Research Carried out by our group has shown All
children with Modern Day Autism are functionally deficient in vitamin B2
The majority
children with Modern Day Autism are functionally deficient in iron
The majority of
children with Modern Day Autism are deficient in vitamin D at time of testing
All children with Modern Day Autism have Paradoxical B12 deficiency
We
have been lucky enough to have available data from around 2000 children with
autism. The data has included Hair Metals Test Analsyis, in which potential
toxic metals have been estimated, but more importantly essential metals have
also been measured. In addition, Organic Acids Test has been dogma on vitamin B12 deficiency implies a direct link
between levels of serum vitamin B12, and sufficiency. Hence as vitamin B12
levels reduce, markers such as MMA and homocysteine increase in an inverse
relationship to serum B12 levels (Minerva etal, 2021; Bailey etal, 2011). A
The current dogma on vitamin B12 deficiency implies a direct link
between levels of serum vitamin B12, and sufficiency. Hence as vitamin B12
levels reduce, markers such as MMA and homocysteine increase in an inverse
relationship to serum B12 levels (Minerva etal, 2021; Bailey etal, 2011). A
consequence of this "Dogma" is that if a person does not have vitamin B12 levels
lower than a highly variable amount, dependent upon study(148 pmol/L Minverva
etal, 2021; 179 pg/ml Spain Sanz-Cuesta et al, 2012), they cannot be B12
deficient. Hence vitamin B12 deficiency would be mainly due to poor diet, or
poor absorption (Elmadfa and Singer, 2009). The traditional correlation of
homocystein and MMA with decreasing serum vitamin B12.
Many people, however, experience symptoms of vitamin B12 deficiency yet
their serum levels of vitamin B12 may be normal or much higher than normal.
Subsequent examination of biochemical markers such as MMA or homocysteine may
show that these markers are moderate to highly elevated. As such the symptoms
and biochemical markers are indicative of vitamin B12 deficiency, yet the serum
vitamin B12 levels are paradoxically high. Such persons are deemed to have
"Paradoxical Vitamin B12 Deficiency". Generally, however, the reason(s)
for "Paradoxical B12 deficiency" are not known, even despite its association
with a greater increase in "all-cause mortality" (Flores-Guerrero etal. 2020),
chronic viral liver disease (Sugihara etal, 2017), Anorexia Nervosa (Corbetta
etal, 2014) and death from COVID-19 .
.
A typical example of
Paradoxical B12 deficiency (as per Dynacare Plus)
It has been known for over 40 years that measurements for serum
vitamin B12 levels can be greatly distorted by the presence of of non-functional
cobalamin analogues (Kolhouse etal, 1978; Kane et al, 1978; Igarai et al, 1978),
and in many cases measurement of serum B12 levels is not predictive of the
levels of functionally active B12 (England and Linnell, 1980; Andrès et al,
2013;
Serraj et al, 2011;
Ermens et al, 2002;
Rochat et a;. 2012l
Podzolkov et a;. 2019;
Zulfiqar et al, 2019). In addition, low
intracellular folate levels can often be associated with the presence of
inactive analogues of cobalamin in serum (Sheppard and Ryrie, 1980).
Alternatively it can be associated with inflammatory conditions such as
Rheumatoid arthritis due to the overproduction of the B12 binding proteins transcobalamin and haptocorin (Christensen et al 1983: Grindulis et al, 1984),
Cystic fibrosis (Lindemans etal, 1984), and patients treated with nitrous oxide
(Parry etal, 1985). Despite the almost completely non-predictive nature of serum
vitamin B12 levels it is still the measurement of choice for vitamin B12
sufficiency. Its utility is arguably restricted to determining conditions such
as dietary insufficiency, where serum levels are routinely low. Little wonder that so many physicians miss
functional vitamin B12 deficiency
in patients!
In the scattergram
above there is no obvious relationship between levels of vitamin B12 in serum,
and the standard marker of vitamin B12 deficiency, MMA
(MethylMalonic Acid). In
absolute vitamin B12 deficiency in serum, MMA starts to increase as vitamin B12
drops below 250 pmol/L.
The major cause of Paradoxical Vitamin B12 Deficiency appears to
lack of functional vitamin B2, which may occur due to overt vitamin B2 deficiency
in a person's diet, Hypothyrodism (Habbar etal, 2008), or due to lack of adequate intake of Iodine, Selenium and/or
Molybdenum, which in turn leads to insufficient production of the two active
forms of vitamin B2, namely FMN and FAD. FMN and FAD both have critical roles in
cycling and maintenance of activity of vitamin B12, particularly methyl B12.
Methyl-Co(III)B12 has a major role in the body in the removal of
homocysteine, and in the regeneration of methionine in the methylation cycling
using the enzyme methionine synthase reductase (MTR).
In the reaction,
homocysteine +
Methyl-Co(III)B12[MTR] => Methionine +
Co(I)B12[MTR].
The
problem with this reaction is that the methyl group is lost from
MethylCo(III)B12, which is reduced to Co(I)B12 and so cannot perform further
methylation reactions. Theoretically if the reaction only happened once you
would need approximately 13.7 gm of MethylCo(III)B12 to remethylate the 1.35 gm
of homocysteine formed per day, and around 1.37 kg of the enzyme methionine
synthase. Since the daily requirement for vitamin B12 is only around 5 ug, of
which around 1.37 ug is MethylCo(III)B12, then clearly this does not happen.
Regeneration of MethylCo(III)B12 is performed by methionine
synthase which transfers the methyl group from 5-methyl-tetrahydrofolate (5MTHF)
to Co(I)B12.
Thus,
5MTHF +
Co(I)B12[methionine synthase] => THF
+
MethylCo(III)B12[methionine
synthase].
If the 5MTHF was only used once, then the
body would require around 459 mg of 5MTHF per day, however, the daily
requirement for folate is around 1000th of this at 400-500 ug/day, so clearly
some other source, apart from diet is required to supply this amount of 5MTHF.
The solution comes from within the folate cycle. Here the THF,
formed above is converted to the folate derivative 5,10-methylene-THF by the
enzyme serine hydroxymethyl transferase (SHMT). The enzyme
methylene-tetrahydrofolate reducate (MTHFR), then converts the 5,10-methylene
group to 5-methyl-THFwhich it transports of the folate cycle into the
methylation cycle, in this way a single folate molecule can be recycled over
1000 times into and out of the folate cycle providing the many 5MTHF groups for
regeneration of MethylCo(III)B12.
The reaction
5,10-methylene-THF [MTHFR] => 5-methyl-THF [MTHFR]
The enzyme, MTHFR, though is critically dependent on FAD and
NADPH for enzymatic activity (McNulty etal, 2014) and as levels of FAD drop, the enzyme rapidly loses
activity, leading to insufficient 5MTHF for remethylation of Co(I)B12 to
MethylCo(III)B12. In this instance the Co(I)B12 is rapidly oxidized to the
biologically inactive Co(II)B12. The body does though have a "way around this"
and it uses the enzyme methionine synthase reductase plus S-Adenosylmethionine
(SAM) to remethylate Co(II)B12.
Thus,
Co(II)B12[MTR] + SAM[MTRR] =>
MethylCo(III)B12 + SAH +
MTRR.
MTRR, like MTHFR is also a "Flavoprotein" and uses both of the
active forms of vitamin B2, FMN and FAD for activity. Once again the activity of
the enzyme is critically dependent upon the concentration of FMN and FAD. The
activity of the enzyme MTRR is so critical for regeneration of MethylCo(III)B12,
that certain mutations in the gene have been found to be conditionally lethal in
the womb, or are associated with much higher rates of Down Syndrome, Neural Tube
Defects, increased homocysteine (Garcia-Minguillan etal, 2014; DeClerc etal,
1998) and increased cancer risks.
From the above it can readily be seen that if there is
insufficient FMN and/or FAD, there will be a gradual accumulation of the inactive
Co(II)B12, which is released from the cell and then starts to accumulate in
serum, leading to paradoxically high serum B12.
Further, the conversion of both hydroxycobalamin and
cyanocobalamin to the active Adenosyl and methyl cobalamins, also involve "Flavoproteins"
(Obeid etal, 2015) and hence if a person takes or is injected with, high doses of hydroxycobalamin
or cyanocobalamin and has functional B2 deficiency, the inactive hydroxycobalamin and cyanocobalamin will accumulate in serum, however the
symptoms of vitamin B12 deficiency will not be resolved. Despite the obvious
consequences of the functional B2 deficiency in the metabolism of B12, the
majority of authors do not seem cognizant of this (Obeid etal, 2015), and seem
to believe that B12 deficiency only occurs due to low intake of the vitamin,
rather than ineffective processing, and are unaware of the phenomenon of
Paradoxical B12 deficiency.
Paradoxical B12 deficiency is also apparent in certain cancers,
such as lung cancer as a result of smoking. In this case one would expect a
build up in inactive CN-Cbl due to the cyanide produced during smoking. The
higher the serum B12, the higher the associated risk of lung cancer (Fanidi etal,
2019). In addition, inhalation of large quantities of nitrous oxide (Marotta and
Keserwani, 2020).
The other major cause of Paradoxical B12 occurs when people take
large oral doses of B12.
Normally when one either obtains vitamin B12 from digestion in
the stomach or from a low dose oral B12 supplement, a protein called haptocorrin
(HC), which is secreted into saliva, binds to the B12 and protects it from acid
degradation in the stomach. Relatively acid resistant analogues of B12 such as
cyanocobalamin have significant hydrolysis at 37oC in the acid environment of
the stomach, the more sensitive methylcobalamin, is rapidly hydrolysed in
stomach acid. The amount of HC, though is relatively low, and whilst it could
protect around 100 ug of B12, there is not enough HC secreted to protect the B12
in some of the high dose oral supplements. Once the B12-HC complex reaches the
small intestine the HC is rapidly degraded and the "protected" B12 that has been
released is bound by the B12 carrier protein, Intrinsic Factor (IF). IF is
relatively non-specific in its binding to B12 and so will bind both intake and
hydrolysed B12. If 90%of it is degraded then 90% of the material bound by IF
will also be degraded. This mix is then taken up from the intestine and bound by
the B12 carrier protein, transcobalamin (TC). TC is even more promiscuous in its
binding than IF and so it will transport both the intact and degraded B12 into
the cell. Once inside the cell, though the two enzymes MMA-CoA mutase and
methionine synthase are very specific for Adenosyl and Methyl cobalamin,
respectively, and so any inactive B12 is rapidly expelled from the cells and
binds to circulating haptocorrin (HC). As more and more high dose oral B12 is
administered the situation gradually gets worse and worse, because now much of
the HC secreted in saliva (Collins etal 1999) already has inactive B12 bound to
it, and so this HC-B12 complex can no longer protect incoming B12 from acid
hydrolysis. Over time, the levels of serum B12 get higher and higher, but more
and more of the B12 is inactive.
From the above it can readily be seen that if levels of the two
functional analogues of vitamin B2, namely FMN and FAD are reduced the following
will happen.
1. The activity of MTHFR will decrease proportionally with the
decrease in FAD, thus resulting in reduced production of 5MTHF.
2. The reduced 5MTHF will result in a build-up in Co(I)B12, which
over time will oxidize to Co(II)B12.
3. The reduced
amounts of FMN and FAD will in turn reduce the activity of
the enzyme MTRR and so the levels of inactive Co(II)B12 will build up inside the
cell and will eventually be discarded from the cell resulting in a build up of
Co(II)B12 in serum. A condition of Paradoxical B12 Deficiency will result.
The major cause of Paradoxical Vitamin B12 Deficiency appears to
lack of functional vitamin B2, which may occur due to overt vitamin B2 deficiency
in a person's diet, or deficiency of Iodine, Selenium and/or Molybdenum. Such
deficiencies are very common, and our studies have shown that 50% of people with CFS or ASD are deficient in Iodine, 80% in Selenium and/or 50% in Molybdenum.
See
http://vitaminb12deficiency.info/hypothyroidism.htm for further
information.
In cases of functional vitamin B2 deficiency, there should be a relationship
between glutaric acid (a standard marker of vitamin B2 deficiency) and MMA, and
other vitamin B12 deficiency markers, HVA, VMA, QA, KA and HMG. There should
also be a correlation between MMA and HVA, VMA, QA, KA and HMG. However, like
MMA, there should be little relationship between these markers and serum vitamin
B12.
One marker of functional B2 deficiency is glutaric acid. As can be seen as
glutaric acid levels increase so too does MMA, indicating reduced activity of
vitamin B12. In contrast there was no relationship between glutaric acid and
absolute B12 levels.
HVA is a surrogate marker for methyl B12 deficiency. There was a good
correlation between HVA levels and glutaric acid, indicating that there is a
correlation between increased B2 deficiency (glutaric acid increasing) and
increase methyl B12 deficiency (as per the HVA marker). There was no correlation
between levels of HVA and total serum B12.
VMA is, like HVA a marker of methyl B12 deficiency. As was the case for HVA,
increased VMA was correlated with increased glutaric acid (left panel) as well
as increased MMA (a classical marker of B12 deficiency).
QA is also a
surrogate marker for methyl B12 deficiency. There was a good correlation between
QA levels and glutaric acid, indicating that there is a correlation between
increased B2 deficiency (glutaric acid increasing) and increased methyl B12
deficiency (as per the QA marker). There was no correlation between levels of QA
and total serum B12.
KA is also a surrogate marker for methyl B12 deficiency. The good correlation
between KA levels and glutaric acid, is not as good as for QA, because you need
functional vitamin B2, as FMN to form KA, so in Iodine and/or Selenium
deficiency, levels of KA are reduced, and so the correlation to glutaric acid is
not as good. In contrast, there was still a good correlation between KA and MMA
indicating the relationship between increasing methyl B12 deficiency (KA marker)
and increased Adenosyl B12 deficency (MMA marker) (Russell-Jones
2022).
The date presented above demonstrates that serum B12 levels do not correlate at
all with levels of functional vitamin B12!!
It is essential that for successful treatment of Paradoxical B12
deficiency that the cause of the functional vitamin B2 deficiency be addressed
including supplementation with sufficient vitamin B2, Iodine, Selenium and
Molybdenum. Such treatment, though, is generally not performed, but it has
immense consequences as far as treatment results, and explains why literature on
treatment of vitamin B12 deficiency is rife with examples in which
supplementation studies using inactive forms of vitamin B12 (cyanocobalamin or hydroxocobalamin) without the co-administration of the necessary B2/I/Se and Mo
have been ineffective in treatment. (see Langan and Goodbred, 2017) There is
though a treatment protocol aimed at fixing the functional vitamin B2 deficiency
and then the functional B12 deficiency see
https://understandingautism.com.au/prevention.htm
As they are approved, links will be
included to PDF copies.
Vitamin B12 deficiency and sleep disorders
Altered Neurotransmitter Metabolites in vitamin B12 deficiency
Much of the information on the metabolic
issues in ASD can also be applied to Dementia and CFS/FM/ME Manuscripts in Preparation
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cobalamin levels in the clinical setting--clinical associations and holo-transcobalamin changes. Clinical and laboratory haematology, 23(6),
365–371. https://doi.org/10.1046/j.1365-2257.2001.00134.x
Russell-Jones, GJ 2022 The
Paradoxical B12 Deficiency
Russell-Jones GJ 2023 The
Biochemistry of Autism
Russell-Jones GJ 2022
Functional
B12 deficiency in autism
Copyright © 2022 B12 Oils. All Rights Reserved.
Research
All children with Modern Day Autism are functionally deficient in vitamin B12
Research Methods
Paradoxical B12 deficiency
Causes of Paradoxical B12 deficiency
Vitamin B2 deficiency and paradoxical B12 deficiency
Treatment of Autism
Publications from research.
References
Rochat, M. C., Vollenweider, P., & Waeber, G. (2012). Hypervitaminémie B12:
implications cliniques et prise en charge [Therapeutic and clinical implications
of elevated levels of vitamin B12]. Revue medicale suisse, 8(360), 2072–2077.
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Medvedev, I. D. (2019). Terapevticheskii arkhiv, 91(8), 160–167. https://doi.org/10.26442/00403660.2019.08.000378
Zulfiqar, A. A., Andres, E., & Lorenzo Villalba, N. (2019). Hipervitaminosis
B12. Nuestra experiencia y una revisión [Hypervitaminosis B12. Our experience
and a review]. Medicina, 79(5), 391–396.
Bailey etal. Monitoring of vitamin B12 nutritional status in
the United States by using plasma methylmalonic acid and serum vitamin B12. Am J
Clin Nutr 2011 94 : 552-61
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Al-Musharaf etal Low Serum Vitamin B12 Levels Are Associated with Adverse Lipid
Profiles in Apparently Healthy Young Saudi Women Nutrients 2020 Aug
10;12(8):2395. doi: 10.3390/nu12082395
Oh, H. K., Lee, J. Y., Eo, W. K., Yoon, S. W., & Han, S. N. (2018). Elevated
Serum Vitamin B12 Levels as a Prognostic Factor for Survival Time in Metastatic
Cancer Patients: A Retrospective Study. Nutrition and cancer, 70(1), 37–44.
https://doi.org/10.1080/01635581.2018.1397711
Russell-Jones GJ 2022
Functional vitamin B2 deficiency in autism
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