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Vitamin D Deficiency in Autism

Vitamin D deficiency is common in Autism

Many mothers of children with autism report very low vitamin D levels during pregnancy and others report extensive use of high SPF cosmetics. Gestational or developmental vitamin D deficiency is associative for a higher risk of ASD (Asad etal, 2019). 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).

Many studies have shown a high and increasing prevalence of vitamin D deficiency in the general population (Diehl and Chiu, 2010) and in pregnant mothers (Dror and Allen, 2010; Erllopta etal, 2011), and a study in the Netherlands showed 26% of mothers to be deficient, with up to 46% of neonates deficient (Vinkhuyzen eatl, 2016). Vitamin D deficiency is extremely prevalent in Kuwait (54% - Al-Mutairi etal, 2012), India (Babu and Calvo, 2010), Indonesia (45.5% of pregnant women - Ilmiawati etal, 2020), Europe (Brouwer etal, 2012); USA (Wentz etal, 2014; Forrest and Stuhldreher 2011), S. Korea (over 75% of females Park etal, 2020) and deficiency is higher in those with darker skin and during winter (Sawicki etal, 2016). More recently it has been calculated that over 80% of Americans are vitamin D deficient. Vitamin D deficiency is also common now in Australia and New Zealand (Shrapnel and Truswell, 2006; Quaggiotto etal, 2014).

Very few foods have significant levels of vitamin D, which is restricted mainly to fatty fish, beef liver, cheese, margarines, milk and eggs. Potentially this explains why vitamin D levels are significantly lower in vegetarians than non-vegetarians (Brooke etal, 1980). The increased incidence of vitamin D has been associated with the increasing use of sunscreens, long sleeves, following skin cancer campaigns. Using sunscreens with as little as a 15-factor protection factor protection cuts the skin's vitamin D production by 99 percent. There has also been a reduced consumption of foods such as salmon, tuna and mackerel, and vitamin D fortified dairy products such as milk, and a switch to such poor nutritional alternatives such as soy and almond detergent homogenized milk substitutes.

Apart from its effect on brain development, maternal vitamin D deficiency has also been associated with seizures in newborns (Visser, 2005).

Whilst many are aware of the role of vitamin D in bone health, vitamin D has a unique role in brain development, including homeostasis, embyrogeneisis, neural differentiation, neurodevelopment, gene regulation and immunological modulation (Duan 2013). Vitamin D also has a role in neurotrophism, neuroprotection, and neuroplasticity (Cannell 2013), and vitamin D deficiency has been associated with developmental disorders and abnormal brain development in conditions such as autism (Eyles etal, 2013; 2009; Eissa etal, 2018; Wang etal, 2022).

Normal activation of vitamin D, is a well known process in which light from the sun, or more specifically UV light from the sun shines on the skin and causes the conversion of the precursor 7-dehydrocholesterol to be converted to vitamin D3 - cholecalciferol. This molecule then is further processed in the liver and converted to the inactive form 25-hydroxy-vitamin D. Finally the 25-hydroxyvitamin D (Calcidiol) is activated in the kidney to form 1,25di-hydroxyvitamin D (Calcitriol).

The brain is unique amongst the other organs in that it has its own enzyme, 1a-hydroxylase, that activates 25-hydroxyvitamin-D to the active form 1,25-dihydroxy-vitamin D. The active vitamin D so produced, then binds to specific vitamin D receptors in the brain, particularly in the hypothalamus, and dopaminergic neurons of the substantia nigra. High levels of expression of the 1-a-hydroxylase has been in the Purkinje cells in the cerebellum (Eyles etal, 2004). Malfunctioning Purkinje cells are directly associated with the reduced capacity for motor learning in children with autism. These cells are responsible for fine-tuned motor control, balance, proprioception, and the vestibulo-ocular reflex (VOR). The VOR is the reflex that stabilizes the eye movement during head turning, such that the eyes can still focus on a target, even when the head is turned. Many studies have found cerebellar dysfunction in people with ASD, and post-mortem studies have shown loss of Purkinje cell volume in the majority of autistic brains studies. Paralleling these studies is the finding by MacDonald that children with autism are about six months behind in gross motor skills such as running and jumping and nearly a year behind in fine motor skills such as holding a spoon or grasping a small toy.

Mode of activation of Vitamin D in the brain, following stimulation of the eye by 482 nm light.

Lack of vitamin D has also been associated with a loss in hippocampal volume (an area of the brain that regulates motivation, emotion, learning and memory), and hence low vitamin D would be associated with difficulty learning. Low vitamin D has been associated with cognitive decline in adults (Wentz etal, 2014). Low vitamin D in utero has been associated with autism spectrum disorder and schizophrenia (Eyles etal, 2013; Ali etal, 2020, 2018), whilst in adults it has been associated with depression and Alzheimer's disease Littlejohns etal, 2014; 2016; Dickens etal, 2011). In experimental models, gestational vitamin D deficiency has been shown to cause permanent changes in the developing brains of rats (Levenson and Figueiroa, 2009; Feron etal, 2005), and has also been shown to lead to persistent changes in the adult brain (Feron etal, 2005; Eyles etal, 2012). Loading of the neonate with vitamin D occurs in utero, as very little vitamin D is contained in milk, so an infant born from a vitamin D deficient mother will be vitamin D deficient (Holick 2006).

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; Kesby etal, 2011). Interestingly vitamin D also promotes tyrosine hydroxylase (TH) and tryptophan hydroxylase 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.

Genetic studies have shown a higher rate of the homozygous recessive genotypes in the gene coding for 1-alpha-hydoxylase in people with autism (15.9% vs 3.8% risk ratio 4.2:1)

The importance of sun-exposure for the production of vitamin D has been known 1822 (nearly 200 years), and particularly exposure to UVB radiation (290-315 nm) (Holick 2006). However with the advent of sun-protection factors in the early 1870s, and the addition of high SPF value cosmetics and the increase in hours worked indoors, plus various sun-avoidance practices has seen a rise in the incidence of vitamin D deficiency, and an increase in the incidence of rickets with the result that vitamin D deficiency in children has once again reached epidemic proportions (Holick 2006). One of the potential sources of vitamin D is dairy, and so, the reduction in the consumption of dairy products, particularly those from free range cows and the switch to alternative products such as soy, and almond drinks, and adoption of a vegan diet can further reduce vitamin D levels.. Vitamin D deficiency is very common in some countries, and over 42% of Singapore residents (92), 45.5% of Saudi residents, and in 2018 over 82.5% of females in South Korea (an increase from 76% in 2008)(93) were found to be vitamin D deficient. Over 46% of neonates were found to be vitamin D deficient in the Netherlands (Vinkhuysen etal, 2016). Vitamin D status decreases with increases in weight (one of the predisposing maternal factors for giving birth to a child with ASD). In Australia in 2012, 30% of women of child bearing age were found to be vitamin D deficient.

Studies have shown that maternal hypovitaminosis D is increasingly associated with a higher incidence of fetal miscarriage, preeclampsia, gestational diabetes, bacterial vaginosis, and impaired fetal and childhood growth and development.

Paralleling the rapid rise in the incidence of ASD in many countries has been the adoption of high SPF value cosmetics in many countries. Thus, when compared to the early 1990s, where very few "daily" cosmetics had any SPF protection in them, in 2018 many "daily" cosmetics "boast" SPF values of 60+ and above. Vitamin D has a critical role in brain development, and even transient deficiency in the womb can result in delayed brain development. Further studies comparing vitamin D sufficient and vitamin D deficient children showed more autism related traits in those who were born to mothers with vitamin 25-OH-D concentrations less than 25nmol/L. Similarly, lower vitamin D levels in the first trimester of pregnancy have also been associated with a higher risk of autism (52). It has also been shown that lower vitamin D levels are common in ASD children than in age matched controls. Associated with this has been a massive increase in the rate of vitamin D deficiency diagnosis. Thus, in the period 2000 to 2014 there was an 83-fold increase in the rate of vitamin D deficiency diagnosis in children in the UK (Basetemur etal 2017), paralleling the massive increase in the rate of autism seen in the US over that time. There has also been a big increase in the rate of vitamin D deficiency in Australia and in the USA..In a study in 2007 - 2010 an estimated 94.3% of the US population had <EAR for vitamin D (see Ref).

Reproduced from Basatemur  et al. 2017

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).

Children with autism have been found to have lower levels of vitamin D, than their age-matched peers (Stainaker etal, 2019; Bivona etal, 2019: George etal, 2019; Alzqhoul etal, 2019; Chauhan etal, 2019). Studies in animal models have shown that vitamin D deficient animals exhibited delayed motor and behavioural features similar to ASD (Ali etal, 2019). Treatment of ASD children with vitamin D (2000 IU/day) showed significant reduction in their autism rating scales (Feng etal, 2019; Mazahery etal, 2019). In Australia, the effectiveness of the "Slip, Slop, Slap" campaign promoting sun-protection (starting in the late 1980s), was severely criticized as early as 2002 (Nowson etal, 2002), as at that stage the prevalence of vitamin D deficiency in women had already reached 23%, increasing the risk of osteoporosis, dementia, schizophrenia, respiratory condition, diabetes, coronary disease, breast, and prostate cancer. In New Zealand as long ago as 2015, they were claiming the Slip, Slop, Slap campaign had gone too far. Interestingly, in 2018, a working party by the QIMR, Berghofer Medical Rearch Institute claimed that using sunscreen every day would have minimal impact on vitamin D levels. This would appear to have been a very costly conclusion (Whiteman, etal, 2018), One wonders about the logic, surely if the sunscreen is supposed to stop the sun from causing melanoma, it must also block the rays that cause vitamin D production in the skin.  More recently the Australian Cancer council has added a warning to their web-site about vitamin D deficiency, thereby absolving themselves of blame.

 

Vitamin D deficiency in Australia in winter

 

Vitamin D Deficiency and Neurological Development

Many studies have now shown that low vitamin D in the mother is associated with behavioural problems in the off-spring, as well as poor neurological outcomes and an increased risk of autism (Arshad etal, 2022; Fiscaletti et al, 2017; Wang et al, 2020; Francis et al, 2021; Principi et al, 2021; Stubbs et al, 2016; Sourander  et al, 2021; Cannell 2017; Aagaard et al, 2023). Low vitamin D levels have been associated with increased use ofsun protection beauty products, insufficient exposure to sunlight, obesity, insufficient vitamin D intake or intestinal malabsorption, seasonal variation that is observed at temperate latitudes, and some pathological conditions like kidney or liver failure, chronic inflammation, and use of contemporary medications, greater use of high SPF make-up, longer hours worked inside,  (Arshad et al, 2022)

Vitamin D Deficiency and Development of Speech

Low vitamin D in utero and in the new-born has been associated with delayed speech development (Hawes etal, 2015).

Vitamin D Deficiency and Epilepsy

Several studies have shown an association between low vitamin D levels and epilepsy in autism (Holló etal, 2014; Miratashi Yazdi etal, 2017; Specht,  etal, 2020; Jésus, etal, 2020; Shellhaas,  abd Joshi, 2010; Kija,  etal, 2019; Elmazny,  etal, 2020; Durá-Travé, etal, 2018; Zhang,  etal, 2020; Fong,  etal, 2020; Snoeijen-Schouwenaars etal, 2015). Epilepsy, intellectual disability and low vitamin D levels were commonly associated (Snoeijen-Schouwenaars etal, 2015)

Vitamin D Deficiency and Iron Deficiency

Several studies have shown an association between low iron and low vitamin D levels, presumably because iron is used in processing of vitamin D (Akermanns etal, 2017; in utero and in the new-born has been associated with delayed speech development (Hawes etal, 2015; Kamau etal, 2018; Malczewska-Lenczowska etal, 2018; Russell-Jones 2024).

Cost of the Slip, Slop, Slap campaign on Autism

Cost estimates reveal a devastating cost to society of the Slip, Slop, Slap campaign as it pertains to the increased rate of autism, with associated costs, plus Parkinson's Disease and Alzheimer's disease. The societal cost of melanoma is dwarfed by the cost of these vitamin D associated conditions.

Elevated Urinary Phosphoric Acid in Autism

Active vitamin D is correlated with increased calcium by HMTA, but is inversely correlated with urinary organic acids data. This can be further complicated by diet, as many children with autism have been placed on GFCF diets, with the mistaken belief that the children are intolerant to casein. Much more likely is that functional B12 deficiency results in decreased production of melatonin with the result that the gastrointestinal mucosa does not secrete sufficient lactase and hence the children are actually lactase intolerant. Fixing functional B2 and B12 deficiency is thus essential. Further, putting the child on a dairy-free diet reduces the amount of calcium in their diet, thus resulting in brittle bones, but since calcium is a signaling molecule in the brain, this can be even more detrimental to the child's well-being.

Recent studies have shown a dependency of functional B2, B12, and iron on activation of vitamin D. These findings have formed the basis for the Nexus TheoryTM

Russell-Jones, 2024 a, b

Resolving Vitamin D Deficiency in Pregnant mothers

Current recommendations are a daily intake of at least 800 IU per day, however many studies suggest that a minimum of 1000 IU per day, particularly during pregnancy, and 2000 IU per day for women "at risk", such as those who are over-weight, have darker skin, or who cover-up extensively. More recently, a study compared 1000 and 2000 IU per day, and found that even with 2000 IU/day serum 25OHD3 was only increased by 20 ng/ml, suggesting that even higher doses may  be required, particularly in those that are deficient (Best et al, 2020).Vitamin D deficiency has been defined as less than 50 nmol/L (20 ng/ml). Good sources of vitamin D are milk, or fortified dairy products such as yogurt, butter, margarine, cheese, and fish, such as tuna, mackerel, sardines and salmon. In some areas of the world vitamin D deficiency in pregnant women is so common, that vitamin D testing is no longer done, due to cost, and vitamin D supplementation is strongly recommended. Vitamin D deficiency in mothers has been associated with multiple sclerosis,  increased cancer risk, metabolic syndrome, premature delivery, pre-eclampsia, and depression.

Vitamin D deficiency in mothers is becoming increasingly more common, and studies in Japan showing 89.5% of mothers below 20 ng/ml vitamin D (Shibata etal, 2011), while in Greece 19.5% of mothers had levels below 10 ng/ml (Nicolaidou etal, 2006), in Turkey 46.6% below 10 ng/ml (Ustuner etal, 2011), Norway 71% (Viljkainen etal, 2010), whilst in the US 42.4% of African Americans, and 4.2% of whites had serum vitamin D less than 15 ng/ml (Nesby-O'Dell etal, 2002). Despite recommendations few mothers take vitamin D supplements, and only 0.6% of Scottish mothers were found to have taken the recommended supplement dose (Haggarty etal, 2013), nor had neonates in a study in UAE despite recommendations to do so (Narchi etal, 2011)

Resolving Vitamin D Deficiency in Autism

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). Vitamin D deficiency is now so common that there has been a dramatic increase  in the rate of Rickets in children in many countries including USA, Canada, UK, Australia, Algeria, Denmark, Finland, France, Netherlands, Norway, Spain, Germany, India, Bangladesh, China, Indonesia, Israel, Japan, Kuwait, Lebanon, Mongolia, New Zealand, and even in the Africa countries, of Ethiopia, Kenya, Nigeria , Sudan and S. Africa. Vitamin D supplementation studies of bread and milk in Denmark, have shown that 9.4 mg per day vitamin D is sufficient to greatly reduce the winter drop of vitamin D levels (73.1 nmol/L to 67.6 nomol/L - supplemented in comparison to 71.1 nmol/L to 41.7 nmol/L in non-supplemented) (Madsen etal, 2013). In the USA, vitamin D is added at 100 IU/cup to most full cream milk. However, "milk substitutes" do NOT have added vitamin D. Recommendations are for pregnant women to supplement with at least 2000 IU vitamin D throughout their pregnancy (Vitamin D (nih.gov))

Associated Deficiencies in Autism

Low vitamin D levels have been associated with many conditions, including ricketts, PCOS, asthma, atopic dermatitis,

Increased vitamin D Deficiency in the Population

Low vitamin D is increasingly prevalent in the community. In the US the overall rate is estimated to be 42%, with the highest rate in the African American population (82%), followed by the Hispanic population (63%). Vitamin D deficiency is now also very high in Japan, with rates as high as 47.7% in summer, and 82.2% in winter in Kumamato and Hokkaido (Asakakura et al, 2020).Apart from autism, low vitamin D has been associated with a range of gut issues, including IBD, diverticulitis, colon cancer and liver disease.

Changing the paradigm

Unfortunately too many cosmetic companies are earning billions of dollars from the sale of the high SPF cosmetics, so it is highly unlikely that they will change the formulations. It is also unlikely that while so many health professionals are making money out of treating vitamin D associated conditions such as autism, dementia, and Parkinson's disease, that they will change their strategy. Hence "“It is difficult to get a man to understand something when his salary depends on his not understanding it.” (John Sinclair, 1932). Hence we have been unable to make progress with the cancer council in getting them to stop recommending the use of sun-protection products, nor several cosmetic companies.  Hence it is not in the best interests of foundations getting millions of dollars in donations, for them to find a mode of prevention or cure for a condition that they are getting donations for. For instance the Australian Cancer Council (https://www.concer.org.au) has a major arm of its fund raising in selling SPF cosmetics, and clothing. This is despite countless publications on the protective effect of vitamin D and also how elevated vitamin D is protective against UVB mediated damage in the skin (Jagoca and Dixon, 2020; Song etal, 2012; Gupta etal, 2006).
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