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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Autism spectrum disorder
Childhood Autism Rating Scale
Central nervous system
Enzyme-linked immunosorbent assay
Polymerase chain reaction
Test of gross motor development
Bjørklund G (2013) The role of zinc and copper in autism spectrum disorders. Acta Neurobiol Exp (Wars) 73:225–236
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
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
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
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
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
Jeoung B (2018) Motor proficiency differences among students with intellectual disabilities, autism, and developmental disability. J Exerc Rehabil 14:275–281
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
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
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
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
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
Krezel A, Maret W (2007) Dual nanomolar and picomolar Zn(II) binding properties of metallothionein. J Am Chem Soc W 129:10911–10921
Kim YS, Leventhal BL (2015) Genetic epidemiology and insights into interactive genetic and environmental effects in autism spectrum disorders. Biol Psychiatry 77:66–74
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
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
Pinter TB, Stillman MJ (2014) The zinc balance: competitive zinc metalation of carbonic anhydrase and metallothionein 1A. Biochemistry 53:6276–6285
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
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
American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders: DSM-IV-TR. American Psychiatric Association, Washington
Rutter M, Le CA, Lord C (2003) Autism diagnostic interview-revised (ADI-R). Western Psychological Services, Los Angeles
Schopler E, Reichler RJ, Rochen-Renner B (1998) The Childhood Autism Rating Scale (CARS). Western Psychological Services, Los Angels
Ulrich BD (2000) Test of gross motor development, 2nd edn. Pro-Ed, Austin
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
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
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
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
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
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
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
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
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
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
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
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
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
Pan CY (2009) Age, social engagement, and physical activity in children with autism spectrum disorders. Res Autism Spectr Disord 3:22–31
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
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
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
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
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
Sakulsak N (2012) Metallothionein: an overview on its metal homeostatic regulation in mammals. Int J Morphol 30:1007–1012
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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
- Cognitive motor performance