The prevalence of attention-deficit hyperactivity disorder (ADHD) according to DSM-5 worldwide is approximately 5% among children, which is more frequent among males than females 1. ADHD constitutes a major public health problem in the USA according to Gapin and Etnier, 2014 2.
The prevalence of ADHD across Arab countries is underestimated. The estimate is from 7.4 to 14.8%, ranging from 7.8 to 18.3% among boys and 3.5–11.4% among girls 3. Specifically, the prevalence of ADHD in Egypt is still underestimated in spite of the major burden of this disorder.
Genetic factors play a major role in the etiology of ADHD. Studies have already found multiple genes involved in the disorder. The identification of DNA polymorphisms has been used by scientists to implicate the genetic basis of cognition 4.
Methylenetetrahydrofolate reductase (MTHFR) has a role in the active cycle of folate metabolism in the body. MTHFR activates 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate (5-MTHF), the active form of folate, which has a role in the methylation reactions of nucleic acid, proteins, neurotransmitters (NTs), phospholipids, and remethylation of homocysteine 5,6. The active form of folate plays a role in cognition and in the production of monoamine NTs that affect psychological functions 7.
Two variants of MTHFR (677C>T and 1298A>C) have been identified and studied. The final pathway of the two variants can be affected by nutritional status, environment, genotype, and race/ethnicity 8,9.
The C677C is the normal variant. The C677T allele could be either heterozygous (C/T) or homozygous (T/T). Individuals homozygous for C677T have at least a 50–60% reduction in MTHFR activity. Similarly for A1298C, compared with the normal homozygotes (AA), enzyme activity has been shown to be lowered in homozygote variants (CC) and to a lesser extent in heterozygotes (AC). The C677T allele [especially the homozygous genotype (T677T) or the combination of C677T with other MTHFR variants such as A1298C] can contribute to hyperhomocysteinemia 6.
A meta-analysis of studies examined the association between polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, including MTHFR C677T and A1298C, and common psychiatric disorders, including unipolar depression, anxiety disorders, bipolar disorder, and schizophrenia, and raised the possibility of use of folate in treatment and prevention 10.
The term executive functions (EFs) refers to cognitive functions that represent an essential role for all individuals as they organize multiple domains. A model of EFs, including activation, focus, effort, emotion, memory, and action, has been shown to be affected in children with ADHD 11.
Most of the studies conducted about folic acid and MTHFR gene polymorphisms were focusing on adult psychiatric disorders with little attention to childhood psychiatric disorders including ADHD and autism 12.
An examination of MTHF gene polymorphisms and their relation to EFs in ADHD has received limited research attention. To our knowledge, this is one of the first attempts to study the role of MTHF gene polymorphisms in ADHD and its relationship to EF in Egypt.
This study aimed to determine the relationship between common MTHFR gene mutations (C677T and A1298C) and Vanderbilt ADHD Diagnostic Parent Rating Scale, Wechsler intelligence scale as well as Wisconsin card sorting test in ADHD, a disorder where genetic factors play an important role in its etiology, versus control, with the following objectives:
- Examining two gene polymorphisms at base pair 677 and 1298 in children with ADHD, as they are linked to enzyme activity.
- Comparing each gene polymorphisms at base pair 677 and 1298 in children with ADHD with the clinical and EFs of those children.
Participants and methods
The study was designed as a case–control study, conducted between November 2015 and March 2016. A total of 95 successive children with ADHD (ADHD group) were enrolled to be involved in the study. The dropouts were owing to refusal to participate in the study (18 participants), or not matched with the selected criteria (12 participants). Finally, a total of 65 subjects with ADHD were involved in the study and were recruited from the child and adolescent psychiatry outpatient clinic of Mansoura University Hospital, which serves Dakahlia Governorate and surrounding areas. The diagnosis of ADHD was based on DSM-IV criteria.
Inclusion criteria of ADHD children were as follows: (a) they are of both genders, (b) their age ranged from 6.5 to 12 years (because Wisconsin card sorting test should be applied to individuals with age ranging from 6.5 to 89 years), and (c) have no past history of sensory or motor disabilities. Exclusion criteria were as follows: (a) having an intelligence quotient (IQ) below than 80; (b) diagnosis of other comorbidities, for example, anxiety, depression, or conduct disorder; (c) diagnosis of pervasive developmental disorders; (d) presence of psychosis, substance abuse, and chronic medical or neurological diseases; and (e) history of physical and/or sexual abuse because they might overlap with ADHD symptoms leading to their exacerbation.
The control group consisted of 69 healthy children of hospital staff members, or members of general community who were interested to participate in the study after being aware of the study details. They were age, sex, socioeconomic as well as IQ matched with the patient group.
The local ethical committee at Mansoura University Hospital, Egypt, approved the study. A written consent was obtained from parents of children with ADHD as well as parents of normal healthy controls.
All the following tools were applied to both cases and controls.
We have developed a set of questionnaires to assess the full items of child psychiatric history. Neurological evaluation was done to exclude any comorbidity.
Psychiatric scales, interview, and batteries
Screening for ADHD
We used the Arabic version 13 of the Vanderbilt ADHD Diagnostic Parent Rating Scale (VADPRS) 14. It is a highly reliable and valid tool used to screen ADHD in various studies 13,15. The Vanderbilt diagnostic rating scale uses a four-point Likert rating, in which a respondent notes whether 18 specific behavior symptoms of ADHD occur rarely, sometimes, often, or very often. Patients screened positive (with 6 or more items in any or both of the inattention and/or hyperactivity impulsivity domains, plus impairment in two settings) were considered to have ‘possible ADHD’ (inattentive, hyperactive, or combined).
Kiddie schedule for affective disorders and schizophrenia, present and lifetime versions (K-SADS-PL)
The Arabic version was used for clinical diagnosis of ADHD and other comorbid psychiatric disorder 16. The K-SADS is an interviewer-based, semi-structured interview for children age 6–18 years. Its primary goals is to assess current and lifetime history of psychiatric disorders, to assess episodes of psychopathology, and to make categorical diagnosis by directly interviewing children and adolescents and their parents, according to DSM-III-R and DSM-IV criteria.
Wechsler intelligence scale for children 17
The Arabic version was used 18.The Wechsler scale provides information about subject’s intelligence. It illustrates verbal IQ (VIQ), performance IQ (PIQ), and total IQ (TIQ). It was developed for children aged from 5 to 15 years.
Executive function assessment using computerized version of Wisconsin card sorting tests 19
The Wisconsin Card Sorting Test or WCST is a task that measures the ability to adjust a strategy to changing demands (set shifting). The task consisted of four stimulus cards and two sets of 64 response cards presented on screen. It is a standardized test used for individuals 6.5 to 89 years of age. The following items are provided after scoring of WCST: total errors raw score; number of categories completed; trials to complete first category (TCFC); numbers of perseverative errors; and nonperseverative errors.
DNA extraction and MTHFR genotyping
From all participants, 5 ml of venous blood samples was obtained on EDTA-containing tubes. DNA of all samples (patients and controls) was extracted from whole blood by using Thermo Scientific Genomic DNA Purification Mini Kit (Thermo Scientific, Vilnius, Lithuania) following the manufacturer’s protocol. PCR-Restriction Fragment Length Polymorphism (PCR-RFLP) was done for all extracted samples to detect the selected two MTHFR gene polymorphisms: one at base pair 677 and the other at 1298.
Two sets of primers were used for each polymorphism. For that involving 677 base pair, the forward primer was 5’-TGAAGGAGAAGGTGTCTGCGGGA-3’ and the reverse primer was 5’-AGGACGGTGCGGTGAGAGTG-3’. The other involving 1298 base pair, the forward primer was 5’-GCA AGT CCC CCA AGG AGG-3’ and the reverse primer was 5’-GGT CCC CAC TTC CAG CAT C-3’. The volume of each PCR reaction was 25 μl containing the following components: 10 Mm tris HCL, 1.5 Mm MgCl2, 50 mMKCl, 1U Taq polymerase, 400 µMdNTP, and 0.5 mM primer.
The PCR protocol for both regions were as follows: 3 min of initial denaturation at 95°C, followed by 35 cycles of 95°C for 30 s, 61°C for 60 s, and 72°C for 60 s, with a final extension at 72°C for 7 min.
The amplified products were digested by two restriction enzymes separately: HinfI restriction enzyme (FD 0804; Thermo Scientific) for 677 region, and MboII restriction enzyme (FD 0824; Thermo Scientific) for 1298 region. The products of digestion were loaded on 2% agarose gel for 677 region and 3% agarose for 1298 for visualization.
The digestion fragment sizes for 677 regions were a single band at 198bp for CC; 198, 175 and 23bp for CT; and 175bp and 23bp for TT. The digestion fragment sizes for 1298 region were fragments at 56, 31, 30, and 28bp for AA; 84, 31, 30, and 28bp for CC; and 84, 56, 31, 30, and 28bp for AC.
Analysis was done using a statistical package for the social sciences, version 22 (SPSS; SPSS Inc., Chicago, Illinois, USA). The results were analyzed using descriptive and analytical statistics. Mean and SD were used for quantitative data. Student’s t-test was used to test for statistical significance of variance between two samples means. χ2-Test as a statistical test was used to determine the probability that an observed deviation from the expect event or outcome occurs solely by chance for qualitative data. Correlation efficiency was done to detect association between variables. P value is significant if less than or equal to 0.05 at confidence interval of 95%.
In this study, we analyzed 65 patients with ADHD and 69 healthy controls. Table 1 shows the age and clinical data of patients and controls. Mean age of patients was 8.03±1.4 compared with 9.38±1.7 in controls, and there was no statistical difference.
However, there was a statistically significant difference in mean Vanderbilt score in patients (33.4±14) compared with in controls (9.7±5). There were significant differences in Wechsler total score, verbal and performance components, between the two groups. Concerning Wisconsin card sorting test, it showed significant difference in the number of categories completed; none of the other items showed any significant difference.
Table 2 presents demographic and genetic results in cases and controls. Regarding sex, both groups were matched, and most individuals were males in both cases and control groups. Concerning residence, most of the individuals in both cases and controls were from rural areas.
There were statistically significant differences in genotype distributions of the C677T alleles and A1298C alleles between the ADHD and control groups (P=0.03). MTHFR Gene C677T Alleles distribution in ADHD was CC 50.8% and CT and TT 49.2%, whereas MTHFR Gene A1298C alleles was AA 30.8% and AC and CC 69.2% (Figs 1 and 2).
Table 3 illustrates the demographic and genetic results in ADHD subtypes. The percentage of ADHD subtypes in males and females was as follows: inattention, 37.5 and 62.5%, respectively; hyperactive, 52 and 48%, respectively; and combined, 83.3 and 16.7%, respectively.
The comparison of clinical variables of ADHD group between each of MTHF C677T gene polymorphisms as well as MTHF A1298C gene polymorphisms showed no statistically significant difference as shown in Tables 4 and 5. These clinical variables included Vanderbilt ADHD score, Wechsler intelligence scale (total as well as verbal and performance scores), and Wisconsin card sorting test (total errors, TCFC, number of categories completed, number of preservative errors, and nonpreservative errors).
The two predominant approaches to understand the molecular genetics underlying ADHD are linkage analyses and association studies. Linkage analyses investigate families to find genetic markers that are present in family members. On the contrary, association studies use unrelated affected patients and unaffected controls to illustrate the candidate genes involved with the disorder. More recently, tools that examine DNA polymorphisms have been implicated in genome-wide association studies 20. Numerous genes involved in biological processes such as synaptic transmission, catecholamine metabolic processes, G-protein signaling pathways, and cell migration were involved in ADHD 21.
Nutrigenomics investigate genetic expression and genes affecting nutrient needs. Individuals with unique genetic expression do not produce adequate MTHFR. Single nucleotide polymorphisms in MTHFR results in production of an enzyme with decreased activity, which affects many biochemical processes. They can also cause hyperhomocysteinemia, affect neural system and vascular health, and can contribute to birth defects 6,22,23.
Folate plays an essential role in nerve growth, differentiation, repair, cognition, and mood. Multiple studies have demonstrated that folate deficiency results in cognitive deterioration in the form of attention, memory, visuospatial memory, and abstract reasoning impairment 24–26. Ghanizadeh et al. 27, reported no superiority of folic acid as an adjuvant to methylphenidate on ADHD symptoms and quality of life and aggression. Most recent theories of ADHD showed that the disorder arises from a deficit in EF as one of the main features 28.
This is one of few studies that asses the role of MTFR C677T and A1298C polymorphisms in children with ADHD. In addition to that, it is the first study to investigate the relation between the EFs and MTFR C677T and A1298C polymorphisms.
In the present cross-sectional case–control study, we investigated the comparison of clinical and EFs with reference to MTHFR C677T and A1298C polymorphism primers of children with ADHD. Furthermore, we explored the EF in children with ADHD, and found no statistically significant difference between both MTHFR C677T and A1298C polymorphisms and EFs using Wisconsin card sorting test. Our study further verified that there are statistically significant differences in genotype distributions of the C677T alleles and A1298C alleles between the ADHD and control groups (P=0.03).
A case-control study conducted by Ergul et al.29, on 100 patients with ADHD and 300 healthy controls in Turkey showed no statistically significant differences in genotype distributions of the C677T alleles and A1298C alleles in both groups. However, a case-control study carried out on Turkish children by Gokcen et al. 30 on 40 ADHD cases and 30 controls revealed statistical significance among A1298C, but no statistically significant differences were found among C677T alleles (P=0.678). Franke et al.31, using genome-wide scans reported no linkage to MTHFR gene in ADHD disorder.
A study conducted by Spellicy et al.32 to examine the relation between the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene and behaviors related to ADHD in individuals with myelomeningocele showed a positive association between the SNP rs4846049 in the 39-untranslated region of the MTHFR gene and the ADHD phenotype in myelomeningocele participants.
Another study aiming to investigate the incidence of ADHD following acute lymphoblastic leukemia therapy revealed that children with the A1298C genotype had a 7.4-fold increase in ADHD diagnosis, whereas those with the C677T SNP had a 1.3-fold increase in ADHD diagnosis 33.
The pathophysiology of MTHFR C677T polymorphisms as a contributor to ADHD disorder in children is still not obvious. Multiple researches have shown that ADHD is attributed to abnormalities in folate, which represents a crucial factor in DNA methylation and gene expression 24–27. Limited studies have investigated the MTHFR polymorphism A1298C, which encodes glutamine 429 alanine substitutions 30,33.
In the present study, there was a significant difference in numbers of categories completed parameter of WCST results between cases and controls. On the contrary, there were no significant differences in total errors, TCFC, preservative errors, and nonpreservative error raw score.
Concerning Wisconsin card sorting test, 17 of 26 studies using the WCST found significant differences between ADHD and normal controls 34. Children with ADHD complete fewer categories than normal controls 35.
The results of a meta-analysis suggest that across all of the studies, individuals with ADHD showed poorer performance as compared with normal controls on the WCST, with particular decreased performance on percent correct, total errors, and perseverative errors 36. Karama et al. 37 showed no significant differences among trials to complete first category, categories completed, total errors, preservative errors and non-preservative error raw score.
In the WCST, the ADHD group showed a greater amount of total errors, TCFC, and perseverative errors, which is comparable to a study by Tellez et al. 2012, who found that the ADHD group showed a greater amount of total errors, perseverative errors, and perseverative responses as well as a lower number of answers on the conceptual level compared with the control group 38.
There are certain explanations for the finding regarding the EF in children with ADHD in the present study. First of all, our sample size is small, and second, EFs are wide complex functions, having multiple components, so they should be evaluated by multiple tests or a comprehensive battery. In our study, we used only WCST, which represents problem solving set shifting domain only.
In the current study, MTHFR gene alleles (C677T and A1298C) were evaluated with respect to Vanderbilt ADHD score, Wechsler intelligence scale (total, verbal and performance), Wisconsin card sorting test (total errors, TCFC, number of category completed, and number of preservative errors and nonpreservative errors), with no statistically significant difference. However, an Indian pilot study on the role of folate gene variants, methylenetetrahydrofolate dehydrogenase (rs2236225), reduced folate carrier (rs1051266), and MTHFR (rs1801131 and rs1801133), in the cognitive function of ADHD probands showed significant difference in genotypic frequencies for female probands. rs1801131 and rs1801133 showed an association with low IQ 39. The difference between the current study and the Indian study could be because of the different sample size, for example, ADHD probands (N=185) and ethnically matched controls (N=216); moreover, the genotypic frequencies of the Indian population were strikingly different from other ethnic groups 39.
Limitation of the study
- This research is self-funded, which limits the sample of the study.
- We did not correlate the MTFR C677T and A1298C polymorphisms with the serum level of folic acid and homocysteine.
- Assessment of EFs using WCST represents some domains of EFs but not all.
- Small sample size limits the statistical power of the study.
- There was limited literature on the relationship between MTHFR gene mutations (C677T and A1298C) and ADHD in children (EFs).
- There was unavailability of genetic studies in Arab countries, so we compared the results with the results in other populations.
- Folic acid supplementation in ADHD in children should be considered in clinical practice, in combinations with other lines of treatment.
- Further studies should be conducted on a large population, to demonstrate the role of MTHFR C677T and A1298C in children with ADHD, in addition to correlating these polymorphisms with serum folic acid, homocysteine level, and EFs using various test batteries.
The present study provides evidence that MTHFR C677T and A1298C polymorphisms may have relationship with ADHD subtypes and with the impairment of EF in children with ADHD. No significant association was founded in comparing Wisconsin Card Sorting test with MTHFR C677T and A1298C polymorphisms. More genetic studies are needed to further analyze the topic.
The authors wish to thank the participants and volunteers who took part in this study.
Conflicts of interest
There are no conflicts of interest.
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