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Prevention of Autism.

There are potentially two major developmental areas where it may be possible to prevent the development of autism. The period in the uterus, and the period of neonatal development that occurs during the first two years of life. During development, there is a period of brain development in the last one-third of pregnancy, which continues into the first 2 years of life. In this time there is extensive dendritic growth (branching of nerves to form new neuronal connections), synaptogenesis (formation of synapses {communication points} between nerves in the nervous system and between nerves and muscles) and glial cell proliferation (nerve helper cells). In the first year of life the brain volume doubles and reaches around 80-90% of the adult volume by the end of the second year. Critical to this period of growth is the provision of nutrients to the foetus and then subsequently to the neonate.

Vitamin B12 Deficiency and Autism

It is known that vitamin B12 deficiency in the neonate can lead to delayed development and poor cognitive development (1-6; Weiss etal, 2004; Shulpis etal, 2004), regression of psychomotor development, brain atrophy and muscular hypotonia (Lucke etal, 2007; Chalouhi etal, 2008). Mechanistically it can be shown that B12 deficiency involves delayed myelination of the nerves (or even demyelination), reduced methylation, imbalance of neurotrophic and neurotoxic cytokines, and/or accumulation of lactic acid in the brains (Dror and Allen, 2008). It is also known that vitamin B12 loading of the brain occurs via transplacental transfer to the foetus (7,8), so obviously the place to start, if you want to reduce the possibility of having an autistic baby,  is to make sure that the mother has sufficient supplies of vitamin B12. Thus, efforts should be directed to ensuring that pregnant mothers, and breast-feeding mothers on vitamin B12 insufficient diets, should receive preventative supplementation with vitamin B12. Potentially such supplementation could prevent not only the development of autism, but many other neurological deficiencies in the young and neural tube defects, cleft palate and other disorders (Molloy etal, 2009). In this regard, Molloy and co-workers (2009) have suggested that women have vitamin B12 levels of >300 ng/L (221 pmol/L) before becoming pregnant. Unfortunately under modern testing methods, most pathology labs will not recognize vitamin B12 deficiency until levels are significantly lower than this (150 pmol/L). Metabolically, though, vitamin B12 deficiency has been seen to start at around 250 pmol/L, and if one considers that B12 levels drop considerably during pregnancy, one would propose that this should be a minimal level. Whether it is possible or reasonable to do this would be a challenge as in many countries, including the UK, Newfoundland, India, and Wales, over half of the mothers already have levels below 250 pmol/L before pregnancy. Further it is known that vitamin B12 deficiency is very prevalent in lactating women of many nationalities, including Guatemala (Casterline etal, 1997; Jones etal, 2007), and yet dietary fortification is still not mandated!

Fortification of mothers, is though, not quite as simple as just taking a multivitamin with vitamin B12 in it. Once a person is deficient in vitamin B12, it is actually very hard to restock with vitamin B12 by taking an oral tablet or just eating more B12 containing foods. The reason for this is that the amount of B12 absorbed is very, very low (around 6 ug maximal per feed). Thus, even though high dose supplementation of mothers both during pregnancy and breast feeding has been shown to raise B12 levels in mother, milk and baby (15, Thomas 1979), there are common instances of B12 deficiency in neonates, despite the mother supplementing with multivitamins during pregnancy (16, Roed etal, 2009). Secondly, in order for the B12 to be "useful" it has to be bound by a protein called transcobalamin (TC), which is in limited supply. If you try to "force-feed" the body with ultra high doses of vitamin B12, you may get an increase in the serum levels of vitamin B12, but the B12 is not bound by TC and so is not available for tissues in the body, or for the placental transport system. The next problem is that most supplements or even injections of vitamin B12 use one of two inactive forms of the vitamin, cyanoB12 or hydroxB12. Both forms need to be "activated" before they are useful to mother or child. In vitamin B2 (riboflavin) deficiency, this activation does not occur, and there are examples where injected cyanoB12 has been transported unmodified into the foetus, and also unmodified via breast milk into the neonate. Further, several studies using cyanoB12 in mothers have neither reduced homocysteine levels, nor affected early stage cognitive outcomes (Srinivasan, 2017). It is therefore essential that the mother is replete in both adenosyl and methyl B12 and also in the active forms of vitamin B2 (FMN and FAD). The good news is that it is known that the levels of B12 in the child reflect those of the mother, the higher the mother, the higher the child (Duggan 15, Schulpis etal 2004; Jones etal, 2007). Conversely, if the mother is deficient so too will the child be. Levels of B12 in milk drop off very quickly after birth, so it is essential to get the B12 into the child during foetal development. In testing mothers for B12 sufficiency, ideally homocysteine levels and MMA levels should be used to evaluate true B12 insufficiency (Lucke etal, 2007). Elevated Homocysteine in the mothers was negatively associated with expressive language and fine motor skill outcomes in the developing child (Srinivasan etal, 2017).

Potentially one hugely under-estimated effect of vitamin B12 deficiency is the reduced production of S-Adenosylmethyionine (SAM) and the subsequent production of creatine. Creatine production consumes 40% of all methyl groups produced from SAM, and lack of creatine production results in Global Developmental Delay, Intellectual disability and Behavioural disorders, all of which are typified in ASD (Curt 2015). Lack of methylation also results in lack of production of melatonin, which has a critical role in maturation of the intestine and also in myelination of the brain.

Melatonin levels are also dependent upon methyl B12, due to the role of methylation in the conversion of serotonin to melatonin. Melatonin has been shown to have a very important role in maturation of myelin producing oligodendrocytes (Olivier etal, 2009), and in promoting myelination during development and after neuronal damage (Villapol etal, 2011, Turgut and Kaplan, 2011; Miller etal, 2014; Biran etal, 2014; Onger etal, 2017). It is also involved in promotion of axonal growth and axonal sprouting, essential functions in brain and peripheral nerve development (Olivier etal, 2009). Recently melatonin supplementation has been suggested for antenatal treatment of children with neurodevelopmental defects (Miller etal, 2014; Biran etal, 2014). Melatonin has been shown to have a calming effect and is particularly effective in the treatment of juvenile epilepsy (common in children with ASD) (Bachach etal, 2011; Fauteck etal, 1999). Given its effectiveness in treatment, one must speculate that lack of melatonin production due to vitamin B12 deficiency may be causal in these conditions.

Vitamin B2 Deficiency and Autism

Central to the cycling of vitamin B12 and the maintenance of it's function is active vitamin B2, as FMN and FAD. The association between obesity and insulin resistance, gestational diabetes and vitamin B12 deficiency, have one thing in common, they are all related to low levels of functional vitamin B2. Deficiency of vitamin B2 though is also related to the ability to process riboflavin (vitamin B2) through to FMN and FAD, the two active forms of the vitamin, and these require Iodine (See section below), Selenium and molybdenum. Many of the mothers of ASD kids and the kids themselves show Selenium and Molybdenum deficiency.

There are no studies on riboflavin deficiency and ASD that we could find, however, dietary insufficiency of riboflavin in mothers has been associated with congenital heart defects (Smedts etal, 2008). Further supplementation with riboflavin was beneficial in treating anemia due to folate and iron deficiency (Ma etal 2008). Low riboflavin intake during pregnancy in mice has been shown to affect embryonic growth and cardiac development (Chan etal, 2010). It has also been suggested that autism rates may be inversely related to riboflavin intake (Shamberger 2011). It must be noted that supplementation with vitamin B2 alone will not reverse functional vitamin B2 deficiency if the person is deficient in Iodine, Selenium and/or molybdenum. Further, as functional vitamin B2 deficiency will eventually cause vitamin B12 deficiency, deficiencies in vitamin B2 (riboflavin), Iodine, Selenium, molybdenum and vitamin B12 would all need to be addressed at once. This possibly explains the lack of efficacy of several trials in which supplementation occurred with B group vitamins alone, rather than with the vitamins plus I/Se/Mo (Chistian 2003). The necessity of adequate functional vitamin B2 is particularly important in the context of mutations in MTHFR and MTRR, where it has been shown that sub-optimal riboflavin status dramatically reduces the activity of both MTHFR (677C>T) and MTRR (66A>G) polymorphisms (Garcia_Minguillan etal, 2014)

Iron Deficiency and Autism

Iron deficiency is the most prevalent micronutrient deficiency in the world, and is the primary cause of anemia, affecting roughly one-quarter of the world's population. The brain is highly susceptible to iron deficiency during the late foetal and early neonatal time period. Deficiency at this time is associated with altered expression of genes critical for development and function, iron deficiency at this time causes neurocognitive dysfunction, which may continue even after iron stores have become replete.

Iron deficiency as judged by haematological parameters occurs at around 15-20 ug/L ferritin in adults, however, metabolically iron deficiency can be measured at 70-100 ug/L. During pregnancy the mother sacrificially loads up the foetus with the result that many women can become iron deficient during pregnancy.

A recent summary of guidelines for management of iron deficiency, world-wide, recommended serum ferritin values should be above 100 ug/L (Peyrin-Biroulet etal, 2015).

It is critical that the developing foetus receives sufficient iron and that there is sufficient iron for the neonate to have adequate stores to last for the first six months of life. This is because the immature neonatal gut is not developmentally mature and as such cannot regulate the uptake of iron (Radlowsky 2013), and additionally breast milk is very low in iron content. Maturation of the gut will be further compromised if the mother is vitamin B12 deficient as melatonin secreted by the mammary gland is required for gut maturation. The majority of the fetal liver stores (66%) are acquired in the last one-third of pregnancy and so infants born prematurely with a low birth weight are at greater risk of iron deficiency. Infants who are born to iron deficient mothers are still found to be abnormally low in iron 9 months after birth, even if provided adequate dietary iron (Radlowsky 2013). Once born, infant brain iron levels decrease in the first 6 months of life, which roughly equates to the onset of myelination. The most sensitive period (and hence the period that can cause the most irreversible damage) is the period between 0 and 24 months. Iron deficiency in this period is correlated with poor auditory recognition memory, delayed cognitive development and poor response to external stimuli. Decreased iron concentration in the brain is associated with irritability, apathy reduced ability to concentrate and with various other deficiencies in cognition. Iron deficiency in the brain is also associated with deficit in language capability. In addition, Iron deficiency is associated with hypomyelination of nerves, thus reducing the maturation of rapid impulse transmission along nerves.

It has been known for some time that the level of iron in the brains of autistic children is much lower than in normal individuals (Bener 2017). Iron deficiency was associated with lower haemoglobin, haematocrit, and MCV values (Gunes 2017), with a negative correlation between lower haematocrit levels and degree of symptomology (Sidra 2014). Iron deficiency in neonates has also been associated with poor emotional outcomes (Kim, 2014; Zumbrennen-Bullough 2004), recognition memory (Geng 2015), poor neural maturation (Armin 2010; Choudhury  2015; Armony-Sivan 2004). Iron is essential for learning and memory, and both the cholinergic and glutamatergic neurotransmission pathways are regulated by iron, and play a huge role in memory performance (Han 2015) and in the production of myelin by oligodendrocytes (Rosato-Siri  2017; Roth 2016). Iron deficiency is very common in pregnancies (40-50% as determined by IDA), however, not all iron mothers with ID have children with ASD. Further the difference in iron levels in the serum of kids +/- ASD is very little. Low iron intake, when combined with advanced age of the mothers, resulted in a five-fold increased risk of having an ASD child (Schmidt 2014).

Vitamin D Deficiency and Autism

Low vitamin D levels have been associated with many conditions, including rickets, PCOS, asthma, multiple sclerosis, atopic dermatitis, cancer risk, metabolic syndrome, etc, and it has been suggested as one of the causative agents in the delayed development in ASD individuals (Cannell 2013). Many mothers report very low vitamin D levels during pregnancy and others report extensive use of high SPF cosmetics. Many studies have also found vitamin D deficiency to be common in ASD individuals (Bener 2017), and have suggested that low maternal vitamin D may be a risk factor for the development of ASD, possibly via its action on fetal brain development and altered immune status (Grant 2009). Our own studies have shown a major shift in vitamin D processing associated SNPs (see the page on genetics). The rapid increase in the use of sun-blocks in cosmetics, as well as the increase in SPF values of these products are some of the few associative factors that could account for the increase in rate of the condition. There are few other factors that could account for such an increase, certainly not de novo mutations as has been suggested by some (Kenney 2010). Whilst many are aware of the role of vitamin D in bone health, vitamin D has a unique role in brain development, including homeostasis, embryogeneisis, neural differentiation, neurodevelopment, gene regulation and immunological modulation (Duan 2013). Vitamin D also has a role in neurotrophism, neuroprotection, and neuroplasticity (Cannell 2013)

Recent recommendations for vitamin D suggest targeting a minimal level of 40-70 ng/ml 25(OH)D in serum in mothers (Wydert 2014). At least one study has shown a decrease in core symptoms of ASD following vitamin D supplementation of a vitamin D deficient child (Jia 2015).

Low vitamin D has been found to impact adversely on brain development, and alters the dopaminergic profile in the forebrain, with a reduction in COMT levels (Kesby 2009). Interestingly vitamin D also promotes tyrosine hydroxylase (TH) and tryptophan hydroxyase 2 (TPH2) expression, AND results in a significant rise in monoamine oxidase A (MAOA) expression (Jianq 2014; Pertile 2016). This later finding is of considerable importance as MAOA is one of the only neurotransmitter related genes that are expressed on the X-chromosome, and hence alterations in MAO expression may provide the first reasonable hypothesis for the increased incidence of the condition in males, who by definition only have one X chromosome. It also supports our observations on increased frequencies of recessive alleles in MAOA in ASD males.

Iodine Deficiency and Autism

Iodine deficiency has been recognized as "the single most common cause of preventable brain damage in the world", yet despite this studies in Australia and the US have both shown that around 50% of pregnant women have inadequate iodine intake (150-220 mcg/day), with the average intake decreasing from 2001 to 2008 (Caldwell etal, 2011; Perrine etal, 2010; Pearce etal, 2004; Charlton etal, 2010).  Further, low iodine intake in mothers has also been associated with obesity and diabetes in the mothers during pregnancy. It has also been associated with ADHD in offspring (Vermiglio etal, 2004). Sub-clinical hypothyroidism in the mothers, due to iodine deficiency in the mother, has been associated with irreversible brain damage in the offspring (Gallego etal, 2010). Clearly the message on the importance of iodine in the diet is not getting out, which is also reflected in the observation that only 10% of total edible salt sales are of iodized salt (Li etal, 2008). Iodine deficiency in the mothers reflects the general increasing prevalence of iodine deficiency in the US, with deficiency increasing from 2.5% of the population in 1970 to 11% of the population in 1990 (Hoption Cann, 2006). Some time ago, iodine deficiency was recognized as a huge problem in China, and the Chinese government, in an historic effort, has virtually eliminated Iodine deficiency from the country (Sun etal, 2017).

Several studies have shown the concentration of urinary iodine was negatively associated with the severity of symptoms in ASD kids, including emotional response, verbal communication, intellectual functioning and adaptation to environmental change (Blazewicz etl, 2016). A similar study in Egypt found that 54% of ASD children and 58% of the mothers were iodine deficient, which was also correlated with lack of intake of iodized salt (Hamza etal, 2013). Such an association of iodine deficiency and ASD has been suggested previously (Sullivan and Maberly 2004), and falling iodine intake in pregnant mothers has meant that iodine nutrition status among pregnant women is becoming marginal (Caldwell etal 2005, Hollowell etal, 1998; Sullivan 2008), such that the American Thyroid Association has now recommended that all pregnant and lactating women take daily iodine supplements (Sullivan 2008). It has also been suggested that hypothyroxinemia in utero may be the cause of ASD in some children (Roman 2007). It has not, though, recommended iodine supplementation to young children, despite the recommendations of WHO and UNICEF, who have recommended 90 ug/day iodine for children 6 to 23 months in at risk populations. An assumption is made that iodine supplementation of children 0 to 6 months of age should occur through breast milk, BUT, if the mothers are not replete, then neither will the children be. Despite mandating the use of iodized salt, studies in the US have shown that around 50% of pregnant women had iodine intakes below those considered sufficient. Iodine deficiency in children is one of the most common cause of preventable mental retardation in the world. Exposure to plants with high thiocyanates, such as cabbage, cauliflower, Kale, lima beans and sweet potatoes, and tobacco smoke, may reduce thyroid function.

It would seem that the cause of autism is multifactorial (hence the "Nexus Theory™"), and that whilst one individual deficiency may not have significant effect to cause the condition, a combination will. Central is the role of vitamin D in development, which is the one factor that has changed significantly enough in the past 20 years to account for the increased rate in ASD. The change in vitamin D levels in the mothers appears to have dramatically changed the frequency of some of the vitamin D associated gene alleles. On top of this is a central role of vitamin B12 in brain development and particularly in methylation. The function of vitamin B12 is dependent upon functional vitamin B2 and its associated dependence upon sufficient dietary Iodine, Selenium and Molybdenum.

Potentially, it is a combination of deficiencies that results in the reduced production SAM, with a resultant lack of production of creatine, leading to the delayed development characteristic of ASD. Creatine is a product in the body responsible for your "back-up" energy supply. It's prime role is to facilitate recycling of the energy molecule, adenosine triphosphate (ATP). It is critically dependent upon the production of S-Adenosylmethionine (SAM) for the methylation reaction. SAM production in turn is dependent upon methyl B12 for proper cycling within the methylation cycle. Without methyl B12, levels of SAM drop and so levels of creatine will drop. Since over 40% of all SAM made goes to make creatine it can easily be seen that any drop in production of SAM will have a huge impact on creatine levels in both muscles and the brain, the two main users of creatine in the body. Many studies have shown that creatine deficiency in the brain results in a group of disorders that are characterized by intellectual disability, language delay, epilepsy, autism spectrum disorder, bipolar and various movement disorders (Fons, 2016; Cameron, 2017, Verbruggen 2007;Ongur 2009). Further lack of production of creatine has been associated with severe speech delays (Vodopiutz 2007), whilst lack of activity of creatine transporter has been associated with mental retardation and verbal dyspraxia (Battini 2007). Creatine has been implicated in working memory.

Studies looking at creatine disorders have shown the following:

 

Creatine Disorder Syndrome:

A deficiency of vitamin B2, Iodine, Selenium or Molybdenum, would result in functional methyl B12 deficiency, which in turn would greatly reduce the production of SAM, which would in turn reduce synthesis of creatine, and creatine-phosphate. This alone would explain the apparent intellectual disability and language delay characteristic of ASD. Further, evidence of this has been found with the reversal of apraxia in children administered B2/I/Se/Mo and then treated with methyl B12.

 

Creatine-phosphate

Creatine is then processed to creatine phosphate a back-up energy supply for high energy phosphate;

Creatine-phosphate + ADP + H+ <=> creatine + ATP

Possibly one of the most amazing things about autism is the illogical approach to treatment and prevention of the condition. Thus, it is well known that vitamin B12 deficiency in the young can lead to delayed development and poor cognitive development, regression of psychomotor development and brain atrophy. It is also known that melatonin, a methylation product ultimately dependent upon methyl B12 for its production, is essential for maturation of neuronal stem cells and differentiation of oligodendrocytes, which are essential for myelination. Further it is known that levels of vitamin B12 in the brain of children are very low, as low as that in the elderly and those with dementia. Further when you test for vitamin B12 deficiency in the children with ASD and even adults with ASD we find that they are very vitamin B12 deficient. Further it is known that vitamin B12 deficiency is associative for dementia in the elderly, YET, for some reason the vast majority of people don't believe vitamin B12 deficiency has anything to do with the condition. Similarly, it is known that Iodine deficiency is the single most preventable cause of mental retardation and that around 50% of the children with ASD have Iodine deficiency, and yet it is not postulated as being causative. Further, iron deficiency in the young has also been toted as the second most preventable cause of mental retardation and yet despite over 80% of children with ASD being iron deficient it is also not toted as a reason for the condition. It is also known that low vitamin D impacts adversely on brain development, and it is also known that vitamin D levels in ASD is low, yet this deficiency and that of Iron, Iodine, Selenium, Molybdenum, functional vitamin B2 and vitamin B12 are ignored as causative agents for the condition. Little wonder that the incidence of the condition is increasing so dramatically and that the treatment of the condition is so poor.

Testing for Deficiencies in mothers and neonate

A study of the urinary metabolites from ASD children of ages 1 to 18 years has shown a uniform deficiency in both vitamin B2 and vitamin B12. These deficiencies, when combined with the lower levels of iron in these individuals strongly suggest that deficiency of B2/B12 and iron in the womb has lead to the delayed development seen in these children. This delay manifests itself in reduced and inefficient energy production in mitochondria, altered neurotransmitter metabolites, and resultant developmental delay. Fetal Insufficiency of iron or vitamin B12 alone has been correlated with lower cognitive function and poor development in neonates (20, 8). Clearly, adequate dietary intake of iron, vitamin B2, Iodine, Selenium, Molybdenum and vitamin B12 before, during and after pregnancy is critical for the child's development and women who fail to do this potentially have a highly elevated risk of giving birth to a child who will subsequently show the developmental delay(s) that are characteristic of ASD. There has been a new directive mandating iodine supplementation in pregnant women. There also appears to be a strong role for vitamin D in the development of ASD, and children with ASD consistently have lower levels of vitamin D, and also have altered genetics in proteins involved in vitamin D processing. The increased use of high SPF value sun-blocking cosmetics, potentially has a dramatic role in increasing the incidence of ASD.

More recently it has been found that maternal multivitamin supplementation has been associated with a reduced risk of autism in the offspring (Guo etal, 2019)

Warning signs in the Mothers

In the best case scenario, a woman will prepare herself for her pregnancy by checking her nutritional status before she becomes pregnant, however, if this has not been the case there are many potential warning signs of nutritional deficiency. The warning signs were outlined before, but are repeated below. Get "assessed" if you have the signs

Warning signs in the children

Remember if the mother is deficient in any of the essential nutrients, the longer the mother breast-feeds the less nutrients that the child is getting from the breast milk, and so may need micronutrient supplementation or early introduction of solid foods.

 Prevention is better than cure  

 

Data to date suggests that nearly all the predisposing factors for autism occur in the mother, which includes the nutritionally biased selection of the embryo and development of the foetus.

Vitamin D

Vitamin D is critical for the developing embryo, not only for the fetal bones, but importantly for autism prevention, the stimulation of vitamin D has a unique role in brain development, including homeostasis, embryogeneisis, neural differentiation, neurodevelopment, gene regulation and immunological modulation, neurotrophism, neuroprotection, and neuroplasticity. Vitamin D also influences the dopaminergic profile in the forebrain, though its action on the expression of COMT and MOA-A, and also on promoting the expression of enzymes tyrosine hydroxylase (TH) and tryptophan hydroxyase 2 (TPH2), which are critical for the production of dopamine, serotonin, nor-epinephrine.

The most natural mode of acquiring vitamin D is through endogenous production of vitamin D by sun exposure, however, this is greatly reduced if the mother uses moderate to high value SPF sunblocks or cosmetics. Glass also filters out the ultraviolet rays that stimulate vitamin D production in the skin.

The finding that the vitamin D associated genetics has already been altered in kids with ASD is an alarming finding and does not bode well for future vitamin deficiency related conditions. Vitamin D3 produced in the skin has to be converted to 25(OH)D (calcidiol) and 1,25(OH2)D (Calcitriol), of these, calcidiol has the longest half-life in serum. Current suggested levels are that serum 25(OH)D should be well above 50 nmol/L (>20ng/ml). Maximal mitochondrial energy output occurs in the range 75-125 nmoml/L.

Vitamin B2

All B group vitamins are important for health, and folate supplementation has been indicated for pregnant mothers for many years now, however, vitamin B2 deficiency has definitely been implicated in the development and maintenance of autism, yet is not generally discussed with mothers before, during or after pregnancy, nor are its levels generally monitored.  Further, there is only a small amount of riboflavin stored in the liver, heart and kidneys. Arguably the best source of vitamin B2 is in dairy produce, and additionally this also provides adequate calcium for the development of strong bones. In the US, many source of milk are supplemented with iodine, thus providing a dual benefit to the mother. In addition to Iodine (150-250 ug/day), in order to convert dietary or supplemental vitamin B2 to the two active forms FMN and FAD, the mother requires also requires Selenium (55-200 ug/day) and Molybdenum (~200 ug/day).

Iodine deficiency is very common in the population and Iodine supplementation is now being suggested for pregnant mothers. Iodine deficiency  "is the most common cause of preventable mental retardation in the world". It is but one possible causative factor in ASD. See https://ods.od.nih.gov/factsheets/Iodine-HealthProfessional/

Given that selenium deficiency is also becoming increasingly common, one presumes that this will soon be added to the suggested list of supplements. Our studies have found that around 80% of the children with ASD are selenium deficient suggesting that this deficiency may be very important in the development of autism in the child.

The current recommended DAILY allowance (RDA) for riboflavin in pregnancy is 1.4-1.6 mg. Doses above this are generally excreted in the urine. If a person is deficient, levels above this should be considered. Further, it does take at least a month to fix some enzymes that are functionally deficient in vitamin B2. MAO is one notable one.

Vitamin B12

Central to the development of ASD is vitamin B12 deficiency, and the role deficiency has on lack of methylation, poor myelination, delayed mental development and greatly reduced production of creatine. Since lack of creatine alone, has been associated with nearly all the symptoms seen in ASD, it is paramount that potential vitamin B12 deficiency be addressed. Vitamin B12 levels (as too iron/biotin/B2 levels) drop significantly during pregnancy and further during breast feeding, it seems obvious that vitamin B12 levels in the mothers should be sufficiently high that the mother is still replete at "term" and also for the period of breast feeding. Vitamin B12 levels appear to drop by about 50 pmol/L during this time, and since functional vitamin B12 deficiency starts at around 250 pmol/L,  mothers should have pre-conception levels above 300 pmol/L. Vitamin B12 sufficiency should be assessed by measurement of deficiency markers such as MMA or homocysteine (preferably MMA) and these levels should be as low as possible. Since the foetus and newborn receive the same form/analogue of vitamin B12 that the mother is "supplemented with", it is also suggested that if supplementation is required that the supplement be a mixture of Adenosyl and Methyl B12 analogues of vitamin B12, the two biochemically active forms of the vitamin.

Iron

Iron deficiency in the neonate has been shown to cause irreversible brain damage in the neonate. Current recommendations are that when a woman enters pregnancy her serum ferritin should be above 70 ug/L (mcg/L).

Current Treatments of Autism

The majority of current treatments for children with autism could be broadly grouped under the general banner of "They have absolutely no idea what to do", and include a variety of behavioural and biochemical interventions including: applied behavioural analysis, cognitive behavioural therapy, Autism Preschool Programme, Early Bird programme, Floortime Therapy, Child's Talk Programme, facilitated communication, More than words programme, picture exchange communication system, relationship development interventions, Sensory integration training, social skills training, social stories, Son-Rise programme, Portage scheme, auditory integration training, music therapy, TEACCH, none of which actually address the biochemical inadequacies patently obvious in the condition.

Of concern in the treatment of autism are that many of the drugs given for the treatment of conditions associated with some symptoms of autism may actually being doing far more damage than good. One such treatment is the use of Valproic acid to treat those children who have epilepsy potentially caused by low iron and/ or B12 (. Despite numerous publications on the use of valproic acid to induce autism like behaviour in animal models of the condition, and the demonstration of the potentially damaging affect that this has on differentiation of oligodendrocytes, we have been made aware of many cases of its use to treat autism, despite the induction of the many side effects associated with over-use of the drug (84-88)

Dietary interventions, which arguably make the condition worse are the casein-free diet, the gluten-free diet, the combined gluten-free Casein-free diet (GFCF diet), extensive use of probiotic, omega-3 fish oil, vitamin A, vitamin B6 plus magnesium and vitamin C, digestive enzymes, and others, none of which address the deficiencies in iron/B2/B12/I/Se/Mo/biotin that are very common in the condition, each of which could be regarded as causative.

In an "If all else fails, try something else" mentality, treatments with melatonin, memantine, risperidine, methylphenidate, secretin, SSRIs, olanzapine, Gabatrol, have all been tried, with very limited alteration to the condition.

More recently a much more rational approach has been tried which is showing immense promise. In this approach the metabolic and metal deficiencies present in the children are identified, and these deficiencies rectified. Major deficiencies identified have been described in the biochemistry section.

Best practice currently involves a simple multivitamin approach with the addition of iodine, selenium and molybdenum, which precedes treatment with mixed Adenosyl/Methyl B12 Transdermoil™ oils applied topically. Many parents report dramatic improvements in speech, receptive language, in socialization skills, in activity and better sleep. In addition, the children have been able to move off the restricted GFCF diet and tolerate a wide variety of foods. If you want to know more about this treatment, please use the contact information on the relevant page.

Of note, supplements containing selenomethionine have not been proven to be useful in overcoming selenium deficiency, as such we would recommend supplements with selenite, or selenate.

References/ Useful links

  1. Whiton etal, 1979 Brain damage in infancy and dietary B12 deficiency PMID 502936

  2. Smolka etal, 2001 Metabolic complications and neurological manifestations of vitamin B12 deficiency in children of vegetarian mothers. PMID 11787236

  3. Zengin etal, 2008 Clinical manifestations of infants with nutritional vitamin B deficiency due to maternal dietary deficiency PMID 18945280

  4. Halicioglu etal, 2011 Nutritional deficiency in infants of vitamin B12 deficient mothers PMID 99429203

  5. Demir etal, 2013 Clinical and neurological findings of severe vitamin B12 deficiency... PMID 23781950

  6. Halicioglu etal, 2011 Nutritional B12 deficiency in infants of vitamin B12-deficient mothers PMID 22419203

  7. Bravo etal, 2014 Haematological and neurological compromise due to vitamin B12 deficient in infant of a vegetarian mother.... PMID 25697251

  8. Troen 2012 Folate and vitamin B12: function and importance in cognitive development PMID 25825305

  9. Schulpis etal 2004 Maternal-neonatal folate and vitamin B12 serum concentrations in Greeks and Albanian immigrants PMID 15357698

  10. Lucke etal, 2007 Maternal vitamin B12 deficiency: cause for neurological symptoms in infancy PMID 17729202

  11. Chalouhi etal, 2008 Neurological consequences of vitamin B12 deficiency and its treatment PMID 18708898

  12. Graber etal, 1971 Placental transport of vitamin B12 in the pregnant rat PMID 5552402

  13. Dror and Allen 2008 Effect of vitamin B12 deficiency on neurodevelopment in infants: current knowledge and possible mechanisms PMID 1845811

  14. Casterline etal 1997 Vitamin B12 deficiency is very prevalent in lactating Guatemalan women and their infants at three months post partum PMID 9311952

  15. Jones etal 2007 Prevalent vitamin B12 deficiency in twelve-month-old Guatemalan infants is predicted by maternal B12 deficiency and infant diet PMID 17449597

  16. Woods etal, 1960 Vitamin B12Co-60 readily passes the placenta into fetal organs and nursing provides B12 from mother to pup... PMC 2137236

  17. Molloy etal, 2009 Maternal vitamin B12 status and risk of neural tube defects in a population with high neural tube defect prevalence and no folic acid fortification. PMID 19255021

  18. Chu etal, 2016 Effects of melatonin and its analogues on neural stem cells. PMID  26499359

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