Vitamin B12 Metabolism I/Se Deficiency

We have got together some of the interdependencies of the vitamins and minerals that are required for maintenance of vitamin B12 function.

Sequentially we have tried to demonstrate what happens under different deficiencies.

Hence the basic methylation pathway, absolute B12 deficiency, functional B12 deficiency due to Molybdenum deficiency, and functional B12 deficiency due to Iodine/and/or Selenium deficiency.

Modification of Methylation pathway in functional B2 deficiency due to Iodine/Selenium deficiency

The pathway shows the critical dependency of the methylation pathway on sufficient Iodine and Selenium. In Iodine and/or Selenium deficiency, there is lack of production of Riboflavin Kinase, which then results in not only FAD deficiency but also FMN deficiency. FMN deficiency, in turn, results in a lack of activation of vitamin B6 to PLP.

Apart from the lack of methylation seen with Molybdenum deficiency and functional vitamin B12 deficiency, additional deficiencies and symptoms occur.

Lack of functional B2 sufficiency, also leads to lack of activity of the B1/B2/lipoate dependent enzyme pyruvate dehydrogenase. This then leads to a block in glycolysis with elevations in lactic acid and elevated blood glucose. Functional B2 deficiency is also associated with lack of activity of the enzyme eNOS, and can lead to high blood pressure. The association of I/Se/Mo deficiency with these conditions is often missed and so can lead to extensive drug treatment, and polypharmacy, due to simple nutritional deficiency.

Lack of PLP reduces the conversion of glutamate to GABA, and hence the typical behavioural problems, such as restricted and repetitive interests and behaviours, and sensory sensitivities. The elevated glutamate results in over-stimulation of the affected individuals, leading to behavioural disturbances, OCD and epilepsy. In addition, evidence suggests that GABA deficiency is also associated with Major Depressive Disorder (Vecchia etal, 2022). Deficiencies in GABA are also associated with developmental regression, motor abnormalities, seizures and features of autism such as stereotypical behaviours (Chao etal, 2010; DeLorey and Olsen 1999; Chiu etal, 2005).

Production of GABA, an inhibitory neurotransmitter in the body requires the conversion of Glutamate to GABA by the enzyme Glutamic Acid Decarboxylase (GAD). This enzyme requires the active form of vitamin B6, pyridoxal-phosphate as a co-factor. Production of PLP, however, requires one of the two active forms of vitamin B2, FMN. In deficiency of Iodine and/or Selenium, levels of FMN are reduced, resulting in elevated glutamate and reduced GABA, with an altered glutamate/GABA ratio. Treatment should consist of fixing the functional B2 deficiency. There is a "realm" of thought that the child should avoid glutamate. Glutamate, though, is a non-essential amino acid, so the body will make it using the aminotransferase of aspartate + a-Ketoglutatate ,<=> oxaloacetate + glutamate, or Alanine + a-Keotglutarate <=> pyruvate + Glutamate. This basic bit of biochemistry seems to have been missed by those who attempt to control behavioural issues in children with autism, rather than fixing the Iodine/Selenium deficiency, that causes the functional B2 deficiency (See Pathway).(Sears et al, 2021; Yang and Chang, 2014; Roja 2014). This increases the number of "mistreatments" performed on children with autism, but those who do not understand basic biochemistry. Interestingly, there are a higher number of mutations in GAD - glutamate decarboxylase, in children with autism (data not publshed).

The lack of P5P also reduces the conversion of homocysteine (Hcy) to Cysteine, and leads to reduced intracellular glutathione. There is an increase in urinary pyroglutamate (Seen in OAT) (Russell-Jones 2022C).

Methylation is further reduced due to the lack of activity of the PLP dependent enzyme SHMT, and lower formation of 5,10-MTHF, and then 5-MTHF

Activity of MTHFR is further reduced as both FMN, and FAD are reduced, leading to lower conversion of 5,10-MTHF to 5-MTHFm thus leading to further reduction in methylation.

Functional B12 deficiency due to I/Se/Mo deficiency, hence is very different to an absolute deficiency of vitamin B12, and hence there are additional complications due to the functional FMN deficiency, causing functional B6 deficiency, which then increases the functional B12 deficiency, but also is associated with many additional symptoms. Careful analysis of the symptoms may be indicative of the type of deficiency.

Publications

Della Vecchia A, Arone A, Piccinni A, Mucci F, Marazziti D. GABA System in Depression: Impact on Pathophysiology and Psychopharmacology. Curr Med Chem. 2022;29(36):5710-5730. doi: 10.2174/0929867328666211115124149. PMID: 34781862.

Chao HT, Chen H, Samaco RC, Xue M, Chahrour M, Yoo J, Neul JL, Gong S, Lu HC, Heintz N, Ekker M, Rubenstein JL, Noebels JL, Rosenmund C, Zoghbi HY. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature. 2010 Nov 11;468(7321):263-9. doi: 10.1038/nature09582. PMID: 21068835; PMCID: PMC3057962.

DeLorey TM, Olsen RW. GABA and epileptogenesis: comparing gabrb3 gene-deficient mice with Angelman syndrome in man. Epilepsy Res. 1999 Sep;36(2-3):123-32. doi: 10.1016/s0920-1211(99)00046-7. PMID: 10515160.

Chiu CS, Brickley S, Jensen K, Southwell A, Mckinney S, Cull-Candy S, Mody I, Lester HA. GABA transporter deficiency causes tremor, ataxia, nervousness, and increased GABA-induced tonic conductance in cerebellum. J Neurosci. 2005 Mar 23;25(12):3234-45. doi: 10.1523/JNEUROSCI.3364-04.2005. PMID: 15788781; PMCID: PMC6725086.

Richdale etal, 2023 Pathways to anxiety and depression in autistic adolescents and adults. Depression and Anxiety Volume 2023 | Article ID 5575932 | https://doi.org/10.1155/2023/5575932 https://www.hindawi.com/journals/da/2023/5575932/

Russell-Jones GJ, 2022A Vitamin B12 deficiency and depression. What is the mechanism? vitamin-b12-deficiency-and-depression-what-is-the-mechanism.pdf (aseanjournalofpsychiatry.org)

Russell-Jones GJ 2022B Functional B2 deficiency in autism REF

Russell-Jones GJ 2022C Functional vitamin B12 deficiency in autism REF2