Updated: Jul 21
Autism Spectrum Disorder
The world of autism is complex. To some point we are all autistic. Under prolonged stress we all revert to type — rigid and misperceiving the other person. It is simply a matter of degree.
High functioning autism can make for incredible engineers and budding scientists, some use their artistic talents to make a successful career, while others really struggle with day to day life. And, someone with autism may be considered as ‘normal’ in a
suitable setting (take Bill Gates, in a safe environment he acts normally, put him in front of a crowd and his behaviour is not considered normal, such as his constant to-and-fro rocking). High functioning adults have more control over their environment, they work out laterally what those differences are and accommodate them to a large degree, while children do not have that control and autism is often more apparent.
Autism labels were used to help researchers and doctors to develop their own understanding, leading to many labels such as: High Functioning Autism, Aspergers, Autism Spectrum Disorder, pervasive Development Disorder not otherwise specified. This was a hinderance to parents as terms were used interchangeably leading to confusion and some diagnosis were outside the remit of autistic services, and even upsetting to some. Thankfully, in 2013, the American Psych Association created a manual, 5th Ed. and all types of autism were put under the one bracket as Autism Spectrum Disorder, on varying degrees for ease and comparison.
Autism is now defined as: Persistent deficits in social communication and social interaction which is not accountable by developmental emotional delays. A lack of emotional reciprocity and social reciprocity. Non-verbal communicative behaviours used for social interactions, developing and maintaining relationships. Restricted repetitive patterns of behaviours, interest or activities with at least two of the following: Repetitive speech, motor movements or use of objects. Excessive adherence to routines. Ritualised patterns of verbal and non-verbal behaviours. Excessive resistance to change. Restricted or highly fixated interests that are abnormal in intensity and focus. Hypo or hyper reactivity to sensory input or unusual interest in sensory aspects of the environment. Interestingly, many have visual processing disorders where the brain fails to accurately receive and read the visual cues sent by the eyes), especially under fluorescent lighting (some say it is like seeing one eye or half a nose on a face and having to piece it together like a jigsaw). Symptoms must be present in early childhood but may not become fully manifested until social demands exceed social capability such as transitions between schools. The symptoms together limit and impart every day functioning. The current concept is that autism is a behavioural syndrome, with dysfunction in the brain and nervous system, but it can also include the endocrine, digestive, immune, and detoxification systems.
The incidence of autism has increased since the 1980s at 1:10.000 to 1:68.000 in just forty years. Recent estimates suggest that up to 3% of children in the United States are affected by an ASD. Increased diagnoses can not alone can not cause such an increase in numbers. So what are the possible causes?
The Refrigerator Mother hypothesis (1943) is now outdated, thankfully! I don’t think it was ever that mothers didn’t care but rather that mothers are overworked as a society and as a result spent less time with their children. We have to remember that how we bring up our children now is far different to our ancestors, as is our world; differences in evolution have the power to change patterns of behaviours and communication, as we respond to our environment. And rather than subsequent genetic based thinking it is now thought to have multiple aetiologies, both genetic and environmental.
Current research is focused on epigenetics. The term epigenetics means ‘above our genes’.
Epigenetic mechanisms influence gene expression in response to our environment, rather than direct genetic changes to our DNA. Epigenetics may provide a reason for the differences in individuals that can’t be explained by genetic differences alone (such as identical twins who have the same DNA but can suffer from different diseases). For example, our muscle cells and nerve cells have the same DNA but epigenetic processes allow the muscle cell to turn ‘on’ genes that it needs to become a muscle cell and turn ‘off’ genes to make a nerve cell, which creates differentiation.
One example of an epigenetic change is in DNA methylation. Methylation is a chemical term for the transfer of a methyl group (single carbon and three hydrogen atoms) from one substance to another. The addition of a methyl group is like chemical tag. Typically, methylation turns genes off’ and demethylation turns genes on. This process happens literally billions of times per second in many roles. Methylation regulates many different processes, such as glutathione production, detoxification, the formation and breakdown of neurotransmitters (chemical messengers in the brain) and control of myelination (the protective layer around nerve cells). You can see how problems in these areas could lead to brain and nervous system dysfunction with widespread and varying effects.
During the biochemical pathway of methylation, chemical reactions convert homocysteine to methionine with the help of specific nutrients to make glutathione and SAMe. Glutathione is our master antioxidant which repairs damage in the body, while SAMe is involved in neurotransmitters (brain chemicals) and hormones. If methylation is deficient, levels of homocysteine remain high associated with inflammation, and of course, oxidative stress due to impacting on glutathione production, reducing the potential for repair.
Are ASD individuals under methlyated?
Recent studies have shown that autistic children have lower levels of methionine, SAMe (s-adenosylmethionine) and high levels of homocysteine and adenosine levels compared to control groups; pointing to decreased activity in methylation processes. 95% of autism are said to be under methylated. Decreased levels of glutathione have been shown in more than 80% of autistic children. Oxidative stress was found in 99% of individuals with autism.
It does makes sense. Those with autism are literally stress magnets. They have to cut off to their own emotion and that of others to survive. A normal body would have processes to cope with stress on the body in the name of antioxidants, methyl donors and clear detoxification pathways, but in many autistic children this is not the case. Oxidative stress is an imbalance between free radicals (things that damage the body and cells) and the ability to detoxify or repair the resulting damage. It is possible that some epigenetic changes in methylation lead to reduced antioxidant production in a world when we need effective production. Our environment has increased toxins and stress and poor nutrition, when really it should be the other way around.
Let’s take a further look at some of the enzymes and processes involved in methylation and what nutrients are involved.
It’s a big word, but thankfully has an memorable acronym! Methylenetetrahydrofolate reductase (MTHFR) is an enzyme which converts synthetic Folic Acid (B9) to the active form of folate, known to be involved brain function. Vitamin B2 and B3 are needed as a co-factors to make this process work.
COMT is another enzyme which helps to detoxify the body and stimulate neurotransmission; responsible for the breakdown of dopamine, adrenaline and noradrenaline - our brain chemicals responsible for mood. In addition it stimulates liver enzymes which help to detoxify the body (phase 1 detox) requiring magnesium and SAMe. SAMe is converted from homocysteine when we have enough B vitamins, zinc and magnesium but if we don’t production will be below par and limit detoxification. We know that people with a change in this gene have a difficult time recovering from a stressful event because they can’t break down neurotransmitters, like epinephrine, which is formed in stressful situations, as rapidly as someone without this mutation or impaired methylation.
Furthermore, monoamine oxidase (MAO) is responsible for the breakdown of dopamine, nor adrenaline, adrenaline and serotonin; signals transmitted by serotonin regulate mood, emotion, sleep, and appetite. The process requires B1, B2 and methionine. GAD1 is also worthy of a mention as it converts glutamate to gaba, turning our excitable neurotransmitters into to calming ones, which need B6 as a co-factor.
You can imagine low levels of any of these nutrients may have a negative effect and affect conversions and methylation production. And this has a knock on effect on glutathione as active methylation increases glutathione production.
Interestingly, Keshan is an area in China that has low levels of selenium in the soils and therefore the food, Keshan has a higher than average incidence of cardiomyopathy, the heart burns through fuel creating oxidation from natural processes and cardiovascular disease is possibly related to poor methylation cycles.
Are we becoming more nutrient depleted as we move through the decades?
Could poor nutrition be passing down through generations over the last 60 years? We know that epigenetic changes can be passed down through generations and our nutrition has taken a nose dive since the 1960’s with the boom of commercial food production and intensive farming methods and could be reasons behind epigenetic changes. Antioxidants, found in fruit and vegetables, are the antidote to oxidation. Our eating habits changed after the war, with refined foods becoming popular. Refined foods are stripped of their goodness (especially B vitamins and why you see them added back in on food labels), relying on synthetic nutrients (we don’t fully know the effects either). Our soils have become nutritionally poorer with intensive farming, so even if we are eating well it is likely many of us are not meeting our nutritional needs. Our ancestral diet contained good amounts folate (B9), B12, B6, zinc, choline, betaine, magnesium - all the nutrients needed for effective methylation.
It is interesting that a commonly prescribed drug, Repiridone, to reduce aggression, was found to have antioxidant properties which combat oxidative stress. Further to support oxidation theory, many autistic children that follow gluten-free and casein-free (milk protein so dairy free) seemed to be helpful in some cases; both gluten and casein are known to cause inflammation in the body which will of course require more antioxidants to combat the inflammation, a cause of oxidative stress. Remove these factors and you have LESS of a need for antioxidants, which reduces the pressure on an otherwise pressurised system.
ASD and nutrient absorption
Let’s consider the possibility of malabsorption. As many as 70 percent of children with autism have gastrointestinal issues at some point during childhood or adolescence. Intestinal integrity is vital to health as it protects us from the outside world and allows us to process and absorb nutrients from food. One of the nutrients involved in developing and maintaining integrity is Zinc. Studies were conducted and found that 99% of those with abnormal EEGs had a zinc deficiency. (But only 33% in those that suffered seizures and therefore possibly looking at a specific phenotype, which is different).
Some symptoms of ASD include digestive symptoms which can reduce the absorption of nutrients from the foods they eat. Interestingly, we know that our stomach acidity decreases with age and many older people struggle with B12 absorption and many ASD children were found to be short of zinc and B6 needed for effective stomach acid, which will impair B12 and folate - both vital for methylation. Poor digestion will also mean that proteins can, in part, remain undigested. A healthy gut is vital to prevent undigested proteins reaching the brain which cause inflammation.
Many children do not have a natural birth, and therefore do not get the beneficial microbiome when passing through their mother’s birth canal, needed for a healthy gut and immune system. Under developed digestive systems and imbalanced gut flora can lead to the inability to fight bacteria, viruses and yeasts, causing dysbiosis; toxins from these pathogens can create inflammation that can affect the gut and the brain. This is further impacted by reduced methylation which can inhibit detoxification, and as a result there may be a higher heavy metal burden, which could contribute to chronic yeast overgrowth, amongst other things. Michael Gershon spent many years researching the gut brain axis. Probiotics, pre-biotic and digestive enzymes have had some effect and now part of mainstream thinking.
Is Environmental Toxicity to Blame?
Are low levels of zinc a possible cause or high levels of copper, and more of a toxicity issue, or both? Many scientists out there have environmental toxins at the top of the list for ASD causes. Zinc and Copper participate in the synthesis of MT proteins. Excesses in copper may exacerbate a zinc deficiency and affect effectiveness of MTs.Literature suggests that mercury accumulation may occur as a cause or consequence of metallothionein (MT) dysfunction. Some studies also indicate that zinc and copper are involved in the GABA neurotransmitter system too, which reduces neuronal excitability.
Interestingly, we know copper and zinc compete for the same sites in the body and therefore should be in a specific ratio. When a mother becomes pregnant the body saves up copper to help expel the baby, and then naturally, the zinc would be replaced by the mothers milk which is high in zinc to bring balance once again. Many of us are not breast-fed and instead obtain zinc from unnatural sources in formula, often less available than in the case of breast milk, which could lead to high levels of copper too. In a meta-analysis, the greatest reduction in the risk of autism spectrum condition was associated with prolonged breastfeeding of young children, between 12 to 24 months, and likely for many other reasons including immune functioning.
Increased environmental toxicity means a greater need for antioxidants?
Without the nutrients needed for methylation and effective methylation processes we can not remove heavy metals and metabolic waste.Many researchers think neuro-developmental toxins including mercury may play a part in autism. Many researchers point the finger at vaccines. Whilst Thimersol has been used as a preservative in vaccines since the 1930s, today it is only found in vaccines for influenza, having been removed in 2002. Yet, often over looked, mercury is found in our environment. For example, in Japan, an accident occurred deposited industrial waste containing mercury in Minamata Bay, and in those that ate the fish, triggered signs of speech impairment, sensory disturbance. Infants of expectant mothers included cerebral palsy, peripheral neuropathy and blindness and become known as Minamata disease. Mercury poisoning also occurred in Iraq when wheat grains were treated with fungicides containing organic mercury in 1971, killing over 500 people. Elemental mercury can pass through cell membranes crossing the blood brain barrier and placental barriers, and possibly more toxic. Elemental mercury is found in thermometers, in electrical devices, and dental fillings, used to be in some paints.
Mercury can form complexes with homocysteine, stopping the conversion absorption of B12 into its active form, needed for methylation, before it is eliminated by glutathione and passed out the body in urine and faeces. Individuals with reduced antioxidant status, such as ASD were found to be especially prone to mercury toxicity, possibly a cause of changes in gene expression.
Lead and aluminium are two other neurotoxins found to inhibit methionine enzyme activity, leading again, to reduce methylation. One of the most studied metals in association with MTHFR mutations is lead, making children child more susceptible to developmental problems if they are exposed to significant amounts of lead before age 2.
The effects of toxic metals effect glutathione-dependent synthesis of B12, required for this enzyme, leading to reduced methylation (Waly et al., 2004). It could be that epigenetic changes in combination with vaccines, rather than vaccines alone, which might pose problems. A study looked at the side effects of the small pox vaccination, those that had MTHFR changes showed an increase in adverse events, suggesting that children may have differing responses to vaccines based on their genetics.
Not to mention fungicides, volatile organic compounds, phthalates, brominated flame retardants, non-stick coatings and BPA. Medications such as valproate, migraine some antidepressants as well as illegal drugs might be risk factors for ASD. Exposure to BPA, found in plastic water bottles, food containers, canned foods, and some papers like receipts, has been associated with poor methylation processes.
And what about our food? MSG, aspartame, salicylates, pesticides, fungicides? All these toxins have had a relatively quick introduction in terms of evolutionary history, have we had time to evolve efficient defence mechanisms to deal with this level of toxicity?
And, if you consider the role of viruses to break down toxicity … perhaps speaks volumes.
Sadly, exposure to toxins may occur in utero before a mother knows they are pregnant, such as drugs and medications. The nervous system and immune system develop in utero 20-24 of gestation, until the first two years after brith. It is thought that exposure at this time can determine expression of genes. It is thought that environmental toxicity may create changes in in 5-15 genes.
A 2013 study of 1.2 million Finnish births found that women with a common inflammation marker in their blood are 80 percent more likely to have children diagnosed with autism compared to lower levels, again patterns of inflammation, oxidative stress and poor detoxification processes. Interestingly, those with ASD are often the first born and the likelihood of a subsequent child is substantially decreased, dubbed the “stoppage effect”, could a reason be that first borns inherit the most toxicity?
The frequency of autism is greater in males than females, a ratio of 4:1. Females are known to have higher methionine cycle regeneration and increased glutathione levels compared to males; it is thought that oestrogen can promote conversions (Geier and Geier, 2006). Not only that, oestrogen demonstrated protection against thimerosal-induced cell death, in comparison to testosterone (male hormone) which caused a loss of nerve cells exposed to thimerosal (Haley, 2005). Interestingly, 12 risk genes for ASD, validated with zebrafish mutant models (!) Provides evidence for the female protective theory (Macrì et al., 2010); Hoffman et al., 2016).Furthermore, recent research has found that children with autism have significantly elevated DHEA and testosterone levels; testosterone influences the methylation cycle and reduces total glutathione production providing a reason for the disparity between male and female.
Pyroluria is a largely unknown metabolic disorder and yet it is thought to be widespread in ASD, around 30%, Elevated Pyrrroles can impair detoxification and create inflammation characterised by depletion of arachidonic acid, which alters the body’s omega-3 to omega-6 fatty acid ratios, known to influence inflammation, a cause of oxidation. Abram Hoffer, Carl Pfieffer and D. G.Irvine are credited with the original research. Pyroluria can be tested for by a simple urine test.
In contrast to a mutation which is not considered normal, a polymorphism is a change in DNA that is common in the population, eg. genetic polymorphisms such as blood group diversity.
In a functioning methylation cycle, homocysteine is converted to methionine with the help of betaine and choline, then transformed into SAMe and glutathione. B12 is converted to tetrahydrofolate before being transformed to tetrahydrofolate, with the help of glutamate, serine and glycine and then finally, regenerated by MTHFR, a rate limiting enzyme.
Natural variation in the MTHFR gene for this enzyme is common. There are two predominant MTHFR polymorphisms, 677C>T and 1298A>C (two single-nucleotide substitutions result in changes of amino acids). In the general population, 55% of individuals will have at least one of these variants of the European population. It has no negative health consequences – unless expressed.
Gene polymorphisms of MTHFR enzyme affect available folate levels. The C677T enzyme affects thermal stability which reduces this this enzyme. A 50% reduction in enzyme activity on TT677 results in increased concentrations of plasma homocysteine and unbalanced folate levels. A1298C polymorphism has a lesser effect on enzyme function but when combined with C677T polymorphism results in a higher reduction of MTHFR enzyme activity. A severe MTHFR deficiency (<20% of the enzyme) results in the clinical picture of homocystinuria, which occurs when this gene is passed by both parents with significant neurological defects.
Sener et al 2014 found the MTHFR enzyme activity, is higher in children with ASD than in non-autistic children (29% versus 24%), although not statistically significant, investigations of other variants may tell us more about the possible role of polymorphism.
Folate receptor autoantibodies (FRAAs) are more common in ASD. There are two types of FRAAs, blocking and binding, which impair folate transport. The binding FRAA binds to the receptor trigger an immune, antibody reaction being researched within autoimmune disease circles. The blocking FRAA directly interferes with the binding of folate. FRAAs bind to folate receptor A (FRA) in the brain, preventing folate from entering the brain. Blocked folate receptors cause cerebral folate deficiency, which impairs methylation and brain function (Delhey et al 2016). Folinic acid, a non-methylated, intermediate form of folate, compared to the active form (methyltetrahydrofolate, 5-MTHF) readily crosses the blood–brain barrier and has been found to improve verbal communication in children with ASD.
Furthermore, it is very possible that that a deficit in the cellular uptake of B12, either through a polymorphism in the B12 binding protein, or binding FRAA interfering with B12 transport, could result in abnormal glutathione metabolism, reduced methylation and dopamine-induced neurotoxicity. The intermediate forms, hydroxocobalamin may have some effect, by correcting glutathione metabolism abnormalities, again bypassing some of the required methylation processes (James et al., 2006)
In a genetically sensitive individual, environmental toxins, poor nutrition, significant oxidative stress are all possibilities for impaired methylation, which might cause abnormal gene expression, which may be passed through generations. For example, we have ‘the gene’ but we don’t necessary develop the traits which in part, depends on our environment which may influence susceptibility.
For example, some women with the 677 polymorphism had with two identical copies of the gene were found to have lower vitamin D levels, it could be that low vitamin D makes made them more susceptible to switching on this gene. Our ‘above’ gene mechanisms may be passed down through generations but it may also be possible to reverse them, when we make changes to possible causes in our environment.
Whilst there are many factors in ASD providing a strong foundation of nutrition, removing known inflammatory foods and toxic chemicals, strengthening the gut biome, supporting methylation and antioxidant levels, can in part help people with ASD.
A 2012 study published by the Journal of Abnormal Child Psychology found a direct link between GI issues and behaviour. Children had symptoms of diarrhoea, constipation and food sensitivities were irritable, erratic or withdrawn so making dietary changes that can help to manage these symptoms could support ASD behaviours.
It is very important to remove inflammatory foods including refined grains sugar, artificial sugars, processed foods including those that contain trans-fats, commonly found in cheap vegetable oils, cakes, baked goods and other food additives help to reduce pressure on an otherwise pressured system. It is an important step in supporting the body and with good reason. For some a more severe dietary approach in gluten and dairy-free (or conventional dairy-free at least) has had some effect within ASD individuals, that said it can be difficult to make such drastic changes and it would be important to seek advice so that all nutrients can be accounted for.
A 2018 dietary invention study showed improvement in autism symptoms with an increased level of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) components of omega 3; Coenzyme Q10; and vitamins A, B2, B5, B6, B12 and Folic Acid compared to the non-treatment group. Results included improved non-verbal IQ and autism symptoms, suggesting the efficacy of comprehensive nutritional and dietary intervention.
Personally I would include zinc, magnesium, choline and betaine as they are needed in the methylation processes. It would be prudent to assess the diet of anyone with autism and try and include foods these nutrients are found in as a start. An ancestral diet provides the nutrients required for methylation, including folate, riboflavin, B6, B12, zinc, choline, betaine, and magnesium. And importantly omega 3.
The minerals of magnesium, zinc, calcium and iron are really important and come from eating a diet rich in vegetables, whole-grains and organic meats (a good source of B vitamins). Beef, ostrich and venison is a good source of zinc. Betaine found in beetroot can help to increase methionine by a pathway independent of folate and B12, simply try and include a little in a few meals per week. Choline can be supplied by eggs (also a great source of protein).
Fats are often demonised but we know low fat diets can lead to depression and vital for the nervous system and healthy cell walls for correct cellular functioning. We should all be eating a range of healthy oils (not trans-fats). Essential Fatty Acids and polyunsaturated fats make up our cell wall. Good sources include coconut oil, olive oil, GLA, avocado and nuts and fish oil. We rarely eat fish and seafoods which contain the anti-inflammatory omega 3. Fish is high in mercury, some more than others and toxicity is a large factor in ASD. In pregnancy it is advised to eat oily fish twice a week, so this is likely fine but supplements may be an option. Fish oil supplements vary in quality and it is important not to give cheap oils. Cytoplan do a range of quality oils, including Krill oil which contains natural antioxidants and generally more optimal.
Antioxidants are vital - they help to deal with oxidation - they are the cure! The are found in coloured vegetables and fruits. A well made smoothie, containing vegetables and complex carbs as well as fruits so sugar is not overloaded, is a good way to supply Vitamin C.
Vitamin D is often low in our Winter months and difficult to obtain from diet so worth considering a supplement. Vitamin A is in liver, or the plant-version is found in orange foods. It makes sense to eat a variety of foods and colours. Vitamin E is found mainly in nuts and seeds.
The benefits of gut health can not be underestimated, a regular transit time to eliminate toxins is vital, as is a healthy microbiome. Fermented foods such as kefir, kombucha, sauerkraut can repopulate the gut but aren’t always popular. I would caution using commercial food products containing probiotics, as they will contain numerous ingredients you can’t recognise on a label - the one thing you are trying to avoid. Cytoplan do a child probiotic; digestive enzymes can sometimes help too.
Whilst it can be difficult to get ASD individuals to make changes with their diet, it can be done, with small, slow changes, a little imagination, sneaky parental behaviours and bribery! If any readers out there would like nutritional support with supplements then please do get in touch. I would say supplementation really varies and it is a complex world, and always prudent to see help with a professional. Cytoplan make nutrients that come from food, the quality of supplements is really important, they offer advice their supplements too.
Help the body to detoxify through exercise and breathing. Slowly try to increase walks in nature, exercise, dancing, and even sauna which can all help to purge toxicity form the body.
Be aware of toxins and try to reduce household chemicals by using natural cleaners. Water filters can be one way to reduce toxins from drinking water. Mediation, colours, crystals are nice ways to get sensory children to interact and gain interest.
Perhaps my final words would be - what confusion! As I wrote this article I felt bombarded by thoughts of our messy, unnatural and toxic world, almost overload, which for me is totally reflected in the behaviours of ASD. For the health of us all, as consumers we need to start creating change. We need to start waking up and understanding that we are highly evolved, living in a highly evolved ecosystem and lean towards our ancestral ways of home cooking, buying organic where we can, and choosing natural products over toxic chemicals. And, making moves away from our fake and unnatural world and get closer to nature.
There are also practitioners out there that have spend their lives studying autism gene related issues. You could consider Ann Pemperton who is a leader in the autism field, after supporting her son’s autism, with many years of experience. You can find out more here: https://www.annepemberton.co.uk/autism/
I hope you found this blog interesting. Get in touch if you would like to find out more!
Adam et al (2018) Comprehensive Nutritional and Dietary Intervention for Autism Spectrum Disorder-A Randomized Controlled 12-Month Trial Nutrients 10(3):369
Blumberg SJ, Bramlett MD, Kogan MDet al. Changes in prevalence of parent-reported autism spectrum disorder in school-aged U.S. children: 2007 to 2011-2012. Natl Health Stat Report. 2013 Mar 20;(65):1-11
Bjorklund G. The role of zinc and copper in autism spectrum disorders. Acta Neurobiol Exp (Wars). 2013;73(2):225-36.
Brown AS, Sourander A, Hinkka-Yli-Salomäki S, McKeague IW, Sundvall J, Surcel HM. Elevated maternal C-reactive protein and autism in a national birth cohort. Mol Psychiatry. 2014 Feb;19(2):259-64.
Cannell, J.J. Vitamin D and autism, what’s new?. Rev Endocr Metab Disord 18, 183–193 (2017).
Cashman, K. D., Dowling, K. G., Škrabáková, Z., Gonzalez-Gross, M., Valtueña, J., De Henauw, S., Moreno, L., Damsgaard, C. T., Michaelsen, K. F., Mølgaard, C., Jorde, R., Grimnes, G., Moschonis, G., Mavrogianni, C., Manios, Y., Thamm, M., Mensink, G. B., Rabenberg, M., Busch, M. A., Cox, L., … Kiely, M. (2016). Vitamin D deficiency in Europe: pandemic?. The American journal of clinical nutrition, 103(4), 1033–1044.
Ghozy, S., Tran, L., Naveed, S., Quynh, T., Helmy Zayan, A., Waqas, A., Sayed, A., Karimzadeh, S., Hirayama, K., & Huy, N. T. (2020). Association of breastfeeding status with risk of autism spectrum disorder: A systematic review, dose-response analysis and meta-analysis. Asian journal of psychiatry, 48, 101916.
Fernandes Azevedo B, Barros Furieri L, Peçanha FM, Wiggers GA, Frizera Vassallo P, Ronacher Simões M, Fiorim J, Rossi de Batista P, Fioresi M, Rossoni L, Stefanon I, Alonso MJ, Salaices M, Valentim Vassallo D. Toxic effects of mercury on the cardiovascular and central nervous systems. J Biomed Biotechnol. 2012;2012:949048.
Frye RE, Delhey L, Slattery J, Tippett M, Wynne R, Rose S, Kahler SG, Bennuri SC, Melnyk S, Sequeira JM, Quadros E. Blocking and Binding Folate Receptor Alpha Autoantibodies Identify Novel Autism Spectrum Disorder Subgroups. Front Neurosci. 2016 Mar 9;10:80.
Frye RE, Slattery J, Delhey L, Furgerson B, Strickland T, Tippett M, Sailey A, Wynne R, Rose S, Melnyk S, Jill James S, Sequeira JM, Quadros EV. Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Mol Psychiatry. 2018 Feb;23(2):247-256.
Gordon N (March 2009). "Cerebral folate deficiency". Developmental Medicine and Child Neurology. 51 (3): 180–2.
Haley B: Mercury toxicity: Genetic susceptibility and synergistic effects, Medical Veritas 2 535-542, 535, 2005.
Hoxha B, Hoxha M, Domi E, Gervasoni J, Persichilli S, Malaj V, Zappacosta B. Folic Acid and Autism: A Systematic Review of the Current State of Knowledge. Cells. 2021 Aug 3;10(8):1976.
James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW, Neubrander JA. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr. 2004 Dec;80(6):1611-7. doi: 10.1093/ajcn/80.6.1611. PMID: 15585776.
James SJ et al: Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism, Am J Clinical Nutrition 80:1611-7, 2004.
Khaghani, S.; Ezzatpanah, H.; Mazhari, N.; Givianrad, M.H.; Mirmiranpour, H.; Sadrabadi, F.S. Zinc and Copper Concentrations in Human Milk and Infant Formulas. Iran. J. Pediatr. 2010, 20, 53–57.
Kandi V, Vadakedath S. Effect of DNA Methylation in Various Diseases and the Probable Protective Role of Nutrition: A Mini-Review. Cureus. 2015 Aug 24;7(8):e309. doi:
Lee, B. K., Eyles, D. W., Magnusson, C., Newschaffer, C. J., McGrath, J. J., Kvaskoff, D., Ko, P., Dalman, C., Karlsson, H., & Gardner, R. M. (2021). Developmental vitamin D and autism spectrum disorders: findings from the Stockholm Youth Cohort. Molecular psychiatry, 26(5), 1578–1588.
Modabbernia A, Velthorst E, Reichenberg A. Environmental risk factors for autism: an evidence-based review of systematic reviews and meta-analyses. Mol Autism. 2017 Mar 17;8:13.
Penn, A. H., Carver, L. J., Herbert, C. A., Lai, T. S., McIntire, M. J., Howard, J. T., Taylor, S. F., Schmid-Schönbein, G. W., & Dobkins, K. R. (2016). Breast Milk Protects Against Gastrointestinal Symptoms in Infants at High Risk for Autism During Early Development. Journal of pediatric gastroenterology and nutrition, 62(2), 317–327
Rylaarsdam Lauren, Guemez-Gamboa Alicia (2019) Genetic Causes and Modifiers of Autism Spectrum Disorder, Frontiers in Cellular Neuroscience 13
Rea V, Van Raay TJ. Using Zebrafish to Model Autism Spectrum Disorder: A Comparison of ASD Risk Genes Between Zebrafish and Their Mammalian Counterparts. Front Mol Neurosci. 2020 Nov 11;13:575575.
Ratto, A. B., Kenworthy, L., Yerys, B. E., Bascom, J., Wieckowski, A. T., White, S. W., Wallace, G. L., Pugliese, C., Schultz, R. T., Ollendick, T. H., Scarpa, A., Seese, S., Register-Brown, K., Martin, A., & Anthony, L. G. (2018). What About the Girls? Sex-Based Differences in Autistic Traits and Adaptive Skills. Journal of autism and developmental disorders, 48(5), 1698–1711.
Sener EF, Oztop DB, Ozkul Y. (2014) MTHFR Gene C677T Polymorphism in Autism Spectrum Disorders. Genet Res Int.. Epub 2014 Nov 6.
Slattery J, Tippett M, Wynne R, Rose S, Kahler SG, Bennuri SC, Melnyk S, Sequeira JM, Quadros E. (2016) Blocking and Binding Folate Receptor Alpha Autoantibodies Identify Novel Autism Spectrum Disorder Subgroups. Front Neurosci. Mar 9;10:80.
Tremblay MW, Jiang YH. DNA Methylation and Susceptibility to Autism Spectrum Disorder. Annu Rev Med. 2019 Jan 27;70:151-166. doi: 10.1146/annurev-med-120417-091431. PMID: 30691368; PMCID: PMC6597259.
Waly M et al: Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal, Molecular Psychiatry 9:358-370, 2004.
Van den Berg MP et al: Hydroxocobalamin uptake into the cerebrospinal fluid after nasal and intravenous delivery in rats and humans, J Drug Target Jul;11(6):325-31, 2003.
Vidmar Golja, M.; Šmid, A.; Karas Kuželički, N.; Trontelj, J.; Geršak, K.; Mlinarič-Raščan, I. Folate Insufficiency Due to MTHFR Deficiency Is Bypassed by 5-Methyltetrahydrofolate. J. Clin. Med. 2020, 9, 2836.