Research indicates that children with autism spectrum disorder (ASD) appear to be at risk for zinc (Zn) deficiency, copper (Cu) toxicity, and often disturbed metallothionein (MT) system functioning (1-4, 6). Working with international researchers, the following is a summary of our work.

Li et al. (2014) investigated the serum levels of Zn and Cu in 60 Chinese children with ASD (48 boys, 12 girls) and a control group of 60 healthy sex-matched and age-matched individuals (2). The researchers also evaluated the autism severity using the Childhood Autism Rating Scale (CARS) score. The mean serum Zn levels and Zn/Cu ratio in the study were significantly lower in the ASD children compared with the control group (P<0.001). At the same, the serum Cu levels were significantly higher in the ASD children compared with the control group (P<0.001). It was in the study found a significant negative association between the Zn/Cu ratio and CARS scores (r=-0.345, P=0.007) (2).

Macedoni-Lukšič et al. (2015) determined the serum levels of Zn and Cu in a group of Slovenian children with ASD (N = 52, average age = 6.2 years) and a control group of children with other neurological disorders (N = 22, average age = 6.6 years), matched in terms of intellectual abilities (3). Compared to the control group, the ASD group had significantly elevated serum Cu/Zn ratio (95% confidence interval for children with ASD=1.86-2.26; 95% confidence interval for the control group=1.51-1.88) (3).

Crăciun et al. (2016) investigated the levels of Zn and Cu in whole blood, as well as the Cu/Zn ratio in a group of 28 Romanian ASD children. No significant difference in whole blood Cu was observed. However, Cu/Zn ratio was ~15 % (p = 0.008) higher in ASD children than that in the control ones. The results of the study may be indicative of Zn deficiency in ASD children (4).

Saldanha Tschinkel et al. (2018) investigated the plasma concentrations of Cu, Zn, and selenium (Se) in 23 patients with ASD (≤ 18 years old, both sexes) residing in Campo Grande, Brazil (5). No marked difference in the intake of the trace elements related to the residential area, dietary habit, or metabolic state was found.

Meguid et al. (2019) investigated 30 Egyptian ASD children (age range 3-8 years) who received Zn supplementation in 12 weeks (6). The daily dosage of Zn was equal to the body weight in kg plus 15-20 mg. Following Zn supplementation, the cognitive-motor performance and the serum MT concentration increased, and the serum levels of Cu decreased significantly. After Zn therapy, the MT-1 gene expression was higher in the ASD patients than before the treatment.

In conclusion, our research suggests that providing Zn to ASD children may be an important component of a treatment protocol, especially in children with Zn deficiency (1-4, 6). Mercury accumulation may occur as a cause or consequence of MT dysfunction in ASD children, which may be one of the causes of Zn deficiency. MTs are proteins with important functions in metal metabolism and protection. It is important to monitor and follow the values for both Cu and Zn together during Zn therapy because these two trace elements are both antagonists in function, and essential for living cells (1).

– Geir Bjørklund

References

1. Bjørklund G. The role of zinc and copper in autism spectrum disorders. Acta Neurobiol Exp 2013; 73: 225–236.
2. Li SO, Wang JL, Bjørklund G, Zhao WN, Yin CH. Serum copper and zinc levels in individuals with autism spectrum disorders. Neuroreport 2014; 25: 1216-1220.
3. 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. Levels of metals in the blood and specific porphyrins in the urine in children with autism spectrum disorders. Biol Trace Elem Res 2015; 163: 2-10.
4. Crăciun EC, Bjørklund G, Tinkov AA, Urbina MA, Skalny AV, Rad F, Dronca E. Evaluation of whole blood zinc and copper levels in children with autism spectrum disorder. Metab Brain Dis 2016; 31: 887-890.
5. Saldanha Tschinkel PF, Bjørklund G, Conón LZ, Chirumbolo S, Nascimento VA. Plasma concentrations of the trace elements copper, zinc and selenium in Brazilian children with autism spectrum disorder. Biomed Pharmacother 2018; 106: 605-609.
6. Meguid NA, Bjørklund G, Gebril OH, Doşa MD, Anwar M, Elsaeid A, Gaber A, Chirumbolo S. The role of zinc supplementation on the metallothionein system in children with autism spectrum disorder. Acta Neurol Belg 2019; 119: 577-583.

There is growing evidence for a gut-brain connection associated with autism spectrum disorder (ASD), which suggests a potential benefit for digestive enzyme therapy in autistic children (1). Working with an Egyptian team, Geir Bjørklund and collaborators performed a double-blind, randomized clinical trial on 101 children with ASD (82 boys and 19 girls) aged from 3 to 9 years (1).

The autistic children were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition, text revision (DSM-IV-TR) diagnostic criteria. Structured interviews of at least one hour were first performed both with the parents and the children. In a later two hours session was the Childhood Autism Rating Scale (CARS) applied.

After this, the children with ASD were randomized to receive digestive enzymes or placebo (1). It was found that autistic children that received digestive enzyme therapy for three months had significant improvement in emotional response, general impression autistic score, general behavior, and gastrointestinal symptoms. These results indicate that digestive enzyme therapy in the future may be a possible option in the treatment protocols for ASD (1).

The first author of the article, Khaled Saad, is an Associate Professor of Pediatrics at Assiut University, Assiut, Egypt. Geir Bjørklund is the founder and president of the Council for Nutritional and Environmental Medicine (CONEM).

Reference

1. Saad K, Eltayeb AA, Mohamad IL, Al-Atram AA, Elserogy Y, Bjørklund G, El-Houfey AA, Nicholson B. A randomized, placebo-controlled trial of digestive enzymes in children with autism spectrum disorders. Clin Psychopharmacol Neurosci 2015; 13(2): 188-193.

Vitamin D deficiency has been previously reported in patients with autism spectrum disorder (ASD). However, the data on the relationship between vitamin D deficiency and the severity of ASD are limited. In collaboration with Egyptian researchers, Geir Bjørklund (2015) performed a case-controlled cross-sectional analysis on 122 children with ASD, to assess their vitamin D status compared to healthy control children and the relationship between the degree of vitamin D deficiency and the severity of ASD (1).

Fifty-seven percent of the patients with ASD in the study had vitamin D deficiency, and 30% had vitamin D insufficiency. The vitamin D levels in children with severe ASD were significantly lower than those in children with mild/moderate ASD. It was found that the vitamin D levels had significant negative correlations with the Childhood Autism Rating Scale (CARS) scores (1).

106 children with low serum vitamin D levels (<30 ng/ml) then participated in an open-label trial of vitamin D supplementation. The patients were given 300 IU/kg/day (not to exceed 5000 IU/day) for three months. Eighty-three ASD patients completed three months of daily vitamin D treatment. 80.72% (67/83) of the children with ASD who received vitamin D3 treatment had significantly improved outcomes, which was mainly in the sections of the Childhood Autism Rating Scale and aberrant behavior checklist subscales that measure behavior, stereotype, eye contact, and attention span (1). Of the 16 parameters measured, ten showed highly statistically significant improvements (see table below).

The researchers concluded that as vitamin D is inexpensive, readily available and safe it may have beneficial effects in ASD patients, particularly when the final serum level is more than 40 ng/ml (1). It should be noted that these results were achieved after only three months of vitamin D supplementation. In a condition that is often present at birth and lasts a lifetime, this is a highly significant finding and should be fully explored immediately.

The first author of the study, Khaled Saad, is an Associate Professor of Pediatrics at Assiut University, Assiut, Egypt. Geir Bjørklund is the founder and president of the Council for Nutritional and Environmental Medicine (CONEM). Also, one of the coauthors is John Cannell, MD. He is the founder of the Vitamin D Council in San Luis Obispo, California, United States. The study is registered in the UMIN Clinical Trials Registry: UMIN000016770.

Reference

1. Saad K, Abdel-rahman AA, Elserogy YM, Al-Atram AA, Cannell JJ, Bjørklund G, et al. Vitamin D Status in Autism Spectrum Disorders and the Efficacy of Vitamin D Supplementation in Autistic Children. Nutr Neurosci. Article first published online: 15 Apr 2015. DOI: http://dx.doi.org/10.1179/1476830515Y.0000000019.

Researchers at Assiut University have in collaboration with Geir Bjørklund evaluated the neuropsychological status in 78 children with early and continuously treated phenylketonuria (PKU) in Assiut, Upper Egypt. PKU is an inborn error of metabolism that results in decreased metabolism of the amino acid phenylalanine. 

In 2015, the article was published in Acta Neurologica Belgica. The first author of the study, Khaled Saad, is an Associate Professor of Pediatrics at Assiut University, Assiut, Egypt. Bjørklund is the founder and president of the Council for Nutritional and Environmental Medicine (CONEM).

Khaled Saad, Yasser Elserogy, Ahmed A. Abdel rahman, Abdulrahman Abdullah Al-Atram, Ismail L. Mohamad, Tarek T. H. ElMelegy, Geir Bjørklund, and Amira A. El-Houfy

ADHD, autism and neuroradiological complications among phenylketonuric children in Upper Egypt

Acta Neurol Belg 2015; 115: 657–663. doi: 10.1007/s13760-014-0422-8 

ABSTRACT

The aim of this study is to evaluate the neuropsychological status in a cohort of children with early and continuously treated phenylketonuria in Assiut, Upper Egypt. The study was implemented in seventy-eight phenylketonuria (PKU) children. Only 34 patients met the inclusion criteria. Investigated patients were evaluated according to detailed history, neurological examination, Childhood Autism Rating Scale, full scale Intelligence Quotient, attention deficit hyperactivity disorder, electroencephalography and magnetic resonance imaging (MRI). This study concluded that the prognosis for early diagnosed children with PKU treated from the first weeks of life is generally good. However, they are at increased risk for neurological complications and behavioral problems. So, neonatal screening for PKU is highly recommended in Egypt, for early detection and management. In addition, neuropsychological and MRI assessments in PKU children should be done.

In collaboration with Chinese researchers, Geir Bjørklund investigated the serum levels of zinc (Zn) and copper (Cu) in 60 Chinese children with autism (48 boys, 12 girls) and a control group of 60 healthy sex-matched and age-matched individuals. The researchers also evaluated the severity of autism using the Childhood Autism Rating Scale (CARS) score. The mean serum Zn levels and Zn/Cu ratio in the study were significantly lower in autistic children compared with the control group (P<0.001). At the same time were the serum Cu levels significantly higher in autistic children compared with the control group (P<0.001). It was in the study found a significant negative association between the Zn/Cu ratio and CARS scores (r=-0.345, P=0.007). 

The original article is published in NeuroReport (2014; 25 (15): 1216–1220). Bjørklund is the founder and president of the Council for Nutritional and Environmental Medicine (CONEM).

Si-Ou Li, Jia-Liang Wang, Geir Bjørklund, Wei-Na Zhao, and Chang-Hao Yin

Serum copper and zinc levels in individuals with autism spectrum disorders

Neuroreport 2014; 25 (15): 1216-1220

ABSTRACT

Trace elements play a critical role in the pathogenesis of autism spectrum disorders (ASD). The aim of this study was to investigate the serum levels of zinc (Zn) and copper (Cu) in Chinese children with ASD. Sixty patients (48 males, 12 females) diagnosed with ASD and 60 healthy sex-matched and age-matched control participants were assessed for serum Zn and Cu content at admission. The severity of ASD was also evaluated using the Childhood Autism Rating Scale (CARS) score. The results indicated that the mean serum Zn levels and Zn/Cu ratio were significantly lower in children with ASD compared with normal cases (P<0.001, respectively), whereas serum Cu levels were significantly higher (P<0.001). There was a significant negative association between Zn/Cu and CARS scores (r=-0.345, P=0.007). On the basis of the receiver operating characteristic curve, the optimal cut-off value of serum levels of Zn/Cu as an indicator for an auxiliary diagnosis of autism was projected to be 0.665, which yielded a sensitivity of 90.0% and a specificity of 91.7%; the area under the curve was 0.968 (95% confidence interval, 0.943-0.993). In conclusion, these results suggested an association between serum levels of Zn and Cu and ASD among Chinese patients, and the Zn/Cu ratio could be considered a biomarker of ASD.

The review article by Geir Bjørklund is published in Acta Neurobiologiae Experimentalis (2013; 73 (2): 225–236). This peer-reviewed journal is published by the Nencki Institute of Experimental Biology in Warsaw, Poland. Bjørklund is the founder and president of the Council for Nutritional and Environmental Medicine (CONEM).

Geir Bjørklund

The role of zinc and copper in autism spectrum disorders

Acta Neurobiol Exp (Wars) 2013; 73 (2): 225-236 

ABSTRACT

Autism spectrum disorders (ASDs) are a group of developmental disabilities that can cause significant social, communication and behavioral challenges. Several studies have suggested a disturbance in the copper (Cu) and zinc (Zn) metabolism in ASDs. Zinc deficiency, excess Cu levels, and low Zn/Cu ratio are common in children diagnosed with an ASD. The literature also suggests that mercury accumulation may occur as a cause or consequence of metallothionein (MT) dysfunction in children diagnosed with an ASD, which may be one of the causes of Zn deficiency. MTs are proteins with important functions in metal metabolism and protection. Zinc and Cu bind to and participate in the control of the synthesis of MT proteins. Studies indicate that the GABAergic system may be involved in ASDs, and that Zn and Cu may play a role in this system.