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The role of zinc supplementation on the metallothionein system in children with autism spectrum disorder

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Abstract

The present research was carried out to elucidate the role of zinc (Zn) supplementation on the plasma concentration and gene expression, as well as the effects on cognitive-motor performance, in a cohort of children with autism spectrum disorder (ASD). The study was performed on a cohort of 30 pediatric subjects with ASD, encompassing an age range of 3–8 years. The impact of Zn supplementation was investigated in 3 months (or 12 weeks) on the ASD children. Each daily dosage of Zn was calculated as being equal to the body weight in kg plus 15–20 mg. The effect of Zn was also evaluated on the serum level of metallothionein 1 (MT-1A), and the severity of autism via scores on the Childhood Autism Rating Scale. The effect of Zn was investigated on the gene expression of MT1-A before and after Zn supplementation. The data of the present study showed an increase in cognitive-motor performance and an increased serum metallothionein concentration, as well as a significant lowering in the circulating serum levels of copper (Cu) following Zn supplementation. In the cohort of ASD patients, the genetic expression of MT-1 was higher after Zn therapy than before the treatment. In conclusion, Zn supplementation might be an important factor in the treatment of children with ASD.

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Abbreviations

ASD:

Autism spectrum disorder

CARS:

Childhood Autism Rating Scale

cDNA:

Copied DNA

CNS:

Central nervous system

Cu:

Copper

ELISA:

Enzyme-linked immunosorbent assay

GABA:

Gamma-aminobutyric acid

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

MT-1A:

Metallothionein 1A

PCR:

Polymerase chain reaction

TGMD:

Test of gross motor development

TMB:

Tetramethylbenzidine

Zn:

Zinc

References

  1. Bjørklund G (2013) The role of zinc and copper in autism spectrum disorders. Acta Neurobiol Exp (Wars) 73:225–236

    Google Scholar 

  2. Babaknejad N, Sayehmiri F, Sayehmiri K, Mohamadkhani A, Bahrami S (2016) The relationship between zinc levels and autism: a systematic review and meta-analysis. Iran J Child Neurol 10:1–9

    PubMed  PubMed Central  Google Scholar 

  3. Sayehmiri F, Babaknejad N, Bahrami S, Sayehmiri K, Darabi M, Rezaei-Tavirani M (2015) Zn/Cu levels in the field of autism disorders: a systematic review and meta-analysis. Iran J Child Neurol 9:1–9

    PubMed  PubMed Central  Google Scholar 

  4. Vela G, Stark P, Socha M, Sauer AK, Hagmeyer S, Grabrucker AM (2015) Zinc in gut-brain interaction in autism and neurological disorders. Neural Plast 2015:972791. https://doi.org/10.1155/2015/972791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kogan MD, Vladutiu CJ, Schieve LA, Ghandour RM, Blumberg SJ, Zablotsky B, Perrin JM, Shattuck P, Kuhlthau KA, Harwood RL, Lu MC (2018) The prevalence of parent-reported autism spectrum disorder among US children. Pediatrics 142:e20174161. https://doi.org/10.1542/peds.2017-4161

    Article  PubMed  Google Scholar 

  6. Bhat AN, Landa RJ, Galloway JC (2011) Current perspectives on motor functioning in infants, children, and adults with autism spectrum disorders. Phys Ther 91:1116–1129

    Article  Google Scholar 

  7. Jeoung B (2018) Motor proficiency differences among students with intellectual disabilities, autism, and developmental disability. J Exerc Rehabil 14:275–281

    Article  Google Scholar 

  8. Nebel MB, Joel SE, Muschelli J, Barber AD, Caffo BS, Pekar JJ, Mostofsky SH (2014) Disruption of functional organization within the primary motor cortex in children with autism. Hum Brain Mapp 35:567–580

    Article  Google Scholar 

  9. Joyce PI, Fratta P, Landman AS, Mcgoldrick P, Wackerhage H, Groves M, Busam BS, Galino J, Corrochano S, Beskina OA, Esapa C, Ryder E, Carter S, Stewart M, Codner G, Hilton H, Teboul L, Tucker J, Lionikas A, Estabel J, Ramirez-Solis R, White JK, Brandner S, Plagnol V, Bennet DL, Abramov AY, Greensmith L, Fisher EM, Acevedo-Arozena A (2016) Deficiency of the zinc finger protein ZFP106 causes motor and sensory neurodegeneration. Hum Mol Genet 25:291–307

    Article  CAS  Google Scholar 

  10. Yasuda H, Yoshida K, Yasuda Y, Tsutsui T (2011) Infantile zinc deficiency: association with autism spectrum disorders. Sci Rep 1:129. https://doi.org/10.1038/srep00129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Owens SE, Summar ML, Ryckman KK, Haines JL, Reiss S, Summar SR, Aschner M (2011) Lack of association between autism and four heavy metal regulatory genes. Neurotoxicology 32:769–775

    Article  CAS  Google Scholar 

  12. Yu M, Cao T, Yu D, Huang F (2018) Association study between metallothionein-3 protein polymorphisms and autism. Neurotox Res 34:74–78. https://doi.org/10.1007/s12640-017-9858-y

    Article  CAS  PubMed  Google Scholar 

  13. Krezel A, Maret W (2007) Dual nanomolar and picomolar Zn(II) binding properties of metallothionein. J Am Chem Soc W 129:10911–10921

    Article  CAS  Google Scholar 

  14. Kim YS, Leventhal BL (2015) Genetic epidemiology and insights into interactive genetic and environmental effects in autism spectrum disorders. Biol Psychiatry 77:66–74

    Article  CAS  Google Scholar 

  15. Petro A, Sexton HG, Miranda C, Rastogi A, Freedman JH, Levin ED (2016) Persisting neurobehavioral effects of developmental copper exposure in wildtype and metallothionein 1 and 2 knockout mice. BMC Pharmacol Toxicol 17:55. https://doi.org/10.1186/s40360-016-0096-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Makkonen I, Riikonen R, Kokki H, Airaksinen MM, Kuikka JT (2008) Serotonin and dopamine transporter binding in children with autism determined by SPECT. Dev Med Child Neurol 50:593–597

    Article  Google Scholar 

  17. Pinter TB, Stillman MJ (2014) The zinc balance: competitive zinc metalation of carbonic anhydrase and metallothionein 1A. Biochemistry 53:6276–6285

    Article  CAS  Google Scholar 

  18. Raudenska M, Gumulec J, Podlaha O, Sztalmachova M, Babula P, Eckschlager T, Adam V, Kizek R, Masarik M (2014) Metallothionein polymorphisms in pathological processes. Metallomics 6:55–68

    Article  CAS  Google Scholar 

  19. 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 

  20. American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders: DSM-IV-TR. American Psychiatric Association, Washington

    Google Scholar 

  21. Rutter M, Le CA, Lord C (2003) Autism diagnostic interview-revised (ADI-R). Western Psychological Services, Los Angeles

    Google Scholar 

  22. Schopler E, Reichler RJ, Rochen-Renner B (1998) The Childhood Autism Rating Scale (CARS). Western Psychological Services, Los Angels

    Google Scholar 

  23. Ulrich BD (2000) Test of gross motor development, 2nd edn. Pro-Ed, Austin

    Google Scholar 

  24. Ulvi H, Yigiter R, Yoldas T, Dolu Y, Var A, Mungen B (2002) Manganese, zinc and copper contents in hair and their serum concentration. in patients with epilepsy. Eastern J Med 7:3–5

    Google Scholar 

  25. Babaei J, Jalali A, Galehdari H, Saki A (2016) MT1A (A > G), MT1A (C > G), MT1 M (A > C), and MT4 (G > A) single nucleotide polymorphism allele frequencies in Iranian populations. Biotechnol Biotechnol Equip 30:963–969

    Article  CAS  Google Scholar 

  26. Faber S, Zinn GM, Kern JC 2nd, Kingston HM (2009) The plasma zinc/serum copper ratio as a biomarker in children with autism spectrum disorders. Biomarkers 14:171–180

    Article  CAS  Google Scholar 

  27. Macedoni-Lukšič M, Gosar D, Bjørklund G, Oražem J, Kodrič J, Lešnik- Musek P, Zupančič M, France-Štiglic A, Sešek-Briški A, Neubauer D, Osredkar J (2015) Levels of metals in the blood and specific porphyrins in the urine in children with autism spectrum disorders. Biol Trace Elem Res 163:2–10

    Article  Google Scholar 

  28. Takeda A, Hirate M, Tamano H, Oku N (2003) Release of glutamate and GABA in the hippocampus under zinc deficiency. J Neurosci Res 72:537–542

    Article  CAS  Google Scholar 

  29. Li SO, Wang JL, Bjørklund G, Zhao WN, Yin CH (2014) Serum copper and zinc levels in individuals with autism spectrum disorders. NeuroReport 25:1216–1220

    Article  CAS  Google Scholar 

  30. Russo AJ, deVito R (2011) Analysis of copper and zinc plasma concentration the efficacy of zinc therapy in individuals with Asperger’s syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS) and autism. Biomark Insights 6:127–133

    Article  CAS  Google Scholar 

  31. Black MM, Baqui AH, Zaman K, Ake Persson L, El Arifeen S, Le K, McNary SW, Parveen M, Hamadani JD, Black RE (2004) Iron and zinc supplementation promote motor development and exploratory behavior among Bangladeshi infants. Am J Clin Nutr 80:903–910

    Article  CAS  Google Scholar 

  32. Gardner JMM, Powell CA, Baker-Henningham H, Walker SP, Cole TJ, Grantham-McGregor SM (2005) Zinc supplementation and psychosocial stimulation: effects on the development of undernourished Jamaican children. A J Clin Nutr 82:399–405

    Article  CAS  Google Scholar 

  33. Colombo J, Zavaleta N, Kannass KN, Lazarte F, Albornoz C, Kapa LL, Caulfield LE (2014) Zinc supplementation sustained normative neurodevelopment in a randomized, controlled trial of Peruvian infants aged 6–18 months. J Nutr 144:1298–1305. https://doi.org/10.3945/jn.113.189365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Castillo-Durán C, Perales CG, Hertrampf ED, Marín VB, Rivera FA, Icaza G (2001) Effect of zinc supplementation on development and growth of Chilean infants. J Pediatr 138:229–235

    Article  Google Scholar 

  35. Russo AJ, Bazin AP, Bigega R, Carlson RS 3rd, Cole MG, Contreras DC, Galvin MB, Gaydorus SS, Holik SD, Jenkins GP, Jones BM, Languell PA, Lyman PJ, March KP, Meuer KA, Peterson SR, Piedmonte MT, Quinn MG, Smaranda NC, Steves PL, Taylor HP, Waddingham TE, Warren JS (2012) Plasma copper and zinc concentration in individuals with autism correlate with selected symptom severity. Nutr Metab Insights 5:41–47. https://doi.org/10.4137/NMI.S8761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Berkeley SL, Zittel LL, Pitney LV, Nichols SE (2001) Locomotor and object control skills of children diagnosed with autism. Adapt Phys Activ Q 18:405–416

    Article  Google Scholar 

  37. Pan CY (2009) Age, social engagement, and physical activity in children with autism spectrum disorders. Res Autism Spectr Disord 3:22–31

    Article  Google Scholar 

  38. Staples K, Reid G (2010) Fundamental movement skills and autism spectrum disorders. J Autism Dev Disord 40:209–217. https://doi.org/10.1007/s10803-009-0854-9

    Article  PubMed  Google Scholar 

  39. Breslin CM, Rudisill ME (2011) The effect of visual supports on performance of the TGMD-2 for children with autism spectrum disorder. Adapt Phys Activ Q 28:343–353

    Google Scholar 

  40. MacDonald M, Lord C, Ulrich D (2013) The relationship of motor skills and adaptive behavior skills in young children with autism spectrum disorders. Res Autism Spectr Disord 7:1383–1390

    Article  Google Scholar 

  41. Allen KA, Bredero B, Van Damme T, Ulrich DA, Simons J (2017) Test of gross motor development-3 (TGMD-3) with the use of visual supports for children with autism spectrum disorder: validity and reliability. J Autism Dev Disord 47:813–833

    Article  CAS  Google Scholar 

  42. Locks LM, Manji KP, McDonald CM, Kupka R, Kisenge R, Aboud S, Wang M, Bellinger DC, Fawzi WW, Duggan CP (2017) The effect of daily zinc and/or multivitamin supplements on early childhood development in Tanzania: results from a randomized controlled trial. Matern Child Nutr. https://doi.org/10.1111/mcn.12306

    Article  PubMed  Google Scholar 

  43. Sakulsak N (2012) Metallothionein: an overview on its metal homeostatic regulation in mammals. Int J Morphol 30:1007–1012

    Article  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Research on Children with Special Needs, National Research Centre, Giza, Egypt

    Nagwa A. Meguid, Ola H. Gebril, Mona Anwar, Amal Elsaeid & Ahmad Gaber

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

    Nagwa A. Meguid

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

    Geir Bjørklund

  4. Department of Pharmacology, Faculty of Medicine, Ovidius University, Constanţa, Romania

    Monica Daniela Doşa

  5. Department of Basic Sciences and Biomechanics, Faculty of Physical Therapy, Heliopolis University, Cairo, Egypt

    Mona Anwar

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

    Salvatore Chirumbolo

  7. CONEM Scientific Secretary, Verona, Italy

    Salvatore Chirumbolo

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  1. Nagwa A. Meguid
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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.

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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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Meguid, N.A., Bjørklund, G., Gebril, O.H. et al. The role of zinc supplementation on the metallothionein system in children with autism spectrum disorder. Acta Neurol Belg 119, 577–583 (2019). https://doi.org/10.1007/s13760-019-01181-9

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