Vitamin B12 Deficiency: What are the consequences?

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Methylation, vitamin B12, the Folate Cycle, Vitamin D and Autism Spectrum Disorders, What is the Link?

Autism spectrum disorder (ASD) is a lifelong development disability characterised by difficulties in social interaction, communication, restricted and repetitive interests and behaviours, and sensory sensitivities.

Each person with ASD exhibits slightly different symptoms, which manifest in an intense and focused interest in a particular subject matter; stereotyped body movements like hand flapping and spinning; and an unusual and heightened sensitivity to everyday sounds or textures.

People with ASD often exhibit developmental delay and may show  difficulties with social interaction and impaired and unusual verbal and non-verbal communication.

Until recently there was no known cause of ASD, however, several recent observations have suggested that there may be a link between environment, genetics and the development of ASD.  A strong correlation has also been found between deficiency in vitamin D, biotin, vitamin B2 deficiency, vitamin B12 deficiency and mutations in genes associated with methylation (see VB12 and MTHFR). Deficiency in vitamin D, biotin, vitamin B2 or vitamin B12 is associated with a loss of mitochondrial function, a common finding in individuals with ASD.

Vitamin D and the Nervous System

Originally it was thought that the major function of vitamin D was in the regulation of calcium homeostasis and bone metabolism. In the past few years it has become apparent that vitamin D has an essential role in the regulation of nervous system development and function. Clinical studies have shown that vitamin D deficiency is associated with an increased incidence of diseases of the central nervous system. Recently is has been shown that the incidence of multiple sclerosis is higher in individuals using high SPF sun-blocks. Similarly, an increasing body of literature has shown that the risk of autism decreases as the level of serum 25-hydroxyvitamin D increases in utero or in early life (Cannell and Grant, 2013). A recent study in the US has shown that higher UVB exposure is correlated with a lower incidence of autism (Grant and Cannell, 2013). Several studies have also established that children with autism have lower serum vitamin D levels than pair matched normal children (Duan et al, 2013; Kočovská et al, 2014; Mostafa, 2012) As a corollary, the increase in autism has parralled the increased use of sunblock, since its development in the early 1960s. Energy output from mitochondria (the small power-houses driving energy metabolism in neruons (and all cells) has been shown to be directly linked to vitamin D concentration.

Vitamin B12, folate and the Nervous System

Vitamin B12 (both adenosyl and methylcobalamin) and folate are intimately associated with the functioning of the nervous system. Folate, through the folate cycle, provides important functional derivatives for the synthesis of Thymine (via 5,10-methylene-tetrahydrofolate), Adenosine and Guanosine (via 10-formyl-tetrahydrofolate), which are essential precursors for DNA bases. In addition, Guanosine is a precursor for the synthesis of tetrahydrobiopterin (BH4), an essential co-factor used in the production important neurotransmitters such as Dopamine, nitric oxide, 5-hyrdoxy-tryptophan, serotonin, nor-adenalin and adrenalin. Levels of BH4 have been found to be low in many children with ASD and supplementation studies using BH4 have shown an improvement in symptoms associated with ASD (Frye etal, 2010; Klaiman etal, 2013). In addition, 10-formyl-THF is required for the generation of N-Formyl-Met-tRNA, which is required for the synthesis of proteins.

Vitamin B2 deficiency and energy production in mitochondria

Examination of energy consumption in the citric acid cycle has shown reduced enzymatic activity of two main FAD-dependent enzymes in the cycle, succinate dehydrogenase and alphaketoglutarate dehydrogenase.

Methylation and the Nervous System

Both folate and vitamin B12 (as methylB12) have important roles in the production of S-adenosylmethionine (SAM), an essential methyl-donor that is used in over 100 methylation reactions in the body. Methylation is essential for the development and functioning of the nervous system. Myelin Basic protein (MBP) is one of the major structures that integrates with the myelin sheath. In order for this to occur, MBP is methylated using SAM. Non-methylated MBP has been shown not to associate strongly with the myelin sheath and to have an open structure that is prone to reaction with NOS, with the subsequent production of citrulline. The relative level of citrulline to methionine is higher in ASD. Methylation is also required in the synthesis of Phosphylcholine, an important component of brain membranes, from phosphatidylethanolamine, in the synthesis of choline, a precursor for the production of acetylcholine, carnitine (essential for fatty acid transport into mitochondria) and for creatine (an essential component of creatine-phosphate). Lower intake of folate in pregnant mothers has shown a higher risk for ASD (Schmidt etal, 2011,2012). Myelination of nerves is a very important post-natal development in the nerves. Recently MRI studies have shown reduced myelination in the brains of ASD children. Vitamin B12, folate, biotin and vitamin D deficiency are all associated with the production of faulty myelin, and poor myelination.

Many ASD children show signs of folate and vitamin B12 deficiency as measured by raised levels of homocysteine in the serum (Kummer 2011; Kałużna-Czaplińska etal 2011; Al-Farsi etal, 2013; Frustaci etal, 2013; Ali etal, 2013), and by reduced levels of vitamin B12 and folate. In addition they show reduced levels of intracellular methionine and S-adenosylmethionine (SAM).Vitamin B12 deficiency in in children is correlated with delayed development of speech, social behaviour, and the development of fine and gross motor movement.

Genetics and Autism

Genetic analysis of SNPs in children with ASD have shown a higher incidence of SNPs in folate processing enzymes, such as FOLR2, MTHFR, SMT, MTHFD, and MTHFS, in B12 processing enzymes (MTR and MTRR), betaine processing (BHMT) and in neuropeptide processing enzymes (GAD, COMT, MAO, TH, TPH2) and  phosphatidylethanolamine (PEMT) and nitric oxide synthase (NOS). Interestingly, many of these enzymes use FAD as a co-factor (MTHFR, MTRR, MAO, NOS, PEMT, TS). Altered GABA metabolism has been associated with several neurological disorders, including ASD (Deidda etal, 2014; Frye 2014; Fatemi etal, 2014). The presence of the MTHFR 1666A>T is correlated with a higher risk of autism (Liu etal, 2011;

Treatment of Autism with folate and Vitamin B12 

Recent studies on the treatment of autism have combined the identification of methylation mutations in autistic children with treatment using a combination of folate derivatives (5-MTHF) and methyl B12  and betaine (James etal, 2008; Bertoglio etal, 2010).  Experiments with high dose vitamin D supplementation have shown significant improvement in many children with ASD (Cannell 2014). More recently, the identification of deficiency in both adenosyl B12 and methyl B12 has lead to a change in treatment to include both forms of the vitamin. In addition, the recent identification of functional vitamin B2 deficiency has resulted in the inclusion of this vitamin in treatment.