The symptoms of both types of ADHD. At least two areas from either type need to be observed for 6 months in children under the age of seven for diagnosis to be made. If symptoms are seen from both types, the diagnosis of the combined type is made. (Information adapted from Dunn and Kronenberger, 2003)
Attention Deficit Hyperactivity Disorder (ADHD) is a genetically transmitted neurological disorder which affects 5.3% of children and adolescents worldwide (Polanczykv et al, 2007). Although the onset and diagnosis usually occurs in children before the age of seven, it is also diagnosed in adults. Many children with ADHD lose their symptoms as they get older although some do suffer from the disorder as adults. A person with ADHD may be predominantly hyperactive and impulsive (Hyperactive-Impulsive Type), they may be predominantly inattentive (Inattentive Type) or they may suffer from a combination of both (Combined Type) (McFadden et al, 2005). The typical symptoms of each type are shown in Table 1. In 2009, the National Collaborating Centre for mental health defined impulsivity as having premature and thoughtless actions, hyperactivity as a restless and excess movement and inattention as a disorganised style preventing sustained effort. Although from time to time, these actions are probably seen in all children and adults, patients with ADHD will persistently be showing these characteristics and have no control of them.
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Makes careless mistakes
Cannot complete a task
Cannot follow instructions
Has poor organisation
Loses and misplaces things
Cannot sit in a seat
Running instead of walking
Shouts out answers to questions
Always loud or noisy
Constantly 'on the go'
Although a definite cause of ADHD is yet to be found, it is for certain that there is a genetic link between ADHD as it is passed on through generations in a family. Twin studies have shown that genetic factors make up between 60% to 94% contribution to ADHD (Hudziak et al 2005). These studies, which compared monozygotic and dizygotic twins showed that if one of the monozygotic twin had ADHD, the chances of the co- twin also having ADHD is much greater than with dizygotic twins. This shows that because the twins are likely to be exposed to a similar environment, the cause of ADHD must have genetic relevance. There have several genes identified which may contribute to ADHD and they can be found in a range of chromosome and affect a range of different chemical systems in the body. The most commonly explored genetic defects are in the dopaminergic systems, with dopamine receptors and transporter genes most commonly associated. Also identified are links to the noradrenaline systems, with defects in genes such as the dopamine Î² hydroxylase gene, the adrenergic receptor genes and the monoamine oxidase A gene, althought there are many others. Some serotonin genes have also been implicated with ADHD (Comings, 2001).
Dopamine is the one of the principle neurotransmitters in the brain and it is important is modulating feelings such as motivation and reward, and is also important in regulation of voluntary movement, sleep, working memory, learning and attention. These functions are often impaired in sufferers of ADHD and are therefore seen as a good target for medical intervention. Many of the drug therapies for ADHD cause the release of dopamine into the brain, such as methylphenidate and amphetamines. These stimulants act by inhibiting the dopamine transporter, which results in an increase in the extracellular concentration of dopamine in the brain (Gozal and Molfese, 2005). The short term of efficiency of these drugs in reducing the hyperactivity and impulsivity of ADHD patients reflects that the lack of or insensitivity to dopamine must play a role in causing ADHD. Studies which explore the genetics of ADHD have consistently revealed that polymorphisms in the DRD4 receptor subtype gene and the dopamine transporter gene are to some extent responsible for ADHD and these will be explored here.
Dopamine Receptor type 4 (DRD4)
There are 5 different subtypes of dopamine receptors. Of these the type 4 receptor and its genotype is of particular interest for looking at causes of ADHD. The DRD4 receptors are found primarily in GABAergic interneurons in the forebrain structures of the cerebral cortex and hippocampus, although not in the striatum. In a healthy person, activation of DRD4 by dopamine prevents the inhibitory affects of GABA, allowing the pyramidal neurons to function. As DRD4 is a G protein coupled receptor, the inhibition mechanism is due to the inhibition of the enzyme adenylyl cyclase, resulting in a decrease in the production of cAMP (Brennan & Arnsten, 2008). The cerebral cortex and the hippocampus are related to advanced cognitive function, suggesting that a defect in this system contributes to the symptoms seen in ADHD (Spruston, 2008)
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The gene that codes for this protein is located on chromosome 11p15.5 in humans (Krämer et al., 2009) and is characterised by a polymorphism which has occurred in exon III with a 48 base pair VNTR. There can be between two to seven repeats of the allele creating a varying size of the third intracellular loop of the GPCR which is important in the intracellular signalling role of the receptor (Grady et al., 2005). Although the evidence of this is disputed between scientists, many experiments have suggested that the seven repeat allele is over expressed in children with ADHD. The 7 repeat allele is less common than the two repeat allele and it is also less potent at inhibiting the production of cAMP (Krämer et al., 2009) when activated, leading to a decrease in pyramidal cell firing due to the lack of inhibition of GABA (Brennan and Arnsten, 2008). This need to link to ADHD
Figure 1. DRD4 Receptor subtypes. Each shaded box is a sequence of 16 conserved amino acids encoded by the polymorphic 48 base pairs. The 2 repeat (a), 4 repeat (b) and 7 repeat (c) are shown. The 7 repeat allele has been seen predominantly in people with ADHD. The number of shaded boxes represents the number of repeats. Here polymorphism in the coding region causes a considerable difference in the structure of the receptor. (adapted from Grady et al., 2005)
This allele has also shown geographical difference as it is less commonly observed in South Asian children (0-2%) but very prevalent in native South Americans (78%) (Nikolaidis and Gray, 2010). This may account for the differences in prevalence of ADHD across the world.
The DRD4 7 repeat allele has been shown to impact upon the time course of ADHD as with time, many patients with ADHD gradually begin to see a decrease in the number and severity of their symptoms, whilst others do see their ADHD characteristic persist into adulthood. ADHD patients who do not have the DRD4 7 repeat allele have a greater reduction in their symptoms with time, compared to those who do bear the DRD4 7 repeat allele (Langley, 2008).
Dopamine Transporter (DAT1)
The dopamine transporter is a protein with twelve transmembrane domains (Lin and Uhl, 2003) in the membranes of axons and presynaptic terminals of neurones in the brain which rapidly reuptakes the dopamine released into the synapse, into the presynaptic terminal in order to terminate the dopamine signal (Zhang et al 2009). This process, often known as dopamine clearance, decreases the amount of dopamine available in the extracellular space. The transporter is usually found in the striatum, which is located in the inner part of the forebrain and is divided into putamen and caudate nucleus by white matter. People with ADHD may have higher levels of DAT1 in their striatum, particularly in the caudate region (Shook, 2011) and hence a higher rate of dopamine clearance, leading to a decrease in the amount of dopamine available to carry out its signalling role (Larisch et al, 2006). Inhibiting this transporter, as occurs by taking the drug methylphenidate, allows the accumulation of extracellular dopamine which may help to restore some of the defects caused from ADHD.
The gene coding for the dopamine transporter (DAT1) has been studied greatly for polymorphisms and mutations which may have caused or contributed to the development of ADHD in individuals. The 15 exon gene is located on chromosome 5 (5p15.3) (Grady et al, 2005). The gene has a number of polymorphism in the form of variable number tandem repeats (VNTR) within a 40 base pair untranslated region at the 3' end of the gene (3' UTR), coded for by exon 15 (Bellgrove et al., 2005). Any variation that occur in the 3' UTR will not affect the transcription of the DNA to the mRNA, as the essential sequence for this should remain unchanged, though there will be an impact upon the transport of the mRNA from the nucleus to the cytosol where it will be translated to the polypeptide sequence making up the transporter. There may also be an adverse effect upon the stability and degradation of the mRNA and this will cause a change in the translation of the protein (Lahey et al., 2011).
A mutation within the coding sequence of the DAT1 causing a single change in an amino acid coding for DAT1 can significantly alter the ability of the transporter to locate its site of action in the plasma membrane and transport dopamine effectively (Lin and Uhl, 2003). The lack of dopamine reaching its site of action is likely to results in the behavioural abnormalities characterised by ADHD.
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There is no difference in the alleles for the DRD4 or DAT1, between children diagnosed with the Inattentive Type or the Hyperactive-Impulsive Type of ADHD (Grizenko et al., 2010)
Research on the linkage between the dopamine transporter (DAT1) and ADHD have been varied with some investigations providing some evidence to suggest that there is relation, but on the other hand many studies have failed to provide any verification (Hawi et al, 2010).
Environmental Causes of ADHD
The environmental causes of ADHD may be divided into three categories, which relate to the time the causes take place. These are pre-natal (before birth), peri-natal (from the 20th week of gestation to four weeks after birth) and post natal (after birth and into childhood). Pre-natal causes tend to relate to maternal life style which affects the developing foetus, rendering it more susceptible to ADHD. There have been studies which have provided strong correlation between maternal smoking and alcoholism and the incidence of ADHD in their offspring. The mother's diet is an essential contributor as the foetus depends on nutrients from its mother for its development and if a lack of these can results in growth abnormalities.
Peri-natal traumas such as premature birth have the implications of underdeveloped organs and systems in the body, which may not be able to develop fully unless the correct procedures are carried out by medical staff in sufficient time. Often, immature lungs and inefficient breathing by the baby can lead to hypoxia, resulting in brain damage in areas of the brain related to cognitive functions which are impaired in ADHD, as well as other areas of the brain and other organs and tissues in the body. Peri-natal factors can also include any infections caught at this time by the mother such as measles or rubella, or by the child such as meningitis.
There are numerous theories and myths which surround the causes of ADHD after birth, especially as people's life experiences vary dramatically, depending upon where they live and their conditions. Toxins from the environment such as lead, which can be abundant in water and soils, have been proven to cause ADHD due to their roles in disrupting the circulation of dopamine. Polychlorinated biphenyl (PCB) exposure causes a reduction in the dopamine levels in the prefrontal cortex and the striatum. The dopamine transporter is affected, resulting in altered synaptic and cytosolic dopamine clearance (Eubig et al, 2010). PCBs have also been shown to affect thyroid function (Mill and Petronis, 2008).
ADHD and Thyroid Function
Thyroid hormones are essential for the growth and development of the foetus and as a child. Thyroid hormones have various roles with a primary role in metabolism. Deficiencies in thyroid levels have shown to cause underdevelopment of the central nervous system, with defects particularly in attention, motor function and memory.
Mother's who suffered from a mild iodine deficiency during pregnancy are more likely to have children with ADHD (Vermiglio et al., 2004). The iodine deficiency is passed on to foetus, resulting in symptoms similar to that of Generalised Resistance to Thyroid Hormone (GRTH).
Generalised Resistance to Thyroid Hormone (GRTH) is characterised by increased serum levels of (triodthyronine) T3 and T4 (thyroxine) and increased thyrotropin concentrations. The pituitary gland and the peripheral tissues are less responsive to the actions of thyroid hormone. The disease arises from a mutation that occurs in the gene encoding the thyroid receptor Î² which is found on chromosome 3. The mutation occurs in the hormone binding domain of the receptor; hence T3 has a lower affinity for the receptor. There have been 30 mutations found in exons 9 and 10 and only one of the two alleles needs to be affected by the mutation to give rise to the disease. This is to say, the abnormal gene is autosomal dominant and is inherited if even one parent suffers from the GRTH. (Hauser et al., 1993)
The mutation is thought to cause inhibitory effects of the action of T3 in several ways. The mutant receptor may heterodimerise with wild type receptors, which are formed from the transcription and translation of the unaffected allele, causing the combinatory receptor to become inactivated. Competition may arise between the mutant receptor and the wild type receptor for a necessary cofactor needed for its function (Melmed & Conn, 2005). This results in a dominant negative phenotype which is thought to down-regulate catecholamine function (Hauser et al., 1993). It is possible for some mutated receptors to become functional is the presence of a high concentration of T3. (Melmed & Conn, 2005)
Thyroid hormone has a crucial role in neuronal development. The thyroid receptors become more predominant between 10 to 16 weeks of foetal development, when the neuroblasts are also proliferating. Experiments carried out in rats showed that activation of the thyroid receptor and interactions with the thyroid response element regulates the expression of myelin basic protein. T3 regulates brain cell proliferation in neonatal rats but not adult rats. These experiments indicate that thyroid hormones play a key role in brain development mechanisms such as cell proliferation, axonal routing and regulation of gene expression which are impaired by mutations in the receptor. (Hauser et al., 1993)
An investigation was conducted by Vermiglio et al. (2004) to see if iodine deficiency in women during pregnancy results in children with ADHD. Almost 70% of the children developed ADHD. Some of the mother's became hypothyroxinaemic (they had low circulating levels of free T4 and thyroid hormone) during the pregnancy, of which nearly 65% had offspring with ADHD. T4 provided from the mother's circulation is essential for foetal growth and development until it is able to produce and secrete its own thyroid hormones from the thyroid gland at the 20th week of gestation. Iodine deficiency is fairly common in all parts of the world, including developed countries, and if identified early (before the 24th week of gestation), administration of iodine or thyroid hormones to the mother may be able to reverse any damage caused to foetus, thereby reducing the risk of the offspring developing ADHD.
Nicotine and ADHD
Exposure to nicotine in utero via maternal smoking has been associated with ADHD. Nicotine can easily cross the placenta and the concentration in the foetus can be up to 15% higher than in the mother. Nicotine causes the constriction of uterine arteries, leading to decreased oxygen and nutrient flow to the foetus (Nomura et al., 2010). As a result of this the developing foetus will suffer from intrauterine growth retardation, and hence a small birth weight, which has also been associated as a cause ADHD.
In 2003, Kahn et al. conducted a study to investigate the affect that maternal smoking during pregnancy has on the dopamine transporter genotype of the child, and how this correlates with the symptoms of ADHD. They found that prenatal nicotine exposure modifies how the genetic polymorphism of the DAT1 gene is likely to impact upon hyperactivity, as it has been shown that the 10 repeat polymorphism of DAT1 does not necessarily lead to ADHD and not everyone with ADHD have the polymorphism. Those that are homozygous for the 10 repeat allele of DAT1 were shown to have an increased risk of hyperactivity-impulsivity. The 10 repeat allele consists of 480 base pairs, although some studies have shown that the 440 base pair allele is also associated with ADHD, in particular when relating to nicotine exposure (Neuman et al., 2007).
Nicotinic acetylcholine receptors are abundant, and exposure to nicotine causes an increase in the number of these receptors. They have very high affinity for nicotine in neurons of the striatum and cerebral cortex and stimulation of these receptors results in increased dopamine release from the synapses, which . Nicotine also stimulates the dopamine D2 receptor family (of which DRD4 is a subtype), altering the outgrowth and branching of the developing neurons (Neuman et al., 2007). Although it had been seen that children with ADHD have insufficiently released dopamine, pre-natal increase in dopamine can affect the development of the dopaminergic system. The brain damage caused by this may result in the behavioural characteristics of ADHD.
Studies conducted on this topic have varied with some studies showing evidence that children whose mother's smoked during pregnancy have double the risk of developing ADHD. Some studies have correlated maternal smoking with ADHD-like symptoms such as aggressive and disruptive behaviour and academic achievement problem. On the other hand, many studies have found that there is no significant relationship between maternal smoking and the offspring developing ADHD. There have been several explanations, which include the difficulty of obtaining a large sample size for the investigations. (Ball et al., 2010)
DAT1 and DRD4 genetic variations can modify frontostriatal (which includes the basal ganglia and dorsolateral prefrontal cortex) gray matter volumes (Neuman et al., 2007). Nicotine causes an increase in the number of nicotine receptors, which enhances the amphetamine induced release of dopamine from DAT1 in the prefrontal cortex of rats.
Pesticides and ADHD
A US study by Bouchard et al. (2010), has identified that organophosphate metabolites which are found in pesticides used to grow fruit and vegetable increases the likeliness of developing ADHD. They measured the urinary concentration of dimethyl alkyphosphate (DMAP), a metabolite of the organophosphate pesticide, to indicate the level of pesticide exposure and to compare this with the prevalence of ADHD. The study was conducted on children between the ages of 8 and 15 and children are more vulnerable to the affects of the pesticides as they are still developing. The organophosphates are thought to contribute to ADHD as it inhibits acetylcholinesterase leading to a disruption in the cholinergic signalling pathway. Even at very low doses, the organophosphates can affect neuronal development and neurotransmitter targeting, which has been has been shown to cause cognitive defects and hyperactivity in animals.
In 1942, Conrad Waddington coined the term epigenetics and defined it as "the branch of biology which studies the causal interaction between genes and their products, which bring the phenotype into being" (McVittie, 2006). In other words, genes can be seen as switches, and chemical modulators and environmental factors can control when and whether or not the gene is expressed. DNA methylation and histone modification are common ways in which gene expression is regulated in an epigenetic manner. A study by Mill and Petronis (2008) looked in particularly at methylation at the fifth position of cytosine residues, where they occur adjacent to guanine residues (CpG sites). Methylation occurs in promoters where there is a high concentration of CpG (CpG islands), thus preventing the binding of transcription factors and attracting methyl binding proteins which cause chromatin condensation. This mechanism prevents the transcription of the gene, and consequently the translation and production of the encoded protein.
The genome of the developing embryo/foetus is more susceptible to epigenetic influences than after birth as, DNA is being synthesised more rapidly during embryogenesis so any environmental change that affects the DNA in one cells can be transmitted to a large proportion of dividing cells. On the other hand, any epigenetic changes that affect the genome after birth are not as likely to be widely incorporated into other cells as the rate of DNA synthesis is slower. (Mill and Petronis, 2008) It is for this reason that the maternal environment, conditions, diet and lifestyle are critical in the development of her offspring.
In order for DNA methylation to take place, methyl donors are required. The methylation of the DNA cytosine residues is carried out by S-adenosylmethionine (SAM) using DNA methyltransferases as a catalyst. SAM needs a methyl donor to become activated and these are often obtained from the diet through vitamins B12, B6 and B2 as wells as folate, methionine and choline. Folate and vitamin B12 are often given supplementary to pregnant vitamin as deficiencies in these can have adverse effects on the development of the central nervous systems of the foetus and has been shown to cause behavioural abnormalities. Folate is essential for the expression of DNA methytransferase, without which, methylation cannot take place, leading to the silencing of certain areas of the genome. (Mill and Petronis, 2008)
With polymorphism is genomes, epigenetic mechanisms can work to either alter the response made by a particular protein as a result of the environmental stimulus, or DNA methylation may influence the expression of the polymorphic gene.
Figure 2. Prenatal and postnatal differences in epigenetic mediation. The filled black circles represent points in the DNA that can be targeted by DNA methylation. Epigenetic regions are not sully established in developing embryos, rendering the DNA more susceptible to epigenetic changes. This in turn leads to changes in gene expression, and hence phenotype. Once DNA synthesis has slowed and epigenetic sites have been established, environmental adversities cannot have a substantial effect. Adapted from Mill and Petronis, (2008)
There is a reduction in the volume of the caudate in subjects with ADHD than controls, which included unaffected siblings (Shook et al., 2011- LOOK HERE AGAIN FOR IMAGE).
"ADHD is characterized by a slightly smaller (by 4%) total brain volume (both white and gray matter), abnormalities of the basal ganglia and a 15% decrease in the volume of decrease in volume of a restricted region of the posterior cerebellum." "suggested causes include brain damage, encephalitis, genetics, food allergies, high lead concentrations and various home and school environments" unlikely to be a single cause. Ritalin is a stimulant which allows a person to concentrate on the task at hand and may have a general affect of sedating children" (Kolb and Whishaw, 2003)
Children who are born with lower than average birth weight have a reduced total brain volume if they were born at the normal gestational period. Children who were born prematurely and had a low birth weight had a significantly smaller absolute cortical gray matter volume and smaller overall total brain volume (Heinonen et al., 2010)
Premature babies are more likely to suffer from ADHD as they are more likely to have suffered from hypoxia and low blood pressure in the womb. Tests conducted in animals have shown that this causes an increase in the number in dopamine receptors in the brain (Khamsi, 2006).
Heinonen et al. (2010) conducted a study comparing the behavioural symptoms of ADHD in children who were born small for their gestational age (SGA) or appropriate for gestational age (AGA). They found that children born SGA suffered three times more ADHD symptoms that children born AGA. SGA infants may have been born prematurely or at full term.
In an experiment conducted in adult rats, which were separated from their mother's for 6 hours a day, as a form a childhood stress, it was found that these rats had
There have been numerous studies conducted which explore the connection between the genetic defects associated with ADHD and its symptoms however there results are contrasting in many situations and can be attributed to a number of factors. For instance small sample sizes used of the scarcity of there being homozygotes of the affected allele.
ADHD has been linked to drug abuse and obesity as the intake of excess foods and drugs is related to the feeling of reward. As people with ADHD have dysfunctional dopamine regulation, which is is involved in the feeling of reward, they are more inclined to take up other methods of rewarding themselves, that is causing further damage to their health.