Vitamin B2 in Autism

Functional Vitamin B2 deficiency has been identified in all children with autism
Functional Vitamin B2 deficiency can be the result of dietary riboflavin, Iodine, Selenium or Molybdenum deficiency.
Pregnant mothers are advised to supplement with 225 ug/day of Iodide during pregnancy.
Functional Vitamin B2 deficiency can lead to functional vitamin B12 deficiency.
Prolonged Vitamin B2 can lead to iron deficiency the person with autism
Vitamin B2 deficiency leads to a reduced ability of the autistic person to metabolize fat for energy
Vitamin B2 deficiency leads to a reduced ability of the autistic person to metabolize sugar for energy
Vitamin B2 deficiency causes functional B6 deficiency
Functional B6 deficiency leads to reduced production of GABA - which is common in Autism
Vitamin B2 deficiency has been associated with elevated oxalates in autism
Vitamin B2 deficiency in the mother should be suspected in those who are over-weight or obese
Vitamin B2 deficiency in the mother should be suspected in those who have gestational diabetes
Vitamin B2 deficiency should be suspected in mothers who have a low dietary intake of dairy

Nutritional Sufficiency of Children

The maternal decision to carry a child to term creates a beneficence-based fiduciary obligation on the part of the mother (and physician) to act in the best interest of the unborn child, and to sacrificially care for and nurture that child, There can be no doubt that this extends to ensuring nutritional sufficiency of the child in its early life. (Centre for Bioethics) Unfortunately the dietary guidelines for pregnant women vary from publication to publication and generally do not include recommendations for Iodine, Selenium and Molybdenum, which are essential minerals involved in the activation of the essential vitamin, riboflavin, vitamin B2. (Ortega, 2001). Further the majority of the health professionals do not understand the importance of these minerals. There are though guidelines on the National Health sites in the US, UK and Australia, particularly for Iodine and Selenium.

Vitamin B2 Deficiency in autism

Activation of dietary or supplemental vitamin B2 (riboflavin) requires a series of activation steps involving Thyroid Stimulating Hormone (TSH), thyroid hormone (T4), deiodinated T4 - triiodothyronine (T3), activation of riboflavin to FMN and finally modification of FMN to form FAD.

Once formed FMN and FAD are required for over 100 enzymes in the body. Specifically FAD is used by each of the enzymes that metabolize fat for energy. Lack of FAD leads to a reduced ability of the foetus, neonate or child with autism to metabolism fat for energy. Deficiency in the activity of fat metabolizing enzymes can lead to many conditions including: failure to thrive, ketotoic hypoglycemia, metabolic acidosis, lethargy, developmental delay, hypotonia, seizures, dystonia, and myopathy (Wolfe etal, 2011)

FAD works together with activated vitamin B1 (TPP) and lipoate in the metabolism of various sugars. Hence deficiency in FAD also leads to a reduced ability of the child with autism to use glucose as the preferred energy system in the brain. The inability of the child to effectively utilize sugar or fat for energy, leads to the need for the child to use either dietary or skeletal muscle for energy, and in turn leads to significant elevation of oxalate in the urine (Russell-Jones 2022).

Dietary deficiency of riboflavin, Iodine, Selenium and Molybdenum in Autism

Deficiency of any of Iodine, Selenium, Molybdenum or vitamin B2, will result in a the possibility of Single Nutrient Deficiency which will cause developmental delay. Further this deficiency then will result in functional deficiencies in vitamin B12, Iron and vitamin D.

Reduced consumption of dairy products in many countries has lead to many mothers being deficient in intake of dietary riboflavin (vitamin B2). In the period 1970 to 2010 average milk consumption in the US dropped from 25 gals/person/year to only 8 gals/person/year. This is compounded by an decrease in the levels of functional vitamin B2, with functional B2 deficiency being found in up to 40% of women of reproductive age being deficient in Canada and nearly 75% of women in Malaysia (Aljaadi etal, 2019). Functional deficiency of B2 can occur due to low intake of any of vitamin B2, Iodine, Selenium and/or Molybdenum. Each of Iodine, Selenium and Molybdenum are required for the "cascade" of reactions that are involved in vitamin B2 activation.

Iodine is required by the thyroid to make thyroid hormone, which is the initiating factor for the activation of vitamin B2.

Iodine deficiency has been recognized by the WHO as the single most preventable cause of mental retardation in the world and has mandated Iodine supplementation in all countries. Current recommendations are for women who are pregnant to consume 225 ug/day Iodide. Despite this recommendation, few doctors notify the mothers about this, and few mothers know of it, this is despite clear recommendations by governments in the US, UK and Australia.

A recent review of iodine status in pregnant women has stated

" Iodine deficiency in pregnancy impairs the neurological development of the fetus... Iodine deficiency in the mother ... causes irreversible brain damage with mental retardation" (Panth etal, 2019). These findings, though, are not new and it has been known for nearly 40 years that Iodine deficiency in the mothers can have disastrous neurological consequences in the neonate (Pharoah, et al, 1971; Morreale de Escobar et al, 2004, 2007; Williams 2008; Pop etal, 1999; 2003; Kooistra etal, 2006; Zoeller, and Rovet, 2004;Skeaff, et al 2009; RohnZoeller, R. T., & Rovet, J. (2004), and can result in Myxedematous cretinism (Zimmerman and Kohrle, 2002).. er etal, 2014).Despite this insufficient iodine intake in mothers is common in many countries including the USA, Canada, UK, Australia (41% of child bearing age - Burns etal, 2018), New Zealand, Croatia (Vidransky etal, 2020) and the majority of European countries (Itterman etal, 2020) Iodine deficiency is more common in families that do not use Iodized salt, who have low dairy intake, or consume "gluten-free" products (Panth etal, 2019). Plant-based diets are low in Iodine, and as such vegans may be at risk of Iodine deficiency (Mangels etal, 2011: Leung etal, 2011).The incidence of "gluten-free" consumption now is very common with as much as 25% of persons in the US, UK, and Australia adopting a nutrient poor gluten-free diet. Women tend to be lower in Iodine, as estrogen inhibits the absorption of Iodide. In a recent study 80% of those on a vegan diet were Iodine deficient (Flechas, 2020). Many families do not use Iodized salt, but instead opt for salt alternatives such as Himalayan Pink Salt, which does NOT provide dietary Iodine. Fear of mercury in fish has also driven many families away from seafood, the other major source of Iodine.

Iodine levels in the population in the US have halved in the US in the past thirty years (See) "Women who are pregnant and lactating require increased iodine intake. Unfortunately, median iodine levels in the United States have decreased by 50% in the past 3 decades, with recent studies demonstrating that pregnant women are mildly iodine deficient. Nevertheless, data from the NHANES 1999–2006 showed that only 22% of US pregnant women take an iodine-containing dietary supplement". Over the same period of time autism rates have increased from 1 in 1000 to 1 in 38 in the US. Iodine deficiency is now so common that in some areas the Pathology Labs have shifted the range of their "normal" data up from TSH of 0.05 to 3.0 to 1.8 to 3.0 mlU/L, which technically means that the "average" person in the population is now hypothyroidic. Iodine deficiency is more likely in those who have limited exposure to dairy, baked goods, table salt and seafood (Booms etal, 2016)..

Iodine is required for the formation of Thyroid Hormone (T4), initially in the pregnant mother, and later, by 16-18 weeks, the fetal thyroid has developed sufficiently for Iodine to be required by the foetus itself for foetal development. Deficiency of Iodine either in the mother or later in the foetus leads to lower metabolism and poor neurological development of the foetus. Comparison of children born to mothers with low Iodine showed a reduced IQ score in Wechshler Intelligence Scale Tests, and 19% children born to mothers with hypothyroidism had an IQ score of 85 or lower, compared to only 5% of control children. Knowledge of the importance of Iodine is generally poor, particularly in women below 40 in many countries including Croatia (Vidransky etal, 2020), Australia (Lucas etal 2014), Northern Ireland (McMullan etal, 2019), the UK (Combet etal, 2015), Norway (Henjum etal, 2018), Ukraine and India (Rai etal, 2016). The United Nations Convention on the Rights of a Child has stated that "Every mother has the right to adequate iodine nutrition to ensure that he unborn child experiences normal mental development" (2007), yet despite this Iodine deficiency is extremely common. Despite recommendations for Iodine supplementation by WHO in 1999, as recently as 2015 and 2020, studies in the UK were still considering whether supplementation was necessary, this despite the rapidly rising rate of autism in the UK (Dineva etal, 2020). Iodine supplementation of bread has only had a marginal effect in reducing Iodine deficiency (Wassie etl, 2019.

Iodine and Thyroid hormone (TH) and development in the brain. Studies on the effect of TH deficiency in the brain have shown that if TH deficiency occurs early in pregnancy (ie Iodine deficiency), the child displays problems in visual processing, visual attention, slower response speeds and lower gross motor skills. If it occurs later in pregnancy, there are problems with subnormal vision, slower response speeds, and fine motor skills. If deficiency occurs after birth language and memory skills are significantly affected (Zoeller, R. T., & Rovet, J. (2004). Further in reduced TH there was a reduced development of GABA secreting neurons, potentially explaining some of the behavioural problems that are common in autism (Manzano etal, 2008)

Selenium is required for the function of 25 enzymes, but importantly for vitamin B2 activation Selenium is required for the enzyme Iodothyronine deiodinase, which converts thyroid hormone (T4) to T3. Declining Selenium levels in the brain of the elderly have been associated with cognitive decline (Berr et al, 2012). Selenium levels in many soils in many countries has recently been identified as a nutrient deficiency of concern in the UK, Europe, New Zealand, many states in the USA, and in Canada. In the period 1975-1955 selenium intake in the UK dropped from 60-34 ug/day, or less the half the RDA (Rayman, 2000). The situation will be worse now (2022). Selenium deficiency is more common in those on a low dairy diet, or those who have adopted the nutrient poor gluten-free diet. Roughly 48% of children with autism have overt Selenium deficiency. Selenium deficiency is also common in large parts of south-west Western Australia and coastal Queensland, as well as parts of NSW, Victoria, South Australia and Tasmania. Given, that Selenium is responsible for the conversion of TH (T4) to T3, then one would expect the same consequences of Iodine deficiency to be seen with Selenium deficiency. Studies by Kamer and co-workers (2012) found that low Selenium was responsible for many food allergies, presumably due to functional B2/ B12 deficiency and maturation of the gut, as well as the role that FAD plays in the activity of the histamine neutralizing enzyme diamine Oxidase (Schwelberger, and Bodner (1997), Chaudhuri and Ghosh (1984)). Low selenium in adults has been associated with cognitive decline (Berr etal, 2000; Akbaraly etal, 2007; Gao etal, 2007),

Molybdenum is required for several molybdopterin-containing enzymes, but most importantly it is required for the enzyme FAD-synthase, which converts FMN to FAD (Giancaspero etal, 2015; Miccolis etal, 2014; Leone et al, 2019; Kisker etal, 1997; Tolomeo etal, 2020) Molybdenum levels in many countries have been steadily declining and molybdenum deficiency is common in those with autism with approximately 50% of children with autism having less than the recommended levels. Molybdenum deficiency is common in children with sulphite sensitivity, a common preservative in many foods, as well as sensitivity to high sulphite-containing foods such as eggs, cabbage, onions, etc (see Sulfite Sensitivity FAQ - Australasian Society of Clinical Immunology and Allergy (ASCIA). Often the association between sulphite sensitivity, and food allergy, and Molybdenum deficiency goes undiagnosed/recognized. This is exemplified by the Sulphite allergy site (quoted before), where they have identified lack of activity of the enzyme sulphite oxidase in treating sulphite sensitivity, YET, have failed to mention the need for Molybdenum for the activity of the enzyme(?!)

Severe sulphite oxidase deficiency (which is associated with Molybdenum deficiency) has been associated with feeding difficulties, decreased activity, neonatal seizures, and movement disorders within a few days after birth (lee etal, 2017; Hobson etal, 2005; Claerhout eta;. 2018).

Vitamin B2 deficiency and Altered glycolysis

Functional vitamin B2 is required for the metabolism of glucose, due to its role as a cofactor in the enzyme pyruvate dehydrogenase. Lack of activity of this enzyme is associated with congenital microcephaly, hypotonia, epilepsy, and ataxia. Developmental delay is universally associated with pyruvate dehyrogenase deficiency (Sofou et al, 2017). Lack of functional B2 in turn causes the accumulation of lactic acid, which alone can cause developmental delay. Elevated lactic acid is very common in ASD (Russell-Jones 2022). Lack of vitamin B1 (thiamine), in addition to lack of functional B2 leads to elevated pyruvate in OAT tests. Functional vitamin B2 deficiency occurs in two phases. Activation of vitamin B2 to FMN requires Iodine and Selenium, whilst the conversion of FMN to FAD requires Molybdenum (See below). Functional vitamin B2 deficiency can be seen by increasing glutaric acid levels in urinary Organic Acids. Accompanying the increase in glutaric acid, there is a steady increase in the levels of lactic acid as the enzyme pyruvate dehydrogenase gradually loses activity.

In Iodine and Selenium deficiency there is a paradoxical reduction in lactic acid, which then plateaus and does not change as glutaric acid levels increase above 1.5. Control of blood glucose is a multi-factorial process. Initially dietary glucose is initially elevated in the post-prandial period. Circulating glucose is rapidly taken up by muscles and the liver and even the brain. There the extra glucose is converted to glycogen and stored as intracellular glycogen. Glycogen is then slowly converted to glucose-1-phoshate by the B6 dependent enzyme glycogen phosphorylase, however, in functional B6 deficiency, due to FMN deficiency, glycogen cannot be utilized for glycolysis. Potentially this would also cause reduction of glycolysis in the brain, further affecting metabolism in the brain in functional vitamin B2 deficiency due to lack of Iodine and Selenium. Functional B2 deficiency, would potenitally explain the association between gestational diabetes and increased incidence of diabetes in children with autism (Cortes etal, 2022; Dhaliwal etal, 2019; Alhowikan etal, 2019).

Vitamin B2 deficiency and Altered GABA

Production of GABA requires the conversion of Glutamate to GABA via the B6-dependent enzyme, Glutamic Acid decarboxylase. In functional B2 deficiency, or specifically FMN deficiency (due to Iodine or Selenium deficiency), brain glutamate levels become highly elevated. Further, the ability of the Autistic child to control their behaviour becomes highly compromised (Gevi etal, 2020). Clearly in the study by Geva, his subjects were Iodine, and/or Selenium deficient.

Vitamin B6 deficiency with the resultant block in production of GABA (Gevi etal, 2020)

Vitamin B2 deficiency and vitamin B12 deficiency

Maintenance of vitamin B12 activity is critically dependent upon functional vitamin B2 sufficiency. Hence the activity of two enzymes MTHFR and MTRR, which are both involved in the methylation cycle, are critically dependent upon active B2 (as FAD and FMN) for function. In addition, the activation of vitamin B6 is dependent upon the FMN (the first of the two active forms of B2), and so in functional B2 deficiency vitamin B6 is not activated and this then affects the formation of the methylation precursor 5,10-methylene-THF, and will result in further reduction in the rate of methylation and hence B12 deficiency (Mosegaard etal, 2020, Shane, 2008)

Demand for Iodine in the Neonate

As soon as the child is born, it must take over the production of TSH and T4 from the mother. The demand for Iodine in the neonate is largely met by Iodine in colostrum (2744 ug/L) and milk (1295 ug/L, 4 weeks post partum), however, it is highly dependent upon the Iodine intake of mothers and hence dietary insufficiency in the mother will result in insufficiency in colostrum and milk (Moon and Kim 1999; Bertinato etal, 2020). Iodine content in milk varies enormously from country to country with levels highest in Korea (>200 ug/L), moderate in Morocco and China (100-200 ug/L) and lowest in countries such as Germany, Italy, USA and New Zealand (<50 ug/L), (Dror and Allen, 2018). The suggested optimal concentration is 150 ug/L (Dror and Allen 2018). "If iodine insufficiency leads to inadequate production of thyroid hormones and hypothyroidism during pregnancy, then irreversible fetal brain damage can result" (American Thyroid Association, 2006) Original recommendations were for 150 ug/day for pregnant women, this has now been increased to 250-300 ug/day, with 90 ug/day for newborns (Toloza etal, 2020). Despite these recommendations and position statements by the governments of Canada, USA, UK and Australia, few women know of them. Iodine deficiency is much more prevalent than has previously been recognized and a recent study in Canada concluded that "that large proportions of pregnant (>50%) and lactating (>75%) women in Canada will not meet iodine requirements without iodine supplementation. Studies from Austria, performed over different ages have shown that over 75% of the population had mild to moderate Iodine deficiency (Kapelari etal, 2008). One thing, though, is almost universal, the role of Iodine in the eventual activation of vitamin B2 is not generally known. The demand for Thyroid production of thyroid hormone by the neonate is reflected in a huge surge in TSH in the neonate (Jayasuriya etal, 2018 - see below). At this stage, if mother is deficient in Iodine, there will be a deficiency in milk and there will be a vast increase in TSH levels.

Iodine deficiency on the increase

Iodine deficiency was all but eliminated in many countries in the 1960-70s, however it has become apparent that Iodine deficiency is now on the increase in the UK. An increase in the rate of veganism, and avoidance of dairy and seafood has lead to a great increase in the rate of Iodine deficiency. This is further exacerbated by the shift in sterilization of the udders of milking cows from Iodine treatment to steam sterilization. In addition in the UK and many other countries there has been a shift away from the use of Iodized salt. Median Iodine intake in the US has declined by half since 1970 (Kerver etal, 2021). Iodine deficiency is particularly prevalent in pregnant women, and consumers of non-dairy products. "Pregnant and lactating women are particularly vulnerable to iodine deficiency disorders because of their increased iodine requirements. Severe maternal iodine deficiency has been associated with cretinism or impaired neurodevelopment in children as well as obstetric complications." (Rodriguez-Diaz and Pearce, 2020). In Australia, in 2009) in an attempt to overcome Iodine deficiency, they have mandated Iodination of commercial bread. However, most commercial breads now have soy flour in them, however the amount varies considerably from <1% to 5% or even 25%). Soy flour contains goitrogenic isoflavones, including genistein, daidzein, and glycitein. These compounds block the TPO enzyme that converts Iodine to Iodide, which is required in the early step in thyroid hormone production. If consumed in excess it can destroy thyroid function. Amazingly stupid, in that they are iodizing bread, but using soy flour in it. In discussions with the Australia Thyroid Foundation, they have admitted that they know about both the use of soy flour in bread, and also of the phytoestrogens and isoflavones, however the use of iodised salt in bread (through measurement of urinary iodine concentration) has corrected iodine deficiency (but not efficacy) (except in pregnancy) as so were not concerned about the use of soy flour in baking of bread. This would appear to be an illogical outcome. Surely if Iodine supplementation was sufficient, there would be NO iodine deficiency in pregnancy. Interestingly at the time of addition of Iodine fortification ASD rates in Australia were 0.5%, and in 202, they were 3.2%. Post supplemental analysis of pregnant women showed no statistically significant increase in urinary Iodine post bread fortification (Rahman etal, 2011). Studies have shown no association between urinary Iodine and TSH levels (Rebagliato et al, 2010). In a study by Zhou (2013), Iodine supplementation during pregnancy was showed no improvements in childhood intelligence, gross development, growth or pregnancy outcomes. Potentially this is due to the type of supplement. Iodine and your family: a guide | Raising Children Network

Gluten Free Diets

Many children with ASD are placed on gluten-free diets, which is then accompanied by additional nutrient deficiencies, such as vitamin D, calcium, folates, vitamin E, iodine and iron. include goitrins from foods such as cabbage, brussel sprouts, rapeseed oils, primrose, kale, spinach, mustard greens, and thiocyanates from foods such as cassava, flaxseed, almond kernels, and Flavinoids, such as soy, over-consumption of such foods greatly inhibits thyroid function.

Goitrogens and vitamin B2

The activation of vitamin B2 begins with the production of thyroid hormone, T4, in the thyroid. A group of foods, called goitrogens, disrupt the production of thyroid hormones by interfering with the uptake of Iodine into the thyroid. These include goitrogens from foods such as cabbage, brussel sprouts, rapeseed oils, primrose, kale, spinach, mustard greens, millet (known to be a strong goitrogen, and to result in Iodine deficiency, it also has prussic acid, a cyanoglycoside) (millets include ragi, foxtail millets, quinoa, jawar, bajira}, and thiocyanates from foods such as cassava, flaxseed, almond kernels, and Flavinoids, such as soy, Over-consumption of such foods can lead to reduced thyroid function, and lack of activation of vitamin B2 results. See List

Vaccines, infection, the Immune Response and vitamin B2

The generation of an effective immune response to vaccines, or to various infections, involves the usage of large amounts of active vitamin B2, as it is used in the activation of over 100 B2 dependent enzymes, 130 B6 dependent enzymes, and the cycling of methyl B12 which is used in over 200 B12-dependent methylation enzymes, the activation and processing of iron and also activation and processing of vitamin D. Further, the generation of this immune response to vaccines and to infections involves the activation of macrophages, which has been shown to be dependent upon vitamin B2 (Araki etal, 1995; Hevel etal, 1991; Steuhr and Ikda-Saito, 1991, Baek etal, 2991; Ghosh and Steuhr, 1995; Steuhr etal, 1990; 1991; . Part of this activation is turning on production of high levels of the enzyme NOS, an enzyme that requires FMN/FAD/BH4/NAD/and heme iron, and lots of energy, which requires folate and B12. Sequestration of folate and vitamin B12 is so high that sites of inflammation can actually be imaged with radioactively labelled folate and vitamin B12. In addition, low vitamin B2 is associated with a reduced ability to deal with infections (Schramm etal, 2014, Dey and Bishayi 2016; Mazur-Bialy etal, 2013; 2015). Thus, it is obvious that reserves of vitamin B2 may be drained as a response to vaccines, or chronic infections, and at such times, there is significant risk of post-vaccination or post infection stress on methylation, and in adults such stress can be an initiator in conditions such as Chronic Fatigue Syndrome, LONG COVID, and potentially in developmental delay in children. The longer the infection or the higher the response, the more likely that prolonged B2 deficiency, with accompanying vitamin B12 deficiency will result. As such, care must be taken to ensure sufficient vitamin B2, and I/Se/Mo at these times, in order to minimalize the effects of these conditions.

Resolving Vitamin B2 Deficiency in Pregnant mothers

Mothers should ensure vitamin B2 sufficiency before they are pregnant, however, if this is not possible, urinary Organic Acids Testing should be carried out to establish sufficiency, and cases of deficiency mothers should supplement not only with vitamin B12, but also with Iodine, Selenium, Molybdenum and vitamin B2 if there is reason to believe that these may also be deficient. Warning signs in the mothers can be fatigue, obesity, gestational diabetes, insufficient dietary intake such as occurs in vegetarian or vegan diets.

Signs of Vitamin B2 Deficiency in Pregnant mothers

There are many warning signs of potential vitamin B2 deficiency in the pregnant mothers, including

i) Gestational Diabetes - lower functional B2 leads to poorer processing of blood glucose, leading to elevated blood sugar

ii) Elevated TSH - Insufficient Iodine in the mothers leads to an increase in TSH levels during pregnancy, leading to hypothyroidism

iii) Low T3 - Insufficient Selenium in the mothers - either due to increased demand, or low intake, leads to lower T3 in the mother

iv) Difficulty in getting pregnant. Often this is due to inadequate nutrition which can also cause irregular cycling before pregnancy

v) PCOS - Insufficient vitamin B2, leads to lower conversion of testosterone to estrogen, with elevated testosterone and lower estrogen levels. PCOS has been associated with autism in the result child (Cherskov etal, 2018; Dubey etal, 2021; Abu-Zaid etal, 2022; Lee etal, 2017)

Resolving Vitamin B2 Deficiency in Autism

Successful resolution of vitamin B2 deficiency requires supplementation with Iodine, Selenium and/or Molybdenum, depending upon deficiency as well as supplementation with sufficient riboflavin. Hence both Iodine and Selenium are involved in the initial activation of riboflavin (vitamin B2) to FMN, the first active B2 molecule. Molybdenum is then used by FAD-Synthase to convert FMN to FAD. Interestingly FMN is also used to activate vitamin B6 to the active molecule PLP (also known as P5P). This is an essential co-factor in the enzyme Serine-hydroxymethyltransferase, the source of 5,10-methylene-THF in the folate cycle see https://b12oils.com/methylation.htm

Associated Deficiencies in Functional B2 deficiency - Functional B12 deficiency

Vitamin B2 is ultimately involved in the processing of vitamin B12 and the maintenance of functional vitamin B12 sufficiency. Lack of functional vitamin B2 (due to a single nutrient deficiency of Iodine, Selenium, Molybdenum and/or vitamin B2, will ultimately result in accumulation of inactive vitamin B12 in the body - as is found in all children with autism that we have data for. Thus both MTHFR and MTRR, which are involved in the methylation cycle are dependent upon FAD for activity with MTRR also requiring FMN

Associated Deficiencies in Autism

Vitamin B2 is ultimately involved in the uptake and processing of the heme molecule, and in uptake of iron from the intestine. A condition called porphyria results from functional vitamin B2, with porphyria being one of the classic symptoms of autism. Every child that we have data for who has autism is also deficient in active vitamin B2 (FMN and FAD) and is deficient in active vitamin B12 (Adenosyl and Methyl B12) (Russell-Jones 2022A), these deficiencies also have to be addressed or the child will not progress developmentally. Accompanying these deficiencies, deficiencies of Iodine, Selenium and/or Molybdenum are very common. Mutations in the fatty acid processing proteins or lack of active B2 also leads to poor processing of fat, with an increased rate of obesity in older chlidren with autism (Patel, etal, 2014; Denton, 2009; Vidal etal, 1996; Scouten etal, 1980).

Active vitamin B2, as FAD is required by the enzyme glutathione reductase (Parsons etal, 1985), and lower B2 is associated with lower GSH:GSSG ratios, which is extremely common in ASD.

Organic Acid analyses shows the difference between various markers associated with functional B2 deficiency that are higher in ASD.

Ethylmalonic acid (Left Panel) and Methylsuccinic acid (Right Panel) in the urine of neurotypical (NT) and individuals with autism (ASD).

Suberic acid (Left Panel) and Adipic acid (Right Panel) in the urine of neurotypical (NT) and individuals with autism (ASD).

Glutaric acid (Left Panel) and Succinic acid (Right Panel) in the urine of neurotypical (NT) and individuals with autism (ASD).

Lactic acid (Left Panel) and Oxalic acid (Right Panel) in the urine of neurotypical (NT) and individuals with autism (ASD).

See Russell-Jones 2022

Elevated glutaric acid, also results in increased levels of Oxalic acid

Pyruvate dehydrogenase

Pyruvate dehydrogenase is the enzyme that processes pyruvate, the end product of glycolysis. Deficiency in co-factors for the enzyme result in greatly increased lactic acid (in functional B2 deficiency) or pyruvate (in functional B1 deficiency).

Structure showing co-factors

References

Ortega, 2001 Food, pregnancy and lactation, Dietary guidelines for pregnant women. Public Health Nutrition, 4(6A), 1343±1346

Panth etal, 2019 A review of Iodine status of women of reproductive age in the USA. Biol Trace Element Res 188 208-220

AAP Recommendations on Iodine Nutrition During Pregnancy and Lactation | American Academy of Pediatrics (aappublications.org)

Morreale etal. Maternal thyroid hormones early in pregnancy and fetal brain development. Best Pract. Res. Clin. Endocrinol. Metab. 2004, 18, 225–248.

Williams, G.R. Neurodevelopmental and neurophysiological actions of thyroid hormones. J. Neuroendocrinol. 2008, 20, 784–794.

Morreale de Escobar et al.. Iodine deficiency and brain development in the first half of pregnancy. Public Health Nutr. 2007, 10, 1554–1570.

Burns et al. Iodine deficiency in women of childbearing age: not bread alone? Asia Pac J Clin Nutr 2018 27:853-859

Morreale de Escobar et al Role of thyroid hormone during early brain development. Eur. J. Endocrinol. 2004, 151, U25–U37.

Pop, et al Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin. Endocrinol. 1999, 50, 149–155.

Pop, et al. Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3 year follow-up study. Clin. Endocrinol. 2003, 59, 282–288.

Rohner et al. Biomarkers of Nutrition for Development - Iodine jn181974 1322..1342 (nih.gov)

Kooistra, et al. Neonatal effects of maternal hypothyroxinemia during early pregnancy. Pediatrics 2006, 117, 161–167.

Zoeller, R.T.; Rovet, J. Timing of thyroid hormone action in the developing brain: clinical observations and experimental findings. J. Neuroendocrinol. 2004, 16, 809–818.

Skeaff, et al Iodine deficiency does exist but is difficult to assess in individuals. N. Z. Med. J. 2009, 122, 101–102.

Costeira etal. Parameters of thryoid function throughout and after pregnancy in an iodine deficient population. Thyroid 2010, 20, 995–1001.

Chen et al, Cretinism revisited. Best Pract. Res. Clin. Endocrinol. Metab. 2010, 24, 39–50.

Rajatanavin et al. Endemic cretinism in Thailand: a multidiciplinary study. Eur. J. Endocrinol. 1997, 137, 349–355.

Ittermann, T., Albrecht, D., Arohonka, P., Bilek, R., de Castro, J. J., Dahl, L., Filipsson Nystrom, H., Gaberscek, S., Garcia-Fuentes, E., Gheorghiu, M. L., Hubalewska-Dydejczyk, A., Hunziker, S., Jukic, T., Karanfilski, B., Koskinen, S., Kusic, Z., Majstorov, V., Makris, K. C., Markou, K. B., Meisinger, C., … Völzke, H. (2020). Standardized Map of Iodine Status in Europe. Thyroid : official journal of the American Thyroid Association -(255, 255, 255)">(9), 1346–1354. https://doi.org/10.1089/thy.2019.0353

Booms S, Hill E, Kulhanek L, Vredeveld J, Gregg B. Iodine Deficiency and Hypothyroidism From Voluntary Diet Restrictions in the US: Case Reports. Pediatrics. 2016 Jun;137(6):e20154003. doi: 10.1542/peds.2015-4003. Epub 2016 May 10. PMID: 27244854.

Kerver JM, Pearce EN, Ma T, Gentchev M, Elliott MR, Paneth N. Prevalence of inadequate and excessive iodine intake in a US pregnancy cohort. Am J Obstet Gynecol. 2021 Jan;224(1):82.e1-82.e8. doi: 10.1016/j.ajog.2020.06.052. Epub 2020 Jul 9. PMID: 32653458; PMCID: PMC7779669.

Zoeller, R. T., & Rovet, J. (2004). Timing of thyroid hormone action in the developing brain: clinical observations and experimental findings. Journal of neuroendocrinology, 16(10), 809–818. https://doi.org/10.1111/j.1365-2826.2004.01243.x

Manzano, J., Cuadrado, M., Morte, B., & Bernal, J. (2007). Influence of thyroid hormone and thyroid hormone receptors in the generation of cerebellar gamma-aminobutyric acid-ergic interneurons from precursor cells. Endocrinology, 148(12), 5746–5751. https://doi.org/10.1210/en.2007-0567

Gevi F, Belardo A, Zolla L. A metabolomics approach to investigate urine levels of neurotransmitters and related metabolites in autistic children. Biochim Biophys Acta Mol Basis Dis. 2020 Oct 1;1866(10):165859. doi: 10.1016/j.bbadis.2020.165859. Epub 2020 Jun 5. PMID: 32512190.

Vidranks, V., Radman, A., Kaji, K, & Bronic, A. (2020). Knowledge and awareness of iodine intake - survey among Croatian women of reproductive age. Biochemia medica, 301), 01705 https://doi.org/10.11613/BM.2020.010705

Lucas CJ, Charlton KE, Brown L, Brock E, Cummins LC. Anenatal shared care: are pregnant women being adequately informed about iodine and nutritional supplementation? Aust NZ J Obstet Gyn. 2014; 54: 515–521. https://doi. org/10.1111/ajo.12239

McMullan P, Hunter A, McCance D, Woodside JV, Mullan K. Knowledge about iodine requirements during pregnancy and breastfeeding among pregnant women living in Northern Ireland. BMC Nutrition. 2019;5:24. https://doi. org/10.1186/s40795-019-0285-8

Combet E, Bouga M, Pan B, Lean ME, Christopher CO. Iodine and pregnancy - a UK cross-sectional survey of dietary intake, knowledge and awareness. Br J Nutr. 2015;114:108–17. 10.1017/S0007114515001464

Henjum S, Brantsæter AL, Kurniasari A, Dahl L, Aadland EK, Folven Gjengedal EL, et al. Suboptimal iodine status and low iodine knowledge in young Norwegian women. Nutrients. 2018;10:941. 10.3390/nu10070941

Rai S, Sirohi S, Khatri AK, Dixit S, Saroshe S. Assessment of knowledge and awareness regarding thyroid disorders among women of a cosmopolitan city of Central India. Natl J Community Med. 2016;7:219–22

Moon S, Kim J. Iodine content of human milk and dietary iodine intake of Korean lactating mothers. Int J Food Sci Nutr. 1999 May;50(3):165-71. doi: 10.1080/096374899101201. PMID: 10627832.

Kapelari K, Kirchlechner C, Högler W, Schweitzer K, Virgolini I, Moncayo R. Pediatric reference intervals for thyroid hormone levels from birth to adulthood: a retrospective study. BMC Endocr Disord. 2008 Nov 27;8:15. doi: 10.1186/1472-6823-8-15. PMID: 19036169; PMCID: PMC2645400.

Dror DK, Allen LH. Iodine in Human Milk: A Systematic Review. Adv Nutr. 2018 May 1;9(suppl_1):347S-357S. doi: 10.1093/advances/nmy020. PMID: 29846524; PMCID: PMC6008959.

Toloza FJK, Motahari H, Maraka S, Consequences of Severe Iodine Deficiency in Pregnancy: Evidence in Humans, MINI REVIEW article, Front. Endocrinol., 19 June 2020, Sec. Thyroid Endocrinology, https://doi.org/10.3389/fendo.2020.00409, https://www.frontiersin.org/articles/10.3389/fendo.2020.00409/full

Berr C, Balansard B, Arnaud J, et al. Cognitive decline is associated with systemic oxidative stress: the eva study. Etude du vieillissement arteriel. J Am Geriatr Soc. 2000;48(10):1285–1291. doi: 10.1111/j.1532-5415.2000.tb02603.x. [PubMed] [CrossRef] [Google Scholar]

Akbaraly TN, Hininger-Favier I, Carriere I, et al. Plasma selenium over time and cognitive decline in the elderly. Epidemiology. 2007;18(1):52–58. doi: 10.1097/01.ede.0000248202.83695.4e. [PubMed] [CrossRef] [Google Scholar]

Gao S, Jin Y, Hall KS, et al. Selenium level and cognitive function in rural elderly chinese. Am J Epidemiol. 2007;165(8):955–965. doi: 10.1093/aje/kwk073. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Bertinato J, Gaudet J, De Silva N, Mohanty S, Qiao C, Herod M, Gharibeh N, Weiler H. Iodine Status of Mother-Infant Dyads from Montréal, Canada: Secondary Analyses of a Vitamin D Supplementation Trial in Breastfed Infants. J Nutr. 2022 Jun 9;152(6):1459-1466. doi: 10.1093/jn/nxac047. PMID: 35218192; PMCID: PMC9178965. https://pubmed.ncbi.nlm.nih.gov/35218192/

Berbel P, Obregón MJ, Bernal J, Escobar del Rey F, Morreale de Escobar G. Iodine supplementation during pregnancy: a public health challenge. Trends Endocrinol Metab. 2007 Nov;18(9):338-43. doi: 10.1016/j.tem.2007.08.009. Epub 2007 Oct 24. PMID: 17962037.

Dineva M, Fishpool H, Rayman MP, Mendis J, Bath SC. Systematic review and meta-analysis of the effects of iodine supplementation on thyroid function and child neurodevelopment in mildly-to-moderately iodine-deficient pregnant women. Am J Clin Nutr. 2020 Aug 1;112(2):389-412. doi: 10.1093/ajcn/nqaa071. PMID: 32320029.

Zimmermann, M.B. Iodine deficiency. Endocr. Rev. 2009, 30, 376–408. 1

Rayman, MP. The importance of selenium to human health. Lancet, 2000, 356; 233-44

Kamer, B., Wąsowicz, W., Pyziak, K., Kamer-Bartosińska, A., Gromadzińska, J., & Pasowska, R. (2012). Role of selenium and zinc in the pathogenesis of food allergy in infants and young children. Archives of medical science : AMS, 8(6), 1083–1088. https://doi.org/10.5114/aoms.2012.32420.

Schwelberger, H. G., & Bodner, E. (1997). Purification and characterization of diamine oxidase from porcine kidney and intestine. Biochimica et biophysica acta, 1340(1), 152–164. https://doi.org/10.1016/s0167-4838(97)00039-3

Murari Mohan Chaudhuri, Bharati Ghosh (1984) Purification and characterization of diamine oxidase from rice embryos, Phytochemistry, Volume 23, Issue 2,241-243

Rodriguez-Diaz E, Pearce EN. Iodine status and supplementation before, during, and after pregnancy. Best Pract Res Clin Endocrinol Metab. 2020 Jul;34(4):101430. doi: 10.1016/j.beem.2020.101430. Epub 2020 Jun 19. PMID: 32792134.

Pharoah, et al. Neurological damage to the fetus resulting from severe iodine deficiency during pregnancy. Lancet 1971, 297, 308–310.

Wolfe etal, 2011 Short-chain Acyl-CoA dehydrogenase deficiency. https://www.ncbi.nlm.nih.gov/pubmed/21938826

Mangels et al. The dietician's guide to vegetarian diets.

Leung etal Iodine status and thyroid function of Boston area vegetarians and vegans. J. Clin Endocrinol Metab. 2011 96

Rebagliato et al, (2010) Iodine intake and maternal thyroid function during pregnancy. Epidemiol, 21(1):62-9.

Zhou et al, (2013) Effect iofine supplemntation in pregnancy on child development and other clinical outcomes: a systematic review of rendomized controlled trials. Am J Clin Nutr. 98(5) 1241-54

Zhou etal (2015) The effect of iodine supplementation in pregnancy on early childhood neurodevelopment and clinical outcomes: resutls of an aborted randomised placebo-controlled trial. Trials 16: 563

Giancaspero TA, Galluccio M, Miccolis A, Leone P, Eberini I, Iametti S, Indiveri C, Barile M. Human FAD synthase is a bi-functional enzyme with a FAD hydrolase activity in the molybdopterin binding domain. Biochem Biophys Res Commun. 2015 Sep 25;465(3):443-9. doi: 10.1016/j.bbrc.2015.08.035. Epub 2015 Aug 12. PMID: 26277395

Miccolis A, Galluccio M, Nitride C, Giancaspero TA, Ferranti P, Iametti S, Indiveri C, Bonomi F, Barile M. Significance of redox-active cysteines in human FAD synthase isoform 2. Biochim Biophys Acta. 2014 Dec;1844(12):2086-95. doi: 10.1016/j.bbapap.2014.08.005. Epub 2014 Aug 15. PMID: 25135855.

Leone P, Galluccio M, Quarta S, Anoz-Carbonell E, Medina M, Indiveri C, Barile M. Mutation of Aspartate 238 in FAD Synthase Isoform 6 Increases the Specific Activity by Weakening the FAD Binding. Int J Mol Sci. 2019 Dec 9;20(24):6203. doi: 10.3390/ijms20246203. PMID: 31835305; PMCID: PMC6941110.

Mosegaard S, Dipace G, Bross P, Carlsen J, Gregersen N, Olsen RKJ. Riboflavin Deficiency—Implications for General Human Health and Inborn Errors of Metabolism. International Journal of Molecular Sciences. 2020; 21(11):3847. https://doi.org/10.3390/ijms21113847

Shane, B. Folate and vitamin B12 metabolism: overview and interaction with riboflavin, vitamin B6, and polymorphisms. Food Nutr. Bull. 2008, 29, S5–S16. [Google Scholar] [CrossRef] [PubMed]

Kisker C, Schindelin H, Rees DC. Molybdenum-cofactor-containing enzymes: structure and mechanism. Annu Rev Biochem. 1997;66:233-67. doi: 10.1146/annurev.biochem.66.1.233. PMID: 9242907.

Tolomeo M, Nisco A, Leone P, Barile M. Development of Novel Experimental Models to Study Flavoproteome Alterations in Human Neuromuscular Diseases: The Effect of Rf Therapy. Int J Mol Sci. 2020 Jul 26;21(15):5310. doi: 10.3390/ijms21155310. PMID: 32722651; PMCID: PMC7432027.

Aljaadi etal. Suboptimal biochemical riboflavin status is associated with lower hemoglobin and higher rates of anemia in a sample of Canadian and Malaysian women of reproductive age.J Nutrit, 2019

Ames etal High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased K(m)): relevance to genetic disease and polymorphisms 11916749

Zimmerman and Kohrle The impact of iron and selenium deficiencies on iodine and thryoid metabolism: biochemistry and relevance to public health; https://www.ncbi.nlm.nih.gov/pubmed/12487769

Flechas 2020 Iodine deficiency and mental retardation https://www.youtube.com/watch?v=kZ-iDbgCupU&app=desktop

Jayasuriya MS, Choy KW, Chin LK, Doery J, Stewart A, Bergman P, Lu ZX. Reference intervals for neonatal thyroid function tests in the first 7 days of life. J Pediatr Endocrinol Metab. 2018 Oct 25;31(10):1113-1116. doi: 10.1515/jpem-2018-0007. PMID: 30063468.

Kusic etal (2012). Current status of iodine intake in Croatia - the results fo 2009 survey. Collegium antropologicaum, 36(1), 123-128

Rahman, A et al.(2011) Urinary iodine deficiency in Gippsland pregnant women: the failure of bread fortification? MJA 194(5), 240-243. https://doi.org/10.5694/j.1326-5477.2011.tb02953.x

Sofou etal (2017) Ketognic diet in pyruvate dehyrogenase complex deficiency: short- and long-term outcomes. J Inherit. Metabol. DIse. 40(2), 237-245 https://doi.org/10.1007/s10545-016-0011-5

Claerhout, H., Witters, P., Régal, L., Jansen, K., Van Hoestenberghe, M. R., Breckpot, J., & Vermeersch, P. (2018). Isolated sulfite oxidase deficiency. Journal of inherited metabolic disease, 41(1), 101–108. https://doi.org/10.1007/s10545-017-0089-4

Hobson, E. E., Thomas, S., Crofton, P. M., Murray, A. D., Dean, J. C., & Lloyd, D. (2005). Isolated sulphite oxidase deficiency mimics the features of hypoxic ischaemic encephalopathy. European journal of pediatrics, 164(11), 655–659. https://doi.org/10.1007/s00431-005-1729-5

Lee, H. F., Chi, C. S., Tsai, C. R., Chen, H. C., & Lee, I. C. (2017). Prenatal brain disruption in isolated sulfite oxidase deficiency. Orphanet journal of rare diseases, 12(1), 115. https://doi.org/10.1186/s13023-017-0668-3

Parsons, M. J., Ku, P. K., Ullrey, D. E., Stowe, H. D., Whetter, P. A., & Miller, E. R. (1985). Effects of riboflavin supplementation and selenium source on selenium metabolism in the young pig. Journal of animal science, 60(2), 451–461. https://doi.org/10.2527/jas1985.602451x

Cherskov A, Pohl A, Allison C, Zhang H, Payne RA, Baron-Cohen S. Polycystic ovary syndrome and autism: A test of the prenatal sex steroid theory. Transl Psychiatry. 2018 Aug 1;8(1):136. doi: 10.1038/s41398-018-0186-7.PMID: 30065244

Dubey P, Thakur B, Rodriguez S, Cox J, Sanchez S, Fonseca A, Reddy S, Clegg D, Dwivedi AK. A systematic review and meta-analysis of the association between maternal polycystic ovary syndrome and neuropsychiatric disorders in children. Transl Psychiatry. 2021 Nov 8;11(1):569. doi: 10.1038/s41398-021-01699-8.PMID: 34750348

Abu-Zaid A, Bhagavathula AS, Rahmani J, Alyoubi RA, Alomar O, Baradwan S, Alkhamis WH, Khalifa M, Alshahrani MS, Khadawardi K, Salem H, A Al-Badawi I. Maternal polycystic ovary syndrome and the potential risk of attention-deficit/hyperactivity disorder and autism spectrum disorder in the offspring: a systematic review and meta-analysis. Eur J Contracept Reprod Health Care. 2022 Jun;27(3):253-260. doi: 10.1080/13625187.2022.2040983. Epub 2022 Feb 22.PMID: 35191798.

Lee BK, Arver S, Widman L, Gardner RM, Magnusson C, Dalman C, Kosidou K. Maternal hirsutism and autism spectrum disorders in offspring. Autism Res. 2017 Sep;10(9):1544-1546. doi: 10.1002/aur.1797. Epub 2017 Apr 6.PMID: 28383189

Araki, S., Suzuki, M., Fujimoto, M., & Kimura, M. (1995). Enhancement of resistance to bacterial infection in mice by vitamin B2. The Journal of veterinary medical science, 57(4), 599–602. https://doi.org/10.1292/jvms.57.599

Hevel, J. M., White, K. A., & Marletta, M. A. (1991). Purification of the inducible murine macrophage nitric oxide synthase. Identification as a flavoprotein. The Journal of biological chemistry, 266(34), 22789–22791.

Stuehr, D. J., & Ikeda-Saito, M. (1992). Spectral characterization of brain and macrophage nitric oxide synthases. Cytochrome P-450-like hemeproteins that contain a flavin semiquinone radical. The Journal of biological chemistry, 267(29), 20547–20550.

Baek, K. J., Thiel, B. A., Lucas, S., & Stuehr, D. J. (1993). Macrophage nitric oxide synthase subunits. Purification, characterization, and role of prosthetic groups and substrate in regulating their association into a dimeric enzyme. The Journal of biological chemistry, 268(28), 21120–21129

Ghosh, D. K., & Stuehr, D. J. (1995). Macrophage NO synthase: characterization of isolated oxygenase and reductase domains reveals a head-to-head subunit interaction. Biochemistry, 34(3), 801–807. https://doi.org/10.1021/bi00003a013

Stuehr, D. J., Cho, H. J., Kwon, N. S., Weise, M. F., & Nathan, C. F. (1991). Purification and characterization of the cytokine-induced macrophage nitric oxide synthase: an FAD- and FMN-containing flavoprotein. Proceedings of the National Academy of Sciences of the United States of America, 88(17), 7773–7777. https://doi.org/10.1073/pnas.88.17.7773

Stuehr, D. J., Kwon, N. S., & Nathan, C. F. (1990). FAD and GSH participate in macrophage synthesis of nitric oxide. Biochemical and biophysical research communications, 168(2), 558–565. https://doi.org/10.1016/0006-291x(90)92357-6

Schramm, M., Wiegmann, K., Schramm, S., Gluschko, A., Herb, M., Utermöhlen, O., & Krönke, M. (2014). Riboflavin (vitamin B2 ) deficiency impairs NADPH oxidase 2 (Nox2) priming and defense against Listeria monocytogenes. European journal of immunology, 44(3), 728–741.

Dey, S., & Bishayi, B. (2016). Riboflavin along with antibiotics balances reactive oxygen species and inflammatory cytokines and controls Staphylococcus aureus infection by boosting murine macrophage function and regulates inflammation. Journal of inflammation (London, England), 13, 36. https://doi.org/10.1186/s12950-016-0145-0

Iodine deficiency in the UK – dietetic implications (bda.uk.com)

Mazur-Bialy, A. I., Buchala, B., & Plytycz, B. (2013). Riboflavin deprivation inhibits macrophage viability and activity - a study on the RAW 264.7 cell line. The British journal of nutrition, 110(3), 509–514. https://doi.org/10.1017/S0007114512005351

Mazur-Bialy, A. I., Pochec, E., & Plytycz, B. (2015). Immunomodulatory effect of riboflavin deficiency and enrichment - reversible pathological response versus silencing of inflammatory activation. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 66(6), 793–802.

Patel MS, Nemeria NS, Furey W, Jordan F. The pyruvate dehydrogenase complexes: structure-based function and regulation. J Biol Chem. 2014 Jun 13;289(24):16615-23. doi: 10.1074/jbc.R114.563148. Epub 2014 May 5. PMID: 24798336; PMCID: PMC4059105.

Denton RM. Regulation of mitochondrial dehydrogenases by calcium ions. Biochim Biophys Acta. 2009 Nov;1787(11):1309-16. doi: 10.1016/j.bbabio.2009.01.005. Epub 2009 Jan 20. PMID: 19413950

Vidal J, Rasschaert J, Sener A, Gomis R, Malaisse WJ. FAD-glycerophosphate dehydrogenase activity in lymphocytes of type-2 diabetic patients and their relatives. Diabetes Res Clin Pract. 1996 Mar;31(1-3):17-25. doi: 10.1016/0168-8227(96)01202-8. PMID: 8792098.

Scouten WH, Visser AJ, Grande HJ, De Kok A, De Graaf-Hess AC, Veeger C. Fluorescence polarization and energy-transfer studies on the pyruvate dehydrogenase complex of Escherichia coli. Eur J Biochem. 1980 Nov;112(1):9-16. doi: 10.1111/j.1432-1033.1980.tb04980.x. PMID: 6161006. Wassie MM, Yelland LN, Smithers LG, Ranieri E, Zhou SJ. Comparison of iodine status pre- and post-mandatory iodine fortification of bread in South Australia: a population study using newborn thyroid-stimulating hormone concentration as a marker. Public Health Nutr. 2019 Nov;22(16):3063-3072. doi: 10.1017/S1368980019001915. PMID: 31397245.

Cortese S, Gabellone A, Marzulli L, Iturmendi-Sabater I, de La Chica-Duarte D, Piqué IM, Solmi M, Shin JI, Margari L, Arrondo G. Association between autism spectrum disorder and diabetes: systematic review and meta-analysis. Neurosci Biobehav Rev. 2022 May;136:104592. doi: 10.1016/j.neubiorev.2022.104592. Epub 2022 Feb 22. PMID: 35217107.

Dhaliwal KK, Orsso CE, Richard C, Haqq AM, Zwaigenbaum L. Risk Factors for Unhealthy Weight Gain and Obesity among Children with Autism Spectrum Disorder. Int J Mol Sci. 2019 Jul 4;20(13):3285. doi: 10.3390/ijms20133285. PMID: 31277383; PMCID: PMC6650879.

Alhowikan AM, Al-Ayadhi LY, Halepoto DM. Impact of environmental pollution, dietary factors and diabetes mellitus on Autism Spectrum Disorder (ASD). Pak J Med Sci. 2019 Jul-Aug;35(4):1179-1184. doi: 10.12669/pjms.35.4.269. PMID: 31372164; PMCID: PMC6659068.

WHO, UNICEF, ICCIDD. Assessment of iodine deficiency disorders and monitoring their elimination, 3rd edition Geneva: World Health Organisation, 2007.

Zimmermann MB. Iodine deficiency. Endocr Rev 2009;30(4):376-408.

Konstantynowicz J, Porowski T, Zoch-Zwierz W, Wasilewska J, Kadziela-Olech H, Kulak W, Owens SC, Piotrowska-Jastrzebska J, Kaczmarski M. A potential pathogenic role of oxalate in autism. Eur J Paediatr Neurol. 2012 Sep;16(5):485-91. doi: 10.1016/j.ejpn.2011.08.004. Epub 2011 Sep 10. PMID: 21911305.

Meo etal, 2017 Ethylmalonic Encephalopathy. Gene Reviews 1993-2024 https://www.ncbi.nlm,nih.gov/books/

Rayman, MP. The importance of selenium to human health. Lancet, 2000, 356; 233-44

Berr etal, 2012 Selenium and cognitive impairment: A brief-review based on results from the EVA study. Int Union of Biochem and Mol Biology 38: 139-144

Berbel P, Mestre JL, Santamaria A, et al. Delayed neurobehavioral development in children born to pregnant women with mild hypothyroxinemia during the first month of gestation: the importance of early iodine supplementation. Thyroid 2009;19(5):511-9.

Velasco I, Carreira M, Santiago P, et al. Effect of iodine prophylaxis during pregnancy on neurocognitive development of children during the first two years of life. J Clin Endocrinol Metab 2009;94(9):3234-41.

Melse-Boonstra A, Jaiswal N. Iodine deficiency in pregnancy, infancy and childhood and its consequences for brain development. Best Pract Res Clin Endocrinol Metab 2010;24(1):29-38.

Bath SC, Steer CD, Golding J, Emmett PM, Rayman MP. Effect of inadequate iodine status in UK pregnant women on cognitive outcomes in their children: results from the Avon Longitudinal Study of Parents and Children (ALSPAC). Lancet 2013:doi:10.1016/S0140-6736(13)60436-5.

Phillips DI. Iodine, milk, and the elimination of endemic goitre in Britain: the story of an accidental public health triumph. J Epidemiol Community Health 1997;51(4):391-3.

Vanderpump MP, Lazarus JH, Smyth PP, et al. Iodine status of UK schoolgirls: a cross-sectional survey. Lancet 2011;377(9782):2007-12.

Bath S, Walter A, Taylor A, Rayman MP. Iodine status of UK women of childbearing age. J Hum Nutr Diet 2008;21:379-80.

Rayman MP, Sleeth M, Walter A, Taylor A. Iodine deficiency in UK women of child-bearing age. Proc Nut Soc 2008;67:E399.

Lampropoulou M, Lean M, Combet Aspray E. Iodine status of women of childbearing age in Scotland. Proc Nutr Soc 2012;71:E143

Bath SC, Walter A, Taylor A, Wright J, Rayman MP. Iodine deficiency in pregnant women living in the South-East of the UK: the influence of diet and nutritional supplements on iodine status. Br J Nutr 2014: E publicatation 7 January 2014; .

Kibirige MS, Hutchison S, Owen CJ, Delves HT. Prevalence of maternal dietary iodine insufficiency in the north east of England: implications for the fetus. Arch Dis Child Fetal Neonatal Ed 2004;89(5):F436-9.

Barnett C, Visser T, Williams F, et al. Inadequate iodine intake of 40% of pregnant women from a region in Scotland. J Endocrinol Invest 2002;25:(Supp. No. 7) 90, P110.

Pearce EN, Lazarus JH, Smyth PP, et al. Perchlorate and thiocyanate exposure and thyroid function in first-trimester pregnant women. J Clin Endocrinol Metab 2010;95(7):3207-15.

Moleti M, Di Bella B, Giorgianni G, et al. Maternal thyroid function in different conditions of iodine nutrition in pregnant women exposed to mild-moderate iodine deficiency: an observational study. Clin Endocrinol (Oxf) 2011;74(6):762-8.

Bath SC, Rayman MP. BDA Food Fact Sheet - Iodine. British Dietetic Association, 2013.

Bath SC, Button S, Rayman MP. Iodine concentration of organic and conventional milk: implications for iodine intake. Br J Nutr 2012;107(7):935-40.

Bath S, Button S, Rayman MP. Availability of iodised table salt in the UK – is it likely to influence population iodine intake? Public Health Nutr 2013:E-Pub 16 Jan.

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