Vitamin B12 Deficiency in Autism

Vitamin B12 loading of the brain happens predominantly in the womb, with little other vitamin B12 loading of the brain for the rest of life

Vitamin B12 loading of the brain increases progressively as the foetus matures.

Premature babies have lower brain vitamin B12.

Vitamin B12 deficiency during pregnancy leads to vitamin B12 deficiency in the neonate

Vitamin B12 deficiency during pregnancy increases the risk for preterm labour, low birth weight and increased infant mortality.

The brains of children with autism have been found to have greatly reduced levels of vitamin B12.

Vitamin B12 deficiency leads to lower production of creatine, and that alone can give most of the symptoms of autism

All children with ASD have been found to be functionally deficient in vitamin B12 at time of assessment

Vitamin B12 deficiency in the neonate is associated with delayed physical and mental development.

Vitamin B12 deficiency in the mothers during pregnancy is known to cause severe retardation of myelination of the nervous system of the foetus.

Vitamin B12 deficiency during development is associated with delay in the development of speech

Inadequate myelination in the various regions of the brain is common in children with autism

Vitamin B12 deficiency reduces the production of melatonin in the child and is associated with sleep disorders in ASD

Vitamin B12 deficiency has been associated with epilepsy in children with ASD

Paradoxical B12 deficiency is common in children with ASD

Vitamin B12 Deficiency in Neonates

Infants born with cobalamin (vitamin B12) deficiency are at significant risk of lasting brain damage. Further, the deficiency can cause developmental and intellectual delay, hypotonia, tremor, seizure, and failure to thrive. In addition the children may have speech, linguistics and social impairments, as well as behavioural disorders, and problems with fine and gross motor movement. Without therapy, there can be irreversible intellectual impairment, as well as cognitive and developmental delay Hasbaoui etal, 2021. Of these the concurrence of hypotonia with developmental and intellectual delay, especially with premature birth, low birth weight, difficulties feeding, and problems sleeping are all "Red Flags" for Vitamin B12 deficiency. They are also all associated with autism. It is almost unbelievable that despite countless publications on the effects of vitamin B12 deficiency in the neonate that this association with autism is missed.

Vitamin B12 Deficiency and Hypotonia

Identification of hypotonia in neonates is a strong indication of potential vitamin B12 deficiency (either absolute or paradoxical) Chalouhi et al, 2008; Demir et al, 2013; Bousselamti et al, 2018;Acıpayam et al, 2020; Akcaboy etal, 2015; Serin et al, 2019; Incecik et al, 2010; Honzik et al, 2010; Bicakci 2015; Smolka etal, 2001;Taskesen et al, 2011; Gupta et al, 2019; Benbir etal, 2007; Vieira etal, 2020; Ma etal, 2011; Borkowska etal 2007; Wagnon etal, 2005; Kamoun etal, 2017; Tosun etal, 2011; Kose etal, 2020; Lövblad etal, 1997; Lücke etal, 2007; Hall 1990; Vieira etal, 2020; Taskesen etal, 2011; Serin etal, 2015; Bicakci 2015; Serin HM, Arslan , 2019; Aguirre etal, 2019; Casella etal, 2005; Acıpayam etal, 020; Bousselamti etal, 2018;Hasbaoui etal, 2021 Hypotonia, is very common in autism, and early diagnosis of autism should be suspected in children with hypotonia, as "Hypotonia is a recognizable marker of ASD and should serve as a "red flag" to prompt earlier recognition and neurodevelopmental evaluation toward an autism diagnosis." (Gabis etal 2021; Lopez-Espejo, etal, 2021). Hypotonia is associated with decreased language development and IQ in autism (Osljeskova etal, 2007; Fillano etal, 2002). Not surprisingly hypotonia is a common symptom in those with autism (Badescu et al, 2016; Oslejskova et al, 2007; Lopez-Espejo et al, 2021; Gabis et al, 2021). Whilst the authors of the aforementioned papers did not come to any conclusion about the reason for vitamin B12 deficiency and hypotonia, clearly in methyl B12 deficiency there is reduced production of creatine, due to the reduced activity of GNMT (Longo etal, 2011; Pacheva etal, 2016; Stöckler et al, 1994; Mercimek-Mahmutoglu et al, 2006; Stockler-Ipsiroglu et al, 2014; Mercimek-Mahmutoglu et al 2014; O'Rourke et al, 2009; Araújo et al, 2005; Lion-François et al, 2006; Mercimek-Mahmutoglu et al, 2009; Leuzzi et al, 2013 Schulze et al, 2006;Verbruggen et al 2007; Morris et al, 2007; Item etal, 2004), and reduced production of CoQ10, both of which would lead to poor muscle tone. Several studies have shown a link between creatine deficiency and hypothonia (Longo etal, 2011), including studies on deficiency of the creatine producing enzyme Guanidoacetate-N-methyl transferase (Nasrallah et al, 2012); and the creatine transporter (Yıldız etal, 2020; Pacheva etal, 2016; Morris etal, 2007; Schulze 2013). Developmental delay was an accompanying symptom.

Vitamin B12 Loading of the Foetal Brain

It is known that the majority of vitamin B12 loading of the brain occurs during foetal development where as much as 17% of transplacentally derived vitamin B12 enters the foetal brain. Loading is maximal during the last trimester of foetal life, and continues until the time of birth and thereafter very, very little enters the brain (Roed etal, 2008: Agarwal and Nathani, 2009). As such foetal loading of the brain is incredibly important for the developing child, and deficiency of vitamin B12 in the mothers has a profound effect on the foetus and new-born child. Deficiency of vitamin B12 in the mothers is also correlated with deficiency of vitamin B12 in the neonate. An alarming rate of vitamin B12 deficiency in pregnant mothers in the UK has recently been reported (Sukumar etal, 206; Knight etal, 2015; Low-Beer etal, 1968), with more that 20% of women deficient as assessed by the haematological definition of deficiency (<150 pmol/L), but a massive 70% being deficient if assessed by metabolic parameters (<250 pmol/L; Sukumar etal, 206; Knight etal, 2015; Low-Beer etal, 1968). It would appear that the rates may have been dropping for some time, because in 1968 (before UK joined the EU), the average B12 levels were much higher at 288 pmol/L (Low-Beer etal, 1968) The rates of deficiency were much higher in India, where 43% were deficient (<150 pmol/L; Krishnaveni etal, 2009). Hopefully this is not a portend of ever increasing rates of autism. Additionally, despite the diagnosis of B12 deficiency, the mothers in the various studies were not treated for B12 deficiency! The incidence of B12 deficiency in pregnancy seems to be very high, with over 50% of woman in Canada being metabolically deficient in the first trimester (Roed etal, 2008). The increase in the adoption of vegan diets will potentially result in a dramatic increase in the rate of both vitamin B12 deficiency and that associated iron deficiency (Lemale etal, 2019), and the associated developmental delay in the upcoming pediatric population. Lower levels of vitamin B12 have been found in the brains of children with autism (Zhang etal, 2016).

In addition, there is increased homocysteine, and reduced levels of methionine, SAM and lower thiol reducing activity with lower Cysteine, and GSH. Of particular note is the lower level of cystathionine, the initial product of CBS through its reduced action on homocysteine, suggesting a block methylation and in conversion of Hcy to Cystathioinine.

Vitamin B12 Deficiency and Creatine deficiency

Over 40% of all methylation within the brain goes to the production of creatine, an essential energy transporter in muscles and brain. As the level of methyl B12 decreases, so too does the formation of creatine. Creatine deficiency has been associated with severe neurodevelopmental delay, intellectual disability, behavioral abnormalities, poorly developed muscle mass and muscle weakness (Stockebrand etal, 2018; Braissant etal, 2011). Creatine deficiency has also been associated with epilepsy and aphasia (difficulty reading, speaking and writing - a common problem in children with autism)(Perna etal, 2016), and with mental retardation, autism, hypotonia, and seizures (Longo etal, 2011). Creatine deficiency has been shown to reduce energy transfer from the electron transport chain (in the mitochondria) to energy available within the cytoplasm of the cell. (Nabuurs etal, 2013). Creatine deficiency has also been shown to affect spatial and object learning (Udobi etal, 2019), Creatine deficiency has also been associated with conditions such as Huntington's, ALS, Parkinson's disease, and Chronic Fatigue Syndrome (Riesberg etal, 2016). Creatine plays an essential role in myelination of neuronal cells by the oligodendrocytes, which use them for energy. In low creatine, there is poor myelination and developmental delay results (Rosko et al 2021). Creatine also has an important role in remyelination, and as such deficiency in creatine, or functional B2/B12 will result in poor remyelination and ultimately lead to myelin breakdown.

Vitamin B12 Deficiency and Developmental Delay

For over 60 years it has been known that Vitamin B12 sufficiency is crucial for the development of myelination of the central nervous system, and poor vitamin B12 status is linked to poor growth and neurodevelopment (Gutierrez-Diaz, 1959; Schrimshaw etal, 1959; Agrawal and Nathani 2009; Sheng etal, 2019), neural tube defects (Lucke etal 2007), and retardation of myelination in the brain (Lovblad etal, 1997; Horstmann etal, 2003), and lower brain volume (Black 2008). Vitamin B12 deficiency is associated with severe brain atrophy with signs of retarded myelination, with the frontal and temporal lobes being the most severely affected (Lövblad et al,1997). The frontal lobes are involved in motor functions, problem solving, memory, language, judgement, impulse control, spontaneity and social and sexual behaviour. The temporal lobes are involved in the formation of long term memory, recognizing faces, and interpreting body language, it aids in the production of speech, remembering the names of objects, and recognition of language. These are the levels of highest creatine usage with creatine having a role in a range of cognitive functions, including learning, memory, attention, speech and language, and possibly emotion. Thus, vitamin B12 deficiency in the mothers, which is later seen in the children, would be expected to have adverse outcomes. Further, maternal vitamin B12 status early in gestation (28 weeks) has been positively associated with child's subsequent mental and social development quotients, as measured at 2 years (Strand etal 2018). Vitamin B12 concentration in the first 2 years of life was positively correlated with cognitive score (Sheng etal, 2019). Infants aged 12-18 months who have lower B12 levels also present with lower psychomotor and mental development scores compared to those with higher vitamin B12 levels (Obeid etal, 2017). This would "fit" with the critical time for foetal brain loading of the child (Agrawal and Nathany, 2009; Chalouhi etal, 2008), and vitamin B12 and folate deficiency, with the accompanying elevated homocysteine have been associated with altered brain morphology, and cognitive and psychological problems in school-aged children (Ars etal, 2019) . Furthermore, vitamin B12 deficiency, particularly of methyl B12, results in lower production of the methylating agent, S-Adenosylmethionine (SAM). Lower SAM in turn leads to lower energy production of creatine (the essential backbone for creatine-phosphate) and ubiquinol (CoQ10), the essential electron transfer molecule in the Electron Transport Chain. Low CoQ10 levels have been associated with lower cognitive function and intellectual disability in autism (Smolka etal, 2001). Reduced production of SAM also affects the activity of the histamine-neutralizing enzyme, Histamine-N-methyl transferase, and would explain much of the food insensitivity of young children with ASD, due to the presence of histamine in a diverse range of foods.

Vitamin B12 and the Production of Melatonin

Melatonin, together with vitamin D, stimulates neuronal stem cells to differentiate into oligodendrocytes, which are the cells in the brain that are responsible for myelination of the nerves in the brain. Production of melatonin gradually increases during pregnancy, peaking in the third trimester. After birth, the newborn child initially relies on melatonin in the mother's milk, as it gradually turns on its own production of melatonin, which in neurotypically normal children peaks at around 5 years of age, and starts to decline after puberty. It has been known for over 60 years, that the production of melatonin involves the O-methylation of N-acetyl serotonin, by the action of enzyme hydroxyindole-O-methyl transferase, using S-Adenosylmethionine (SAM), as the methyl donor (Axelrod and Weissbach 1960, Weissbach and Axelrod 1960). As such production of melatonin, ultimately relies on methyl cobalamin as the initial methyl donor for the production of SAM, and so in mothers that are low in vitamin B12, foetal melatonin will be lower, as too will neonatal melatonin, thereby resulting in the delayed myelination typical of ASD. Despite the obvious correlation between low functional vitamin B12 resulting in a reduced ability to produce melatonin, we could find very little evidence that this association has been made in the literature. This is despite countless publications, finding an association between lower melatonin production in the mother, the fetus, or in the neonate, and the severity of symptoms in autism (Wiebe etal, 2018; Yunho etal, 2018; Gagnon and Godbout, 2018; Rossignol and Frye, 2011; 2014, Sanchez-Barcelo et al, 2017; Haidar etal 2016). Further, rather than to measure and address the vitamin B12 deficiency in such children, melatonin is the more common treatment (Blackmer and Feinstein, 2016). Further, the association was still not made in studies showing the elevated melatonin precursor, N-acetylserotonin, and reduced melatonin in ASD (Pagan etal, 2014).

Melatonin levels in mothers in the 1st, 2nd, and 3rd Trimester

Voiculescu etal, 2014

Melatonin levels during developmentr

Grivas and Savvidou, 2007

The final step in production of Melatonin is the methylation of N-Acetyl-Serotonin (NAcSer) by the enzyme HydroxyIndole-O-methyltransferase (HIOMT), which has an absolute requirement for S-Adenosylmethionine (SAM), a product of the methylation cycle (Axelrod and Weissbach 1960, Weissbach and Axelrod 1960).

Melatonin synthesis and SAM

In Methyl B12 deficiency, there is a greatly reduced production of SAM, and breakdown products of tryptophan, Kynurenic acid (KA) and Quinolinic acid (QA), as well as the breakdown product of Serotonin, 5-Hydroxyindoleacetic acid (5HIAA) start to accumulate and can be detected as elevated levels in urine.

Metabolites increased in SAM deficiency

In functional B2 deficiency due to lack of Iodine and/or Selenium, riboflavin is not converted to FMN and then levels of serotonin and KA are reduced.

The typical symptoms of vitamin B12 deficiency in the neonate are very similar to those observed in autism and include megaloblastic anemia, feeding difficulties, developmental delay (Casella etal, 2005; Honzik etal, 2010; Hall 1990), microcephaly (Honzik etal, 2010; Hall 1990), failure to thrive, hypotonia (Aquirre etal, 2019; Casella etal, 2005; Kanra etal, 2005; Chandra etal, 2006; Lucke etal, 2007; Schlapbach etal, 2007; Borkowska etal, 2007; Honzik etal, 2010; Hall 1990), and cerebral atrophy with symptoms of lethargy (Hall 1990; Shevell and Rosenblat 1992), and occasionally seizures (Benbir etal, 2007;Aquirre etal, 2019; Hall 1990), and psycho-motor delay. Seizures may also occur during treatment for B12 deficiency, however, these go away within days or weeks (Benbir etal, 2007) Many of these symptoms can be explained by the critical role that vitamin B12 plays in the production of melatonin, through its role in methylation. Melatonin in turn is critical for the differentiation of neuronal stem cells into myelin-producing oligodendrocytes, potentially explaining the delayed myelination found in children with autism. A deficiency in the Adenosyl-form of vitamin B12 has been linked to tiredness, vomiting, weak muscle tone, developmental delay, intellectual disability, and frequent illnesses.

Vitamin B12 Deficiency in Vegetarian Mothers

Children born of vegan and vegetarian mothers often have moderate to severe vitamin B12 deficiency, and such deficiencies have been associated with delayed myelination, weight loss, and reduction of motor skills, delayed development, neuro-regression, regression of psychomotor development, growth retardation, neuropathy (Renault etal, 1999) brain atrophy and apathy (Davis and Melina 2014; Kanra etal, 2005; Stollhoff and Schulte 1987; Von Schenck et al, 1997). Many of these conditions persist through later life (von Schenck etal, 1997), and even with supplementation after birth, children can still show apathy, muscular dystonia, abnormal movements and language delay (Smolka etal 2001). Despite these deficiencies being well documented, for more than 30 years, many vegetarian and vegan mothers do not supplement before, during or after pregnancy, nor do their health professionals check them for deficiency.

Accompanying the vitamin B12 deficiency of the vegan and vegetarian diets are deficiencies in protein, calcium, iron, zinc, and omega-3 fatty acids (97-98-99), so much so that the German Nutrition Society does NOT recommend such diets during pregnancy, lactation, and childhood (99).

Maternal serum B12 levels are closely correlated with the vitamin B12 levels in the mother's milk. In the years 2009 to 2017, there was an increase in the rate of veganism in the US from 0.1% to 6%, and in increase in the rate of autism from 1:200 to 1:35 over the same period.

Vitamin B12 and the Development of Speech

Myelination of Brocca's region in the brain precedes the development of speech, and as such delayed myelination would be expected to cause the delay in speech which is so characteristic of many children with autism.

Vitamin B12 deficiency and Depression

Depression is a common side-effect of vitamin B12 deficiency, and can lead to thoughts of, and commitment of, suicide in children with autism

Vitamin B12 deficiency and Nitrous oxide and anaesthetics.

Nitrous oxide was commonly used as an anaesthetic gas, yet as long ago as 1956 (Lassen et al, 1956) it was realized that it the activity of vitamin B12 was destroyed by nitrous oxide and could cause megaloblastic anemia. In 1968, Banks and co-workers demonstrated that nitrous oxide could react with the cobalt in vitamin B12 and lead to the inactive NO-CoB12 complex. The destruction of the activity of vitamin B12 is dependent upon the time and dose of administration of nitrous, with over 50% of individuals producing signs of megaloblastic depression of bone marrow function (Nunn and Chanarin, 1978). As early as 1978 (Amess et al, 1987) the use of nitrous oxide for anaesthesia was found to be contra-indicated, yet to this day it is still used, and many individuals report signs of B12 deficiency following use. Unbelievably, despite numerous publications showing poor outcomes of nitrous oxide use in pregnancy, and several demonstrating an association between nitrous and autism, and over 200 publications, demonstrating inactivation of vitamin B12 with subsequent sequelae, clinicains in the US, UK and Australia claim "“ Initiation and management of nitrous oxide by registered nurses is a safe and cost-effective option for labor pain.”. (See PDF). One of the problems with Nitrous inactivation of vitamin B12 activity is that the levels of B12 in serum still remain high, yet paradoxically the B12 is inactive - as per the discussion on paradoxical vitamin B12 deficiency. Unbelievably, nitrous oxide is still used as an anaesthetic to this day in the USA, both on mothers during pregnancy, and also on young children. Evidence suggests that this alone is responsible for many cases of autism

Determination of vitamin B12 Deficiency

Simplistically one would assume that simply measuring vitamin B12 levels in serum would determine if a person was sufficient or insufficient, and to a large extent this is what is done. Most Pathology labs simply measure the amount of B12 in serum and using an arbitrary cut-off value (generally 150 pmol/L) assign values above this as being sufficient. Unfortunately it is nowhere near that simple. Even in common dietary insufficiency, signs of biochemical deficiency of vitamin B12 can be observed when vitamin B12 levels drop below 250 pmol/L.

Measurement of biochemical deficiency has uncovered a huge range of serum B12 levels even as high as 2000 pmol/L in which biochemical deficiency of vitamin B12 can be measured. This, then is paradoxical and the term "Paradoxical vitamin B12 deficiency" has been used to describe this condition. It appears that in "paradoxical B12 deficiency", the form of B12 that is in serum is an inactive form of B12 (most likely to be Co(II)B12). If this form of B12 was present in the mother during pregnancy it would be this form of B12 (the inactive Co(II)B12) that would have stocked the brain, with the result that the child would be born with what seems to be adequate vitamin B12 levels, however, the child would be functionally deficient in vitamin B12. Further, the B12 in breast milk from the mother would also be inactive. Paradoxical B12 deficiency is common in children with ASD (Hope etal, 2020). Studies by Dr Russell-Jones have shown that every child with ASD was functionally deficient in vitamin B12, with the majority also having Paradoxical B12 deficiency.

Thus, the only way to tell if the vitamin B12 in serum is active or inactive is to measure metabolic by-products of B12 metabolism and see if they are raised. The two most commonly raised markers in vitamin B12 deficiency are homocysteine and methyl malonic acid (MMA). There are a number of others that are readily identified if an assessment of urinary Organic Acids is performed. Interpretation of such data should though only be attempted by those sufficiently trained in such assessment, which the general medical profession are not. Elevated homocysteine is common in children with autism (Kałużna-Czaplińska, etal, 2011; Altun etal, 2018)

Resolving Vitamin B12 Deficiency in Pregnant mothers

Mothers should ensure vitamin B12 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. Correcting of deficiency cannot be achieved by large oral doses of vitamin B12 due to both the very limited uptake of vitamin B12 from the gut, as well as the extensive denaturation of the majority of the orally administered dose of vitamin B12, by gastric acid. Instead vitamin B12 should be given by injection or via the Transdermoil^TM delivery route. Any person on antidepressant medication going into or during pregnancy should suspect vitamin B12 or iron deficiency, and get checked via OAT.

Resolving Vitamin B12 Deficiency in Autism

Vitamin B12 deficiency has been shown to occur in all children with ASD and this needs to be addressed if the child is going to have any chance of normal development. Several studies on children who were vitamin B12 deficient have shown significant increase in growth and cognitive scores when supplemented with vitamin B12 (Sheng etal, 2019; Strand etal, 2015). Given that co-deficiency in functional vitamin B2 is universal in autistic children this deficiency must be fixed first, and then the active forms of vitamin B12, adenosyl B12 and methyl B12 must be given either by injection of via the Transdermoil^TM delivery route. NO oral formulation of vitamin B12 has ever been shown to resolve symptoms in autism.

Other signs of Vitamin B12 Deficiency in Neonates

Other signs of vitamin B12 deficiency in the neonate include megalobastic anaemia, feeding difficulties (difficulties in suckling), developmental delay, microcephaly, hyptonia, lethargy, irritability, involuntary movements, seizures and cerebral atrophy" (Benbir etal, 2007).

Associated Deficiencies in Autism

The majority of studies looking at vitamin B12 deficiency in children and in autism have now addressed the likely co-deficiency of iron, however, one could assume that a diet low in vitamin B12 would also be a diet low in iron. 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), 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.

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