Evaluation of plasma amino acid levels in children diagnosed with autism spectrum disorder

Abstract

Aim: Autism Spectrum Disorder (ASD) is a neurodevelopmental disease with an average diagnosis age over three years. Metabolomic studies pointing out candidate amino acids are of major importance to guide trained clinicians for an early and faster diagnosis. We aimed to evaluate 37 plasma amino acids in children with ASD compared to age and sex matched controls in this study. Method: Twenty three children diagnosed with ASD in Research and Training Hospital (19 boys and 4 girls) and, age and gender matched 24 children without ASD were enrolled in this study. A total of 37 amino acid levels were measured with LC-MS/MS device. Results: While anserine, asparagine, citrulline, glutamic acid, hydroxyproline, N-methyl-histidine, ornithine, valine were significantly lower, sarcosine was significantly higher in ASD group compared with control group. Conclusions: Studying the combination of plasma and urine amino acids related to urea cycle disorders can be recommended for new investigations. The significant decrease in hydroxyproline can create the potential to explain muscle weakness in ASD. Although it is difficult to say whether the difference in the levels of conflicting amino acids in the literature is due to methodological or biological differences, further studies will make the subject clearer.

Keywords

• Autism spectrum disorder
• amino acids
• liquid chromatography–tandem mass spectrometry
• hydroxyproline
• urea cycle disorders

Otizm spektrum bozukluğu tanılı çocuklarda plazma amino asit düzeylerinin değerlendirilmesi

Abstract

Amaç: Otizm Spektrum Bozukluğu (OSB) ortalama tanı yaşı üç yıl civarında olan nörogelişimsel bir bozukluktur. Erken ve daha hızlı tanıda aday amino asitlere ilişkin metabolomik çalışmalar klinisyenler için büyük önem taşımaktadır. Bu çalışmada OSB'li çocuklarda 37 plazma amino asit, yaş ve cinsiyet olarak eşleştirilmiş kontrol grubu ile karşılaştırılması amaçlanmıştır. Yöntem: Bu çalışmaya Eğitim ve Araştırma Hastanesinde OSB tanısı almış yirmi üç çocuk (19 erkek ve 4 kız) ve OSB'si olmayan yaş ve cinsiyeti eşleştirilen 24 çocuk alınmıştır. 37 plazma amino asit LC-MS/MS cihazı ile ölçülmüştür. Bulgular: OSB grubunda kontrol grubuna göre anserin, asparagin, sitrülin, glutamik asit, hidroksiprolin, N-metil-histidin, ornitin, valin anlamlı olarak düşük saptanırken ve sarkozin anlamlı olarak yüksek saptanmıştır. Sonuç: Üre döngüsü bozuklukları ile ilişkili plazma ve idrar amino asitlerinin kombinasyonunun incelenmesi yeni araştırmalar için önerilebilir. Hidroksiprolindeki önemli düşüş, OSB'deki kas zayıflığını açıklama potansiyeli yaratabilir. Literatürdeki amino asit seviyelerindeki çelişkili düzeylerin metodolojik veya biyolojik farklılıklardan kaynaklanıp kaynaklanmadığını söylemek zor olsa da, daha ileri çalışmalar konuyu daha net hale getirecektir.

Keywords

• Otizm spektrum bozukluğu
• amino asitler
• sıvı kromatografi-tandem kütle spektrometrisi
• hidroksiprolin
• üre döngüsü bozuklukları

References

1. 1. Baio J, Wiggins L, Christensen D, et al. Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years — Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2014. MMWR Surveill Summ. 2018;67(6):1-23. doi:10.15585/mmwr.ss6706a1
2. 2. Howsmon D, Kruger U, Melnyk S, James S, 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. doi: 10.1371/journal.pcbi.1005385
3. 3. Cheng N, Rho J, Masino S. Metabolic Dysfunction Underlying Autism Spectrum Disorder and Potential Treatment Approaches. Front Mol Neurosci. 2017;10. doi: 10.3389/fnmol.2017.00034.
4. 4. Levy S, Giarelli E, Lee L, et al. Autism Spectrum Disorder and Co-occurring Developmental, Psychiatric, and Medical Conditions Among Children in Multiple Populations of the United States. J Dev Behav Pediatr. 2010;31(4):267-275. doi: 10.1097/DBP.0b013e3181d5d03b
5. 5. Dawson G, Rogers S, Munson J, et al. Randomized, Controlled Trial of an Intervention for Toddlers With Autism: The Early Start Denver Model. Pediatrics. 2009;125(1):e17-e23. doi: 10.1542/peds.2009-0958
6. 6. Jo H, Schieve L, Rice C, et al. Age at Autism Spectrum Disorder (ASD) Diagnosis by Race, Ethnicity, and Primary Household Language Among Children with Special Health Care Needs, United States, 2009–2010. Matern Child Health J. 2015;19(8):1687-1697. doi: 10.1007/s10995-015-1683-4
7. 7. De Rubeis S, Buxbaum J. Genetics and genomics of autism spectrum disorder: embracing complexity. Hum Mol Genet. 2015;24(R1):R24-R31. doi: 10.1093/hmg/ddv273
8. 8. Anwar A, Abruzzo P, Pasha S, et al. Advanced glycation endproducts, dityrosine and arginine transporter dysfunction in autism - a source of biomarkers for clinical diagnosis. Mol Autism. 2018;9(1). doi: 10.1186/s13229-017-0183-3

9. 9. Zheng H, Wang W, Li X, Rauw G, Baker G. Body fluid levels of neuroactive amino acids in autism spectrum disorders: a review of the literature. Amino Acids. 2016;49(1):57-65. doi: 10.1007/s00726-016-2332-y
10. 10. El-Ansary A, Al-Ayadhi L. GABAergic/glutamatergic imbalance relative to excessive neuroinflammation in autism spectrum disorders. J Neuroinflammation. 2014;11(1). 189. doi: 10.1186/s12974-014-0189-0
11. 11. Tirouvanziam R, Obukhanych T, Laval J, et al. Distinct Plasma Profile of Polar Neutral Amino Acids, Leucine, and Glutamate in Children with Autism Spectrum Disorders. J Autism Dev Disord. 2011;42(5):827-836. doi:10.1007/s10803-011-1314-x
12. 12. Robertson C, Ratai E, Kanwisher N. Reduced GABAergic Action in the Autistic Brain. Curr Biol. 2016;26(1):80-85. doi:10.1016/j.cub.2015.11.019
13. 13. Cochran D, Sikoglu E, Hodge S, et al. Relationship among Glutamine, γ-Aminobutyric Acid, and Social Cognition in Autism Spectrum Disorders. J Child Adolesc Psychopharmacol. 2015;25(4):314-322. doi:10.1089/cap.2014.0112
14. 14. Dawson G, Rogers S, Munson J, et al. Randomized, Controlled Trial of an Intervention for Toddlers With Autism: The Early Start Denver Model. Pediatrics. 2009;125(1):e17-e23. doi:10.1542/peds.2009-0958
15. 15. Ganz M. The Lifetime Distribution of the Incremental Societal Costs of Autism. Arch Pediatr Adolesc Med. 2007;161(4):343-349. doi:10.1001/archpedi.161.4.343
16. 16. Pubchem. 1-Methyl-L-histidine. https://pubchem.ncbi.nlm.nih.gov/compound/92105. 02 Mayıs 2019 tarihinde erişilmiştir.
17. 17. Mayatepek E and Jaeken J. Disorders in the Metanbolism of Glutathione and Imidazole Dipeptides. İçinde: Saudubray J-M, van den Berghe G, Walter JH, ed. Inborn Metabolic Diseases: Diagnosis and Treatment. 5. baskı. Berlin Heidelberg: Springer-Verlag; 2012: 423-430.
18. 18. Aldred S, Moore KM, Fitzgerald M, Waring RH. Plasma amino acid levels in children with autism and their families. J Autism Dev Disord. 2003;33(1):93-97. doi:10.1023/a:1022238706604. doi:10.1023/a:1022238706604
19. 19. Bugajska J, Berska J, Wojtyto T, Bik-Multanowski M, Sztefko K. The amino acid profile in blood plasma of young boys with autism. Psychiatr Pol. 2017;51(2):359-368. doi:10.12740/PP/65046
20. 20. Yang P, Chang C. Glutamate-Mediated Signaling and Autism Spectrum Disorders: Emerging Treatment Targets. Curr Pharm Des. 2014;20(32):5186-5193. doi:10.2174/1381612819666140110120725
21. 21. El-Ansary A. Data of multiple regressions analysis between selected biomarkers related to glutamate excitotoxicity and oxidative stress in Saudi autistic patients. Data Brief. 2016;7:111-116. doi:10.1016/j.dib.2016.02.025
22. 22. Zheng Z, Zhu T, Qu Y, Mu D. Blood Glutamate Levels in Autism Spectrum Disorder: A Systematic Review and Meta-Analysis. PLOS ONE. 2016;11(7):e0158688. doi:10.1371/journal.pone.0158688
23. 23. Cai J, Ding L, Zhang J, Xue J, Wang L. Elevated plasma levels of glutamate in children with autism spectrum disorders. NeuroReport. 2016;27(4):272-276. doi:10.1097/WNR.0000000000000532
24. 24. Arnold G, Hyman S, Mooney R, Kirby R. Plasma amino acids profiles in children with autism: potential risk of nutritional deficiencies. J Autism Dev Disord. 2003;33(4):449-454. doi:10.1023/a:1025071014191
25. 25. Tu W, Chen H, He J. Application of LC-MS/MS analysis of plasma amino acids profiles in children with autism. J Clin Biochem Nutr. 2012;51(3):248-249. doi:10.3164/jcbn.12-45
26. 26. Novarino G, El-Fishawy P, Kayserili H, Meguid N, Scott E et al. Mutations in BCKD-kinase Lead to a Potentially Treatable Form of Autism with Epilepsy. Science. 2012;338(6105):394-397. doi:10.1126/science.1224631
27. 27. García-Cazorla A, Oyarzabal A, Fort J, et al. Two Novel Mutations in the BCKDK (Branched-Chain Keto-Acid Dehydrogenase Kinase) Gene Are Responsible for a Neurobehavioral Deficit in Two Pediatric Unrelated Patients. Hum Mutat. 2014;35(4):470-477. doi:10.1002/humu.22513
28. 28. Liu A, Zhou W, Qu L et al. Altered Urinary Amino Acids in Children With Autism Spectrum Disorders. Front Cell Neurosci. 2019;13:7. doi:10.3389/fncel.2019.00007
29. 29. Pubchem. L-Hydroxyproline. https://pubchem.ncbi.nlm.nih.gov/compound/54196981. 03 Mayıs 2019 tarihinde erişilmiştir.
30. 30. Kern J, Geier D, Adams J, Troutman M, Davis G, King P et al. Autism severity and muscle strength: A correlation analysis. Research in Autism Spectrum Disorders. 2011;5(3):1011-1015 doi: 10.1016/j.rasd.2010.11.002.
31. 31. Pubchem. Sarcosine. https://pubchem.ncbi.nlm.nih.gov/compound/1088. 02 Mayıs 2019 tarihinde erişilmiştir.
32. 32. Lee M, Lin Y, Tu Y, et al. Effects of sarcosine and N, N-dimethylglycine on NMDA receptor-mediated excitatory field potentials. J Biomed Sci. 2017;24(1):18. doi:10.1186/s12929-016-0314-8
33. 33. Zhang HX, Hyrc K, Thio LL. The glycine transport inhibitor sarcosine is an NMDA receptor co-agonist that differs from glycine. J Physiol. 2009;587(13):3207-3220. doi:10.1113/jphysiol.2009.168757
34. 34. Schür RR, Draisma LW, Wijnen JP, et al. Brain GABA levels across psychiatric disorders: A systematic literature review and meta-analysis of (1) H-MRS studies. Hum Brain Mapp. 2016;37(9):3337-3352. doi:10.1002/hbm.23244