphate concentrations. Clin Chem. 2000;46(2):265–72.CrossRef
19.
go back to reference Melnyk S, Pogribna M, Pogribny I, Hine RJ, James SJ. A new HPLC method for the simultaneous determination of oxidized and reduced plasma aminothiols using coulometric electrochemical detection. J Nutr Biochem. 1999;10(8):490–7.CrossRef Melnyk S, Pogribna M, Pogribny I, Hine RJ, James SJ. A new HPLC method for the simultaneous determination of oxidized and reduced plasma aminothiols using coulometric electrochemical detection. J Nutr Biochem. 1999;10(8):490–7.CrossRef
20.
go back to reference Collet T-H, Sonoyama T, Henning E, Keogh JM, Ingram B, Kelway S, et al. A Metabolomic signature of acute caloric restriction. J Clin Endocrinol Metab. 2017;102(12):4486–95.CrossRef Collet T-H, Sonoyama T, Henning E, Keogh JM, Ingram B, Kelway S, et al. A Metabolomic signature of acute caloric restriction. J Clin Endocrinol Metab. 2017;102(12):4486–95.CrossRef
21.
go back to reference Evans AM, Br B, Liu Q, Mitchell MW, Rj R, Dai H, et al. High Resolution Mass Spectrometry Improves Data Quantity and Quality as Compared to Unit Mass Resolution Mass Spectrometry in High- Throughput Profiling Metabolomics. 2014;. Evans AM, Br B, Liu Q, Mitchell MW, Rj R, Dai H, et al. High Resolution Mass Spectrometry Improves Data Quantity and Quality as Compared to Unit Mass Resolution Mass Spectrometry in High- Throughput Profiling Metabolomics. 2014;.
22.
go back to reference DeHaven CD, Evans AM, Dai H, Lawton KA. Organization of GC/MS and LC/MS metabolomics data into chemical libraries. Aust J Chem. 2010;2(1):9. DeHaven CD, Evans AM, Dai H, Lawton KA. Organization of GC/MS and LC/MS metabolomics data into chemical libraries. Aust J Chem. 2010;2(1):9.
23.
go back to reference Anderson TW, Darling DA. A test of goodness of fit. J Am Stat Assoc. 1954;49(268):765.CrossRef Anderson TW, Darling DA. A test of goodness of fit. J Am Stat Assoc. 1954;49(268):765.CrossRef
24.
go back to reference Massey FJ. The Kolmogorov-Smirnov test for goodness of fit. J Am Stat Assoc. 1951;46(253):68.CrossRef Massey FJ. The Kolmogorov-Smirnov test for goodness of fit. J Am Stat Assoc. 1951;46(253):68.CrossRef
25.
go back to reference Welch BL. The generalization of `Student’s’ problem when several different population variances are involved. Biometrika. 1947;34(1/2):28–35.CrossRef Welch BL. The generalization of `Student’s’ problem when several different population variances are involved. Biometrika. 1947;34(1/2):28–35.CrossRef
26.
go back to reference Mann HB, Whitney DR. On a test of whether one of two random variables is stochastically larger than the other. Ann Math Stat. 1947:50–60. Mann HB, Whitney DR. On a test of whether one of two random variables is stochastically larger than the other. Ann Math Stat. 1947:50–60.
27.
go back to reference F.R.S KP. X. On the criterion that a given system of deviations from the probable in the case of a correlated system of variables is such that it can be reasonably supposed to have arisen from random sampling. London Edinb Dublin Philos Mag J Sci. 1900;50(302):157–75.CrossRef F.R.S KP. X. On the criterion that a given system of deviations from the probable in the case of a correlated system of variables is such that it can be reasonably supposed to have arisen from random sampling. London Edinb Dublin Philos Mag J Sci. 1900;50(302):157–75.CrossRef
28.
go back to reference Storey JD. A direct approach to false discovery rates. J R Stat Soc. 2002;64(3):479–98.CrossRef Storey JD. A direct approach to false discovery rates. J R Stat Soc. 2002;64(3):479–98.CrossRef
29.
go back to reference Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology. 1982;143(1):29–36.CrossRef Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology. 1982;143(1):29–36.CrossRef
30.
go back to reference Fisher R. The use of multiple measurements in taxonomic problems. Ann Eugenics. 1936;7(2):179–88.CrossRef Fisher R. The use of multiple measurements in taxonomic problems. Ann Eugenics. 1936;7(2):179–88.CrossRef
31.
go back to reference Sperandei S. Understanding logistic regression analysis. Biochem Med (Zagreb). 2014;24(1):12–8.CrossRef Sperandei S. Understanding logistic regression analysis. Biochem Med (Zagreb). 2014;24(1):12–8.CrossRef
32.
go back to reference Kohavi R. A Study of Cross-validation and Bootstrap for Accuracy Estimation and Model Selection. In: Proceedings of the 14th International Joint Conference on Artificial Intelligence - Volume 2 [Internet]. San Francisco: Morgan Kaufmann Publishers Inc.; 1995. p. 1137–43. (IJCAI’95). Available from: http://dl.acm.org/citation.cfm?id=1643031.1643047, [cited 2018 May 1]. Kohavi R. A Study of Cross-validation and Bootstrap for Accuracy Estimation and Model Selection. In: Proceedings of the 14th International Joint Conference on Artificial Intelligence - Volume 2 [Internet]. San Francisco: Morgan Kaufmann Publishers Inc.; 1995. p. 1137–43. (IJCAI’95). Available from: http://​dl.​acm.​org/​citation.​cfm?​id=​1643031.​1643047, [cited 2018 May 1].
33.
go back to reference Wang M, Li K, Zhao D, Li L. The association between maternal use of folic acid supplements during pregnancy and risk of autism spectrum disorders in children: a meta-analysis. Molecular Autism. 2017;8(1):51.CrossRef Wang M, Li K, Zhao D, Li L. The association between maternal use of folic acid supplements during pregnancy and risk of autism spectrum disorders in children: a meta-analysis. Molecular Autism. 2017;8(1):51.CrossRef
34.
go back to reference Chen J, Xin K, Wei J, Zhang K, Xiao H. Lower maternal serum 25(OH) D in first trimester associated with higher autism risk in Chinese offspring. J Psychosom Res. 2016;89:98–101.CrossRef Chen J, Xin K, Wei J, Zhang K, Xiao H. Lower maternal serum 25(OH) D in first trimester associated with higher autism risk in Chinese offspring. J Psychosom Res. 2016;89:98–101.CrossRef
35.
go back to reference Geier DA, Kern JK, Davis G, King PG, Adams JB, Young JL, et al. A prospective double-blind, randomized clinical trial of levocarnitine to treat autism spectrum disorders. Med Sci Monit. 2011;17(6):PI15–23.CrossRef Geier DA, Kern JK, Davis G, King PG, Adams JB, Young JL, et al. A prospective double-blind, randomized clinical trial of levocarnitine to treat autism spectrum disorders. Med Sci Monit. 2011;17(6):PI15–23.CrossRef
36.
go back to reference Fahmy SF, El-hamamsy MH, Zaki OK, Badary OA. L-Carnitine supplementation improves the behavioral symptoms in autistic children. Res Autism Spectr Disord. 2013;7(1):159–66.CrossRef Fahmy SF, El-hamamsy MH, Zaki OK, Badary OA. L-Carnitine supplementation improves the behavioral symptoms in autistic children. Res Autism Spectr Disord. 2013;7(1):159–66.CrossRef
37.
go back to reference Adams JB, Audhya T, Geis E, Gehn E, Fimbres V, Pollard EL, et al. Comprehensive nutritional and dietary intervention for autism Spectrum disorder—a randomized, controlled 12-month trial. Nutrients. 2018;10(3):369.CrossRef Adams JB, Audhya T, Geis E, Gehn E, Fimbres V, Pollard EL, et al. Comprehensive nutritional and dietary intervention for autism Spectrum disorder—a randomized, controlled 12-month trial. Nutrients. 2018;10(3):369.CrossRef
38.
go back to reference Frye RE, James SJ. Metabolic pathology of autism in relation to redox metabolism. Biomark Med. 2014;8(3):321–30.CrossRef Frye RE, James SJ. Metabolic pathology of autism in relation to redox metabolism. Biomark Med. 2014;8(3):321–30.CrossRef
39.
go back to reference Panjwani AA, Ji Y, Fahey JW, Palmer A, Wang G, Hong X, et al. Maternal obesity/diabetes, plasma branched-chain amino acids, and autism Spectrum disorder risk in urban low-income children: evidence of sex difference. Autism Res. 2019;12(10):1562–73.CrossRef Panjwani AA, Ji Y, Fahey JW, Palmer A, Wang G, Hong X, et al. Maternal obesity/diabetes, plasma branched-chain amino acids, and autism Spectrum disorder risk in urban low-income children: evidence of sex difference. Autism Res. 2019;12(10):1562–73.CrossRef
40.
go back to reference Panjwani AA, Ji Y, Fahey JW, Palmer A, Wang G, Hong X, et al. Maternal dyslipidemia, plasma branched-chain amino acids, and the risk of child autism Spectrum disorder: evidence of sex difference. J Autism Dev Disord. 2020;50(2):540–50.CrossRef Panjwani AA, Ji Y, Fahey JW, Palmer A, Wang G, Hong X, et al. Maternal dyslipidemia, plasma branched-chain amino acids, and the risk of child autism Spectrum disorder: evidence of sex difference. J Autism Dev Disord. 2020;50(2):540–50.CrossRef
41.
go back to reference Ritz B, Yan Q, Uppal K, Liew Z, Cui X, Ling C, et al. Untargeted Metabolomics Screen of Mid-pregnancy Maternal Serum and Autism in Offspring. Autism Res. 2020. Ritz B, Yan Q, Uppal K, Liew Z, Cui X, Ling C, et al. Untargeted Metabolomics Screen of Mid-pregnancy Maternal Serum and Autism in Offspring. Autism Res. 2020.
Metadata
Title
Altered metabolism of mothers of young children with Autism Spectrum Disorder: a case control study
Authors
Kathryn Hollowood-Jones
James B. Adams
Devon M. Coleman
Sivapriya Ramamoorthy
Stepan Melnyk
S. Jill James
Bryan K. Woodruff
Elena L. Pollard
Christine L. Snozek
Uwe Kruger
Joshua Chuah
Juergen Hahn
Publication date
01-12-2020
Publisher
BioMed Central
Published in
BMC Pediatrics / Issue 1/2020
Electronic ISSN: 1471-2431
DOI
https://doi.org/10.1186/s12887-020-02437-7

Other articles of this Issue 1/2020

BMC Pediatrics 1/2020 Go to the issue