Skip to main content
SpringerLink
Log in

Evaluation of Branched-Chain Amino Acids in Children with Autism Spectrum Disorder and Epilepsy

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Autism spectrum disorder (ASD) and epilepsy run hand-to-hand in their pathophysiology. Epilepsy is not an uncommon finding in patients with ASD. The aim of the present study was to identify the metabolic abnormalities of BCAAs (leucine, isoleucine, and valine) in children with ASD with and without seizures in comparison with neurotypical controls. Also, this study aimed to investigate the presence of epileptiform discharges on electroencephalography (EEG) in ASD patients and to describe the types and frequency of seizures observed. The study included 90 children aged 2–7 years, 30 of whom were diagnosed with both ASD and epilepsy. The other 30 children were diagnosed as ASD without epilepsy, and a comparable 30 normally developed children served as a control group. The groups were matched by age and gender. All patients were referred to the Autism Disorders Clinic for interviews and examinations. The Childhood Autism Rating Scale (CARS) was applied to all study participants to assess the degree of autism. The present study results show that all types of seizures may be identified in ASD children. The median serum levels of BCAAs were lower in ASD children with and without epilepsy than in neurotypical controls. This opens the door for discussion about new etiologies and better categorizations of ASD based on genotype and genetic abnormalities detected. More studies with larger samples are needed to understand ASD better and to more reliable evaluate the association between ASD, EEG changes, seizures, and BCAAs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Data Availability

The datasets generated during and analyzed during the current study are available from Prof. Nagwa A. Meguid (e-mail meguidna@yahoo.com) upon reasonable request.

References

  1. American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders. 5th Edition, American Psychiatric Publishing, Washington DC. https://doi.org/10.1176/appi.books.9780890425596.

  2. Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, Engel J, Forsgren L, French JA, Glynn M, Hesdorffer DC, Lee BI, Mathern GW, Moshé SL, Perucca E, Scheffer IE, Tomson T, Watanabe M, Wiebe S (2014) ILAE official report: a practical clinical definition of epilepsy. Epilepsia 55:475–482. https://doi.org/10.1111/epi.125502

    Article  PubMed  Google Scholar 

  3. WHO (2016) Epilepsy fact sheets. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/epilepsy. Accessed 26 September 2022

  4. Levisohn PM (2007) The autism-epilepsy connection. Epilepsia 48:33–35. https://doi.org/10.1111/j.1528-1167.2007.01399.x

    Article  PubMed  Google Scholar 

  5. Reilly CJ (2011) Attention deficit hyperactivity disorder (ADHD) in childhood epilepsy. Res Dev Disabil 32:883–893. https://doi.org/10.1016/j.ridd.2011.01.019

    Article  PubMed  Google Scholar 

  6. Viscidi EW, Johnson AL, Spence SJ, Buka SL, Morrow EM, Triche EW (2014) The association between epilepsy and autism symptoms and maladaptive behaviors in children with autism spectrum disorder. Autism : Int J Res Prac 18:996–1006. https://doi.org/10.1177/1362361313508027

    Article  Google Scholar 

  7. Wakeford S, Hinvest N, Ring H, Brosnan M (2015) Autistic characteristics in adults with epilepsy and perceived seizure activity. Epilepsy Behav 52:244–250. https://doi.org/10.1016/j.yebeh.2015.08.031

    Article  PubMed  Google Scholar 

  8. Frye RE, Delhey L, Slattery J, Tippett M, Wynne R, Rose S, Kahler SG, Bennuri SC, Melnyk S, Sequeira JM, Quadros E (2016) Blocking and binding folate receptor alpha autoantibodies identify novel autism spectrum disorder subgroups. Frontiers in neurosciencehttps://doi.org/10.3389/fnins.2016.00080

  9. Sowers S (2009) A Primer On Branched Chain Amino Acids. Knoxville, TN. https://www.huhs.edu/literature/BCAA.pdf. Accessed 26 September 2022

  10. Tom A, Nair KS (2006) Assessment of branched-chain amino acid status and potential for biomarkers. The Journal of nutritionhttps://doi.org/10.1093/jn/136.1.324S

  11. Monirujjaman M, Ferdouse A (2014) Metabolic and physiological roles of branched-chain amino acids. Adv Mol Biolhttps://doi.org/10.1155/2014/364976

  12. Skeie B, Petersen AJ, Manner T, Askanazi J, Steen PA (1994) Effects of valine, leucine, isoleucine, and a balanced amino acid solution on the seizure threshold to picrotoxin in rats. Pharmacol Biochem Behav 48:101–103. https://doi.org/10.1016/0091-3057(94)90504-5

    Article  CAS  PubMed  Google Scholar 

  13. Walls AB, Waagepetersen HS, Bak LK, Schousboe A, Sonnewald U (2015) The glutamine-glutamate/GABA cycle: function, regional differences in glutamate and GABA production and effects of interference with GABA metabolism. Neurochem Res 40:402–409. https://doi.org/10.1007/s11064-014-1473-1

    Article  CAS  PubMed  Google Scholar 

  14. Fernstrom JD (2005) Branched-chain amino acids and brain function. The Journal of nutritionhttps://doi.org/10.1093/jn/135.6.1539S

  15. Institute of Medicine (US) Committee on Nutrition Trauma, and the Brain (2011) Nutrition and traumatic brain injury: improving acute and subacute health outcomes in military personnel. Washington (DC). https://www.ncbi.nlm.nih.gov/books/NBK209314/. Accessed 26 September 2022.

  16. Harris RA, Joshi M, Jeoung NH (2004) Mechanisms responsible for regulation of branched-chain amino acid catabolism. Biochem Biophys Res Commun 313:391–396. https://doi.org/10.1016/j.bbrc.2003.11.007

    Article  CAS  PubMed  Google Scholar 

  17. Harris RA, Joshi M, Jeoung NH, Obayashi M (2005) Overview of the molecular and biochemical basis of branched-chain amino acid catabolism. J Nutr 135:1527S-S1530. https://doi.org/10.1093/jn/135.6.1527S

    Article  CAS  PubMed  Google Scholar 

  18. Novarino G, El-Fishawy P, Kayserili H, Meguid NA, Scott EM, Schroth J, Silhavy JL, Kara M, Khalil RO, Ben-Omran T, Ercan-Sencicek AG, Hashish AF, Sanders SJ, Gupta AR, Hashem HS, Matern D, Gabriel S, Sweetman L, Rahimi Y, Harris RA et al (2012) Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Sci 338:394–397. https://doi.org/10.1126/science.1224631

    Article  CAS  Google Scholar 

  19. García-Cazorla A, Oyarzabal A, Fort J, Robles C, Castejón E, Ruiz-Sala P, Bodoy S, Merinero B, Lopez-Sala A, Dopazo J, Nunes V, Ugarte M, Artuch R, Palacín M, Rodríguez-Pombo P, Alcaide P, Navarrete R, Sanz P, Font-Llitjós M, Vilaseca MA et al (2014) 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 35:470–477. https://doi.org/10.1002/humu.22513

    Article  CAS  PubMed  Google Scholar 

  20. Averbukh Z, Berman S, Kishinevsky E, Feldman L, Cohn M, Rapoport M, Galperin E, Dishi V, Weissgarten J (2004) Loss of captopril-bound Fe by end-stage renal failure patients during hemodialysis. J Nephrol 17:101–106

    CAS  PubMed  Google Scholar 

  21. Brooks-Kayal A (2010) Epilepsy and autism spectrum disorders: are there common developmental mechanisms? Brain Develop 32:731–738. https://doi.org/10.1016/j.braindev.2010.04.010

    Article  Google Scholar 

  22. Sundelin HE, Larsson H, Lichtenstein P, Almqvist C, Hultman CM, Tomson T, Ludvigsson JF (2016) Autism and epilepsy: A population-based nationwide cohort study. Neurol 87:192–197. https://doi.org/10.1212/WNL.0000000000002836

    Article  Google Scholar 

  23. McCue LM, Flick LH, Twyman KA, Xian H, Conturo TE (2016) Prevalence of non-febrile seizures in children with idiopathic autism spectrum disorder and their unaffected siblings: a retrospective cohort study. BMC neurologyhttps://doi.org/10.1186/s12883-016-0764-3

  24. Jokiranta E, Sourander A, Suominen A, Timonen-Soivio L, Brown AS, Sillanpää M (2014) Epilepsy among children and adolescents with autism spectrum disorders: a population-based study. J Autism Dev Disord 44:2547–2557. https://doi.org/10.1007/s10803-014-2126-6

    Article  PubMed  Google Scholar 

  25. Bolton PF, Carcani-Rathwell I, Hutton J, Goode S, Howlin P, Rutter M (2011) Epilepsy in autism: features and correlates. Bri J Psychiatry: J Mental Sci 198:289–294. https://doi.org/10.1192/bjp.bp.109.076877

    Article  Google Scholar 

  26. Boutros NN, Lajiness-O’Neill R, Zillgitt A, Richard AE, Bowyer SM (2015) EEG changes associated with autistic spectrum disorders. Neuropsychiatric Electrophysiologyhttps://doi.org/10.1186/s40810-014-0001-5

  27. Tirouvanziam R, Obukhanych TV, Laval J, Aronov PA, Libove R, Banerjee AG, Parker KJ, O’Hara R, Herzenberg LA, Herzenberg LA, Hardan AY (2012) Distinct plasma profile of polar neutral amino acids, leucine, and glutamate in children with autism spectrum disorders. J Autism Dev Disord 42:827–836. https://doi.org/10.1007/s10803-011-1314-x

    Article  PubMed  Google Scholar 

  28. Arnold GL, Hyman SL, Mooney RA, Kirby RS (2003) Plasma amino acids profiles in children with autism: potential risk of nutritional deficiencies. J Autism Dev Disord 33:449–454. https://doi.org/10.1023/a:1025071014191

    Article  PubMed  Google Scholar 

  29. Zheng HF, Wang WQ, Li XM, Rauw G, Baker GB (2017) Body fluid levels of neuroactive amino acids in autism spectrum disorders: a review of the literature. Amino Acids 49:57–65. https://doi.org/10.1007/s00726-016-2332-y

    Article  CAS  PubMed  Google Scholar 

  30. Evangeliou A, Spilioti M, Doulioglou V, Kalaidopoulou P, Ilias A, Skarpalezou A, Katsanika I, Kalamitsou S, Vasilaki K, Chatziioanidis I, Garganis K, Pavlou E, Varlamis S, Nikolaidis N (2009) Branched chain amino acids as adjunctive therapy to ketogenic diet in epilepsy: pilot study and hypothesis. J Child Neurol 24:1268–1272. https://doi.org/10.1177/0883073809336295

    Article  PubMed  Google Scholar 

  31. Yudkoff M, Daikhin Y, Nissim I, Horyn O, Luhovyy B, Luhovyy B, Lazarow A, Nissim I (2005) Brain amino acid requirements and toxicity: the example of leucine. J Nutr 135:1531S-S1538. https://doi.org/10.1093/jn/135.6.1531S

    Article  CAS  PubMed  Google Scholar 

  32. Shimomura Y, Harris RA (2006) Metabolism and physiological function of branched-chain amino acids: discussion of session 1. J Nutr 136:232S-S233. https://doi.org/10.1093/jn/136.1.232S

    Article  CAS  PubMed  Google Scholar 

  33. Ribeiro CA, Sgaravatti AM, Rosa RB, Schuck PF, Grando V, Schmidt AL, Ferreira GC, Perry ML, Dutra-Filho CS, Wajner M (2008) Inhibition of brain energy metabolism by the branched-chain amino acids accumulating in maple syrup urine disease. Neurochem Res 33:114–124. https://doi.org/10.1007/s11064-007-9423-9

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank all study participants.

Funding

The National Research Centre funded the study.

Author information

Authors and Affiliations

  1. Research On Children With Special Needs Department, National Research Centre, Giza, Egypt

    Nagwa A. Meguid, Heba S. Hashem, Adel Hashish & Ahmed M. Elwan

  2. CONEM Egypt Child Brain Research Group, National Research Centre, Giza, Egypt

    Nagwa A. Meguid

  3. Faculty of Medicine, Department of Neurology and Psychiatry, Ain Shams University, El-Abaseya, Egypt

    Mohamed H. Ghanem & Samia A. Helal

  4. Nazarbayev University School of Medicine, Astana, Kazakhstan

    Yuliya Semenova

  5. Department of Neurology, Cairo University, Cairo, Egypt

    Saher Hashem

  6. Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy

    Salvatore Chirumbolo

  7. CONEM Scientific Secretary, Verona, Italy

    Salvatore Chirumbolo

  8. Council for Nutritional and Environmental Medicine (CONEM), Toften 24, 8610, Mo I Rana, Norway

    Geir Bjørklund

Authors
  1. Nagwa A. Meguid
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Heba S. Hashem
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mohamed H. Ghanem
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Samia A. Helal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuliya Semenova
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Saher Hashem
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Adel Hashish
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Salvatore Chirumbolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ahmed M. Elwan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Geir Bjørklund
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors confirmed they have contributed to the intellectual content of this paper and have met the following three requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Corresponding author

Correspondence to Geir Bjørklund.

Ethics declarations

Ethics Approval

The study was approved by the Medical Research Ethics Committee of the National Research Centre (No. 2011/10220), following the principles of the Declaration of Helsinki.

Consent to Participate

Informed oral and written consent was obtained from all caregivers of the participants included in the present study.

Consent for Publication

Consent to publish the data has been received from the caregivers of all patients.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Meguid, N.A., Hashem, H.S., Ghanem, M.H. et al. Evaluation of Branched-Chain Amino Acids in Children with Autism Spectrum Disorder and Epilepsy. Mol Neurobiol 60, 1997–2004 (2023). https://doi.org/10.1007/s12035-022-03202-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-022-03202-w

Keywords

Search

Navigation