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Metabolism-Associated Markers and Childhood Autism Rating Scales (CARS) as a Measure of Autism Severity

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Abstract

Autism spectrum disorder (ASD) is a neuro-behavioral syndrome with a broad spectrum of different mechanisms and etiologies that are caused by abnormal brain development. To date, no highly reliable and effective diagnostic biomarker to assess ASD is available so far. The present study investigated the predictivity potential of some suggested markers in ASD diagnosis focusing onto the relative ratios of several plasma biomarkers of electron transport chain function, and mitochondrial metabolism in 41 patients with ASD evaluated for behavior deficits measured using Childhood Autism Rating Scales (CARS). The control matched for further 41 healthy subjects. The relation of these relative ratios to ASD severity was also examined, as well as their ability to distinguish ASD children from neurotypical children. All predictive ratios were found to be markedly altered and correlated in ASD patients. However, no ratio was connected with autism severity. Interestingly, MRCC-I/caspase-7, GSH/GST, and MRCC-I/COQ10 were the most distinctive relative ratios between neurotypical controls and ASD patients and may thereby be useful biomarkers for early diagnosis of ASD. Overall, this investigation proves that relative ratios of numerous mitochondrial biomarkers might be predictive and efficient to differentiate between neurotypical children and ASD.

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References

  • Al-Gadani Y, El-Ansary A, Attas O, Al-Ayadhi L (2009) Oxidative stress and antioxidant status in Saudi autistic children. Clin Biochem 42:1032–1040. https://doi.org/10.1016/j.clinbiochem.2009.03.011

    Article  PubMed  CAS  Google Scholar 

  • Al-Mosalim O, El-Ansary A, Attas O, Al-Ayadhi L (2009) Metabolic biomarkers related to energy metabolism in Saudi autistic children. Clin Biochem 42:949–957

    Article  CAS  Google Scholar 

  • Al-Otaish H, Al-Ayadhi L, Bjørklund G, Chirumbolo S, Urbina MA, El-Ansary A (2018) Relationship between absolute and relative ratios of glutamate, glutamine and GABA and severity of autism spectrum disorder. Metab Brain Dis 33:843–854. https://doi.org/10.1007/s11011-018-0186-6

    Article  PubMed  CAS  Google Scholar 

  • Al-Yafee YA, Al-Ayadhi LY, Haq SH, El-Ansary AK (2011) Novel metabolic biomarkers related to sulfur-dependent detoxification pathways in autistic patients of Saudi Arabia. MC Neurol 11:139. https://doi.org/10.1186/1471-2377-11-139

    Article  CAS  Google Scholar 

  • Amador E, Dorfman LE, Wacker WE (1963) Serum lactic dehydrogenase activity: an analytical assessment of current assays. Clin Chem 9:391–399

    CAS  Google Scholar 

  • Ames A (2000) CNS energy metabolism as related to function. Brain Res Brain Res Rev 34:42–68

    Article  PubMed  CAS  Google Scholar 

  • APA–American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders: DSM-5. American Psychiatric Association Publishing, Arlington

    Book  Google Scholar 

  • Baum SH, Stevenson RA, Wallace MT (2015) Behavioral, perceptual, and neural alterations in sensory and multisensory function in autism spectrum disorder. Prog Neurobiol 134:140–160. https://doi.org/10.1016/j.pneurobio.2015.09.007

    Article  PubMed  PubMed Central  Google Scholar 

  • Beutler E, Duron O, Kelly BM (1963) Improved method for the determination of blood glutathione. J Lab Clin Med 61:882–888

    PubMed  CAS  Google Scholar 

  • Brigelius-Flohe R, Maiorino M (2013) Glutathione peroxidases. Biochim Biophys Acta 1830:3289–3303

    Article  PubMed  CAS  Google Scholar 

  • Brookman-Frazee L, Stadnick N, Chlebowski C, Baker-Ericzén M, Ganger W (2017) Characterizing psychiatric comorbidity in children with autism spectrum disorder receiving publicly funded mental health services. Autism:1362361317712650. https://doi.org/10.1177/1362361317712650

  • Burbaeva GS, Savushkina OK, Dmitriev AD (1999) Brain isoforms of creatine kinase in health and mental diseases: Alzheimer’s disease and schizophrenia (in Russian). Vestn Ross Akad Med Nauk 1:20–24

    Google Scholar 

  • Chauhan A, Gu F, Essa MM, Wegiel J, Kaur K, Brown WT, Chauhan V (2011) Brain region-specific deficit in mitochondrial electron transport chain complexes in children with autism. J Neurochem 117:209–220. https://doi.org/10.1111/j.1471-4159.2011.07189.x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Christensen DL (2016) Prevalence and characteristics of autism spectrum disorder among children aged 8 years — autism and developmental disabilities monitoring network, 11 sites, United States, 2012. MMWR Surveill Summ 65(3):1–23. https://doi.org/10.15585/mmwr.ss6503a1

    Article  PubMed  Google Scholar 

  • Dawson G, Rogers S, Munson J, Smith M, Winter J, Greenson J, Donaldson A, Varley J (2010) Randomized, controlled trial of an intervention for toddlers with autism: the Early Start Denver Model. Pediatrics 125:e17–e23. https://doi.org/10.1542/peds.2009-0958

    Article  PubMed  Google Scholar 

  • De Meirleir L, Lissens W, Denis R, Wayenberg JL, Michotte A, Brucher JM, Vamos E, Gerlo E, Liebaers I (1993) Pyruvate dehydrogenase deficiency: clinical and biochemical diagnosis. Pediatr Neurol 9:216–220

    Article  PubMed  Google Scholar 

  • Dixon SJ, Stockwell BR (2014) The role of iron and reactive oxygen species in cell death. Nat Chem Biol 10:9–17

    Article  PubMed  CAS  Google Scholar 

  • Dudley J, DelBello MP, Weber WA, Adler CM, Strakowski SM, Lee JH (2016) Tissue-dependent cerebral energy metabolism in adolescents with bipolar disorder. J Affect Disord 191:248–255. https://doi.org/10.1016/j.jad.2015.11.045

    Article  PubMed  CAS  Google Scholar 

  • El-Ansary A (2016) Data of multiple regressions analysis between selected biomarkers related to glutamate excitotoxicity and oxidative stress in Saudi autistic patients. Data Brief 7:111–116

    Article  PubMed  PubMed Central  Google Scholar 

  • El-Ansary A, Al-Ayadhi L (2012) Neuroinflammation in autism spectrum disorders. J Neuroinflammation 9:265. https://doi.org/10.1186/1742-2094-9-265

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • El-Ansary A, Al-Daihan S, Al-Dbass A, Al-Ayadhi L (2010) Measurement of selected ions related to oxidative stress and energy metabolism in Saudi autistic children. Clin Biochem 43:63–70

    Article  PubMed  CAS  Google Scholar 

  • El-Ansary AK, Ben Bacha A, Al-Ayadhi LY (2011) Proinflammatory and proapoptotic markers in relation to mono and di-cations in plasma of autistic patients from Saudi Arabia. J Neuroinflammation 8:142. https://doi.org/10.1186/1742-2094-8-142

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • El-Tarrasa AE, Awed NS, Midway N, Alsulaimani AA, Said MM (2012) Association between polymorphisms of SLC6A3 and DRD1 genes and autism among Saudi Arabia Taif population using PCR-restriction fragment length polymorphism (PCR-RFLP). Afr J Biotechnol 11:11665–11670

    Google Scholar 

  • Erecinska M, Cherian S, Silver IA (2004) Energy metabolism in mammalian brain during development. Prog Neurobiol 73:397–445

    Article  PubMed  CAS  Google Scholar 

  • Frye RE, Rossignol DA (2011) Mitochondrial dysfunction can connect the diverse medical symptoms associated with autism spectrum disorders. Pediatr Res 69(5 Pt 2):41R–47R. https://doi.org/10.1203/PDR.0b013e318212f16b

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Frye RE, Rossignol DA (2014) Treatments for biomedical abnormalities associated with autism spectrum disorder. Front Pediatr 2:66. https://doi.org/10.3389/fped.2014.00066

    Article  PubMed  PubMed Central  Google Scholar 

  • Ganz ML (2007) The lifetime distribution of the incremental societal costs of autism. Arch Pediatr Adolesc Med 161:343–349

    Article  PubMed  Google Scholar 

  • Giulivi C, Zhang YF, Omanska-Klusek A, Ross-Inta C, Wong S, Hertz-Picciotto I, Tassone F, Pessah IN (2010) Mitochondrial dysfunction in autism. JAMA 304:2389–2396

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gonzalez-Cabo P, Palau F (2013) Mitochondrial pathophysiology in Friedreich’s ataxia. J Neurochem 126 Suppl 1:53–64. https://doi.org/10.1111/jnc.12303

    Article  PubMed  CAS  Google Scholar 

  • Henry RJ, Chiamori M, Golub OJ, Berkman S (1960) Revised spectrophotometric methods for the determination of glutamate oxaloacetic transaminase, glutamic pyruvate transaminase and lactic acid dehydrogenase. Am J Clin Pathol 34:381–398

    Article  PubMed  CAS  Google Scholar 

  • Hertz L, Song D, Xu J, Peng L, Gibbs ME (2015) Role of the astrocytic Na(+), K(+)-ATPase in K(+) homeostasis in brain: K(+) uptake, signaling pathways and substrate utilization. Neurochem Res 40:2505–2516

    Article  PubMed  CAS  Google Scholar 

  • Hollis F, Kanellopoulos AK, Bagni C (2017) Mitochondrial dysfunction in autism spectrum disorder: clinical features and perspectives. Curr Opin Neurobiol 45:178–187. https://doi.org/10.1016/j.conb.2017.05.018

    Article  PubMed  CAS  Google Scholar 

  • Huang ML, Lane DJ, Richardson DR (2011) Mitochondrial mayhem: the mitochondrion as a modulator of iron metabolism and its role in disease. Antioxid Redox Signal 15(12):3003–3019. https://doi.org/10.1089/ars.2011.3921

    Article  PubMed  CAS  Google Scholar 

  • Islam MT (2017) Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders. Neurol Res 39:73–82

    Article  PubMed  CAS  Google Scholar 

  • Ivanov HY, Stoyanova VK, Popov NT, Vachev TI (2015) Autism spectrum disorder—a complex genetic disorder. Folia Med (Plovdiv) 57:19–28. https://doi.org/10.1515/folmed-2015-0015

    Article  Google Scholar 

  • Kann O, Kovács R (2007) Mitochondria and neuronal activity. Am J Physiol Cell Physiol 292:C641–C657. https://doi.org/10.1152/ajpcell.00222.2006

    Article  PubMed  CAS  Google Scholar 

  • Karmen A, Wroblewski F, LaDue JS (1953) Quantitative estimation of glutamic-oxaloacetic transaminase activity in human serum. Clin Res Proc 1:90

    Google Scholar 

  • Khemakhem AM, Frye RE, El-Ansary A, Al-Ayadhi L, Bacha AB (2017) Novel biomarkers of metabolic dysfunction is autism spectrum disorder: potential for biological diagnostic markers. Metab Brain Dis 32:1983–1997

    Article  PubMed  CAS  Google Scholar 

  • Mannervik B (1985) The isoenzymes of glutathione transferase. Adv Enzymol Relat Areas Mol Biol 57:357–417

    PubMed  CAS  Google Scholar 

  • Mattson B, Koya E, Simmons D, Mitchell T, Berkow A, Crombag H, Hope B (2008) Context-specific sensitization of cocaine-induced locomotor activity and associated neuronal ensembles in rat nucleus accumbens. Eur J Neurosci 27:202–212

    Article  PubMed  Google Scholar 

  • Noda M, Hiyama TY (2015) Sodium sensing in the brain. Pflugers Arch 467:465–474

    Article  PubMed  CAS  Google Scholar 

  • Rezin GT, Cardoso MR, Gonçalves CL, Scaini G, Fraga DB, Riegel RE, Comim CM, Quevedo J, Streck EL (2008) Inhibition of mitochondrial respiratory chain in brain of rats subjected to an experimental model of depression. Neurochem Int 53:395–400

    Article  PubMed  CAS  Google Scholar 

  • Rossignol DA, Frye RE (2012a) Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry 17:290–314

    Article  PubMed  CAS  Google Scholar 

  • Rossignol DA, Frye RE (2012b) A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures. Mol Psychiatry 17:389–401

    Article  PubMed  CAS  Google Scholar 

  • Rossignol DA, Genuis SJ, Frye RE (2014) Environmental toxicants and autism spectrum disorders: a systematic review. Transl Psychiatry 4(2):e360–e360

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Schopler E, Reichler RJ (1971) Parents as cotherapists in the treatment of psychotic children. J Autism Child Schizophr 1:87–102

    Article  PubMed  CAS  Google Scholar 

  • Schopler E, Reichler RJ, DeVellis RF, Daly K (1980) Toward objective classification of childhood autism: Childhood Autism Rating Scale (CARS). J Autism Dev Disord 10:91–103

    Article  PubMed  CAS  Google Scholar 

  • Schopler E, Van Bourgondien M E, Wellman GJ. (2010) Childhood autism rating scale. 2nd. CARS-2. Western Psychol Serv, Los Angeles

  • Schumann G, Bonora R, Ceriotti F, Clerc-Renaud P, Ferrero CA, Férard G, Franck PF, Gella FJ, Hoelzel W, Jørgensen PJ, Kanno T, Kessne A, Klauker R, Kristiansen N, Lessinger JM, Linsinger TP, Misaki H, Panteghini M, Pauwels J, Schimmel HG, Vialle A, Weidemann G, Siekmann L (2002) IFCC primary reference procedures for the measurement of catalytic activity concentrations of enzymes at 37 degrees C. Part 2. Reference procedure for the measurement of catalytic concentration of creatine kinase. Clin Chem Lab Med 40:635–642

    PubMed  CAS  Google Scholar 

  • Serasinghe MN, Chipuk JE (2017) Mitochondrial fission in human diseases. Handb Exp Pharmacol 240:159–188. https://doi.org/10.1007/164_2016_38

    Article  PubMed  CAS  Google Scholar 

  • Terri AE, Sesin PG (1958) Determination of serum potassium by using sodium tetraphenylboron. Am J Clin Path 29:86–90

    Article  Google Scholar 

  • Thye MD, Bednarz HM, Herringshaw AJ, Sartin EB, Kana RK (2017) The impact of atypical sensory processing on social impairments in autism spectrum disorder. Dev Cogn Neurosci 2017. https://doi.org/10.1016/j.dcn.2017.04.010, 29, 151, 167

  • Tsao CY, Mendell JR (2007) Autistic disorder in 2 children with mitochondrial disorders. J Child Neurol 22:1121–1123

    Article  PubMed  Google Scholar 

  • Wacker WE, Ulmer DD, Vallee BL (1956) Metalloenzymes and myocardial infarction: malic and lactic dehydrogenase activities and zinc concentrations in serum. N Engl J Med 255:449–456

    Article  CAS  Google Scholar 

  • Weindling H, Henry JB (1974) Laboratory test results altered by the pill. JAMA 229:1762–1768

    Article  PubMed  CAS  Google Scholar 

  • Weiwer M, Bittker JA, Lewis TA, Shimada K, Yang WS, MacPherson L, Dandapani S, Palmer M, Stockwell BR, Schreiber SL, Munoz B (2012) Development of small-molecule probes that selectively kill cells induced to express mutant RAS. Bioorg Med Chem Lett 22:1822–1826. https://doi.org/10.1016/j.bmcl.2011.09.047

    Article  PubMed  CAS  Google Scholar 

  • WMA-General Assembly of the World Medical Association (2014) World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. J Am Coll Dent 81:14–18

    Google Scholar 

  • WMA-World Medical Association (2013) World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 310:2191–2194. https://doi.org/10.1001/jama.2013.281053

    Article  CAS  Google Scholar 

  • Wu M, Gu J, Guo R, Huang Y, Yang M (2016) Structure of mammalian respiratory supercomplex I1III2IV1. Cell 167:1598–1609.e10. https://doi.org/10.1016/j.cell.2016.11.012

    Article  PubMed  CAS  Google Scholar 

  • Yamada K, Toribe Y, Yanagihara K, Mano T, Akagi M, Suzuki Y (2012) Diagnostic accuracy of blood and CSF lactate in identifying children with mitochondrial diseases affecting the central nervous system. Brain and Development 34:92–97

    Article  PubMed  Google Scholar 

  • Yang WS, Stockwell BR (2016) Ferroptosis: death by lipid peroxidation. Trends Cell Biol 26:165–176

    Article  PubMed  CAS  Google Scholar 

  • Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB, Brown LM, Girotti AW, Cornish VW, Schreiber SL, Stockwell BR (2014) Regulation of ferroptotic cancer cell death by GPX4. Cell 156:317–331. https://doi.org/10.1016/j.cell.2013.12.010

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zeron MM, Fernandes HB, Krebs C, Shehadeh J, Wellington CL, Leavitt BR, Baimbridge KG, Hayden MR, Raymond LA (2004) Potentiation of NMDA receptor-mediated excitotoxicity linked with intrinsic apoptotic pathway in YAC transgenic mouse model of Huntington’s disease. Mol Cell Neurosci 25:469–479

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This research project was supported by a grant from the “Research Centre of the Female Scientific and Medical Colleges,” Deanship of Scientific Research, King Saud University.

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Authors and Affiliations

  1. Autism Research and Treatment Center, King Saud University, Riyadh, Saudi Arabia

    Afaf El-Ansary

  2. Shaik AL-Amodi Autism Research Chair, King Saud University, Riyadh, Saudi Arabia

    Afaf El-Ansary & Laila Al-Ayadhi

  3. Central Laboratory, King Saud University, Riyadh, Saudi Arabia

    Afaf El-Ansary & Laila Al-Ayadhi

  4. Council for Nutritional and Environmental Medicine, Toften 24, 8610, Mo i Rana, Norway

    Geir Bjørklund

  5. Laboratory of Plant Biotechnology Applied to Crop Improvement, Faculty of Science of Sfax, University of Sfax, Sfax, Tunisia

    Asma M. Khemakhem & Abir Ben Bacha

  6. Department of Physiology, Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia

    Laila Al-Ayadhi

  7. Department of Neurological and Movement Sciences, University of Verona, Verona, Italy

    Salvatore Chirumbolo

  8. Biochemistry Department, Science College, King Saud University, Riyadh, Saudi Arabia

    Abir Ben Bacha

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  1. Afaf El-Ansary
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  2. Geir Bjørklund
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  3. Asma M. Khemakhem
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Correspondence to Geir Bjørklund.

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All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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El-Ansary, A., Bjørklund, G., Khemakhem, A.M. et al. Metabolism-Associated Markers and Childhood Autism Rating Scales (CARS) as a Measure of Autism Severity. J Mol Neurosci 65, 265–276 (2018). https://doi.org/10.1007/s12031-018-1091-5

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