ERRORS OF B GROUP VITAMIN METABOLISM:
Summarising the information around what is known about genetic errors for the way B12 and other B group vitamins are utilised in the body is probably a task for a geneticist, molecular biologist or biochemist, or all three. However, there are many good websites which deal with this information. This page is to introduce the topic to people with multiple sclerosis, who may wish to investigate further.
In 1990 the human genome project began, and the mapping was completed in 2003. Our understanding of how human genes function, is still therefore in its infancy, but hopefully we are entering a period of discovery which will lead to personalised medicine aimed at correcting genetic errors that cause ill health.
Various studies have isolated genes which are thought to be ‘associated’ with MS. There seems to be over a hundred. The word ‘associated’ is used, since there is no causal link to any ‘MS genes’ yet. Pick up any textbook on MS, and there will usually be a statement to the effect that whilst it is thought that persons with MS must have a genetic susceptibility to the disease, one or more environmental factors are thought to play a greater part. The genes they have isolated so far seem to work to increase people’s susceptibility to developing MS, but just because someone has some of these genes does not mean they will get MS. The understanding of the complexities of genetic susceptibility to MS is also in its infancy. Even in identical twins, if one twin falls ill with MS, the risk to the other twin is only about 30%.
This page is not about the so called MS genes. It is about some of the now well-known genes which can negatively impact on neurological function, because of errors in the way the body handles B group vitamins, and mainly the gene known as MTHFR. This is because B group vitamin deficiencies (especially B12 can look exactly like MS), and some of these genes are common in the population.
In a nutshell:
More detail:
For information on how B12 Deficiency can affect the nervous system and be related to errors of B12 metabolism, please see the page ‘Vitamin B12 deficiency’.
The main gene thought to control a B group vitamin metabolic pathway with implications for MS is called MTHFR, but there are others that relate to this process
MTHFR is short for methylenetetrahydrofolate reductase. Found on chromosome 1, it is responsible for making the enzyme methylenetetrahydrofolate reductase (MTHFR), so the gene is named after the enzyme it makes. The purpose of the enzyme is to take dietary folate and turn it into the active form that can be used by the body (methylfolate).
Methylation is a bodily chemical process where a carbon and three hydrogens atoms (a methyl group) is attached to an enzyme so that the enzyme can perform its task. If the gene is a variant (once a mutation and now common in the population) the gene will not make the enzyme as it should be made. There is said to be a disruption in the methylation pathway.
This is a problem, because the MTHFR enzyme is a key enzyme for metabolising homocysteine. It does this by converting homocysteine into methionine which is an amino acid the body needs for growth and metabolism, and also to produce glutathione, the body’s master antioxidant. So people with this genetic variation may not be able to detoxify heavy metals, toxins, and other wastes as efficiently. Methionine is converted in the liver to SAM-e which is needed for its anti-inflammatory properties, immune support, and the proper growth and maintenance of our cells and the proper functioning of our neurotransmitters.
If you have variants in this gene, you may find high levels of homocysteine in the blood, which has been recognised as a risk for heart disease, high blood pressure, clotting, stroke, micro strokes, complications in type 1 and 2 diabetes, osteoporosis, irritable bowel syndrome, obesity, foetal neural tube defects, multiple miscarriage, stillbirths, cognitive fog, dementia, Alzheimer’s, anxiety, depression, autistic spectrum disorders, epilepsy and more.
An under functioning thyroid gland (hypothyroidism) may also compound the effects of MTHFR defect, because the thyroid produces hormones needed by the MTHFR gene. Vitamin B12 deficiency will be accelerated in the body if there is untreated hypothyroidism or low Vitamin B2. In these cases, the function of people with MTHFR and MTRR variations are both compromised. The MTRR protein is responsible for regenerating inactivated B12 and so when it doesn't work, or there are low levels of B2, then B12 consumption goes up dramatically.
Caution! If your homocysteine is high, your doctor may prescribe ‘folate’. Many authorities suggest that 'folate' is contraindicated for people with MTHFR genetic variations, who may need the active form of folate, or an active form of B12, or both, or indeed, input from an expert who understands the complex interplay of biochemical reactions that are involved, and is able to monitor your supplements and your response to them.
Most commonly, MTHFR gene mutations are found at position 677 and/or position 1298 on the MTHFR gene. One copy comes from the mother and one copy comes from the father. So if you have your blood tested and no variations are found (that is, your MTHFR 677CC and MTHFR 1298AA are normally functioning MTHFR genes) then the report will come back as something like ‘not detected’.
If you get one copy from one parent, it is called a heterozygous variation. If you get a copy from each parent, it is called a homozygous variation. So here are the possible combinations:
•Normal/Normal for both 677 and 1298
•Heterozygous 1298 / Normal 677 (a 1298 mutation from one parent)
•Homozygous 1298 / Normal 677 (a 1298 mutation from both parents)
•Heterozygous 677 / Normal 1298 (a 677 mutation from one parent)
•Homozygous 677 / Normal 1298 (a 677 mutation from both parents)
•Heterozygous 677 / Homozygous 1298 (a 677 mutation from one parent; a 1298 mutation from both parents)
•Homozygous 677 / Heterozygous 1298 (a 677 mutation from both parents; a 1298 from one parent)
•Heterozygous 677 / Heterozygous 1298 (Compound Heterozygous: a 677 mutation from one parent, a 1298 mutation from another parent)
•Homozygous 677 / Homozygous 1298 (Compound Homozygous, a 677 mutation from both parents, and a 1298 mutation from both patients)
As noted earlier, these variations can cause a disruption in the methylation pathways, the way in which a methyl group is attached to an enzyme so that the enzyme can perform its task. Estimates vary, but the combinations of these MTHFR variants are thought to produce the following levels of impairment in the methylation pathway;
MTHFR A1298C Heterozygous: 20% impairment
MTHFR C677T Heterozygous: 40% impairment
MTHFR C677T & MTHFR A1298C heterozygous (compound heterozygous): 50% impairment
MTHFR A1298C Homozygous: 50-70% impairment
MTHFR C677T Homozygous: 70% impairment
Whilst the MTHFR gene is crucial to this methylation pathway there are many other genes involved, so it is not a simple matter of supplementing with methylfolate. This compound has side effects and it may be that a person can over methylate. It may well be that an active form of B12 is called for, and ultimately it may be wise to see a professional who understands the multitude of genes involved and the complex biochemical interactions, particularly where a severe neurological condition is involved.
A test for your MTHFR status is a straightforward blood test but this won’t show any other genes that may be involved in the same metabolic pathway
In Australia the two main MTHFR mutations can be analysed via a simple blood test ordered by your doctor and organised through a local pathology lab. However, the results may only refer to a risk for clotting, pregnancy loss and neural tube defects. The other relationships are unlikely to be mentioned, nor the interrelationship with B12 deficiency, and folate may be recommended to reduce high homocysteine. Your doctor may not be aware of the neuropsychiatric implications of this gene defect, or the need to check other genes related to this impaired methylation cycle, in order to assess what compound effects are being experienced by the patient.
You can have your DNA analysed to detect your MTHFR genetic variations, including a wider panel of SNPs related to the metabolism of B group vitamins. This is relatively inexpensive and you can then refer your data to a specialist for analysis and advice.
Companies like 23andme (which is based in America) will send you a kit and analyse your DNA for a fee which at the time of writing is $99 US. At the time of writing the only analysis they do is to provide you with ancestry data and a raw data file. Health reports have been suspended by the FDA, but may be reinstated in the future. https://www.23andme.com/?
If you have one or more variations that affect your metabolism of B group vitamins, expert advice can help you to correct any imbalances
Once you have your raw data file, various organisations can assist you in running reports, and you can have your data analysed by an appropriate professional. MTHFR Support Australia is one organisation dedicated to unravelling the complexities of the gene interactions and their biochemical effects surrounding MTHFR variations (LINK). http://www.mthfrsupport.com.au/
The effect of an MTHFR variation and associated defects on MS - like symptoms:
Even low to moderate levels of homocysteine is thought to be neuroexcitatory, promoting nerve cell destruction, and it is also thought that having the genetic defect interferes with the body’s capacity to properly form the myelin sheath and nerves. Impaired production of the master antioxidant glutathione is also thought to contribute to oxidative stress and impaired excretion of toxins in the central nervous system, causing harm.
This link notes the association with the C677T mutation and multiple sclerosis http://www.ncbi.nlm.nih.gov/pubmed/21190091
The following link notes the association of MTHFR mutations and neurological, MS – like symptoms and MRI findings
http://www.jrheum.com/subscribers/07/02/341.html
MTHFR mutations are now common. Estimates vary, but it is thought that up to 60% of the population could be at risk of the effects of these variations.
Given the potentially catastrophic consequences of poor metabolism of B group vitamins on neurological function (not to mention other disease risks), and given that there is yet no known cause for MS, people with MS may consider investigating their MTHFR gene status, together with associated genes involved in the methylation pathway, with a view to optimising their health in as many dimensions as possible.
Links:
Folate Metabolism and MTHFR
http://www.seekinghealth.com/media/MTHFR-Introduction-Basic.pdf
Active Folate - 5-methyltetrahydrofolate (5-MTHF)
http://www.anaturalhealingcenter.com/documents/Thorne/monos/5mthf_mono_11.4.pdf
INTRACELLULAR INFECTIONS:
Summarising the information around what is known about genetic errors for the way B12 and other B group vitamins are utilised in the body is probably a task for a geneticist, molecular biologist or biochemist, or all three. However, there are many good websites which deal with this information. This page is to introduce the topic to people with multiple sclerosis, who may wish to investigate further.
In 1990 the human genome project began, and the mapping was completed in 2003. Our understanding of how human genes function, is still therefore in its infancy, but hopefully we are entering a period of discovery which will lead to personalised medicine aimed at correcting genetic errors that cause ill health.
Various studies have isolated genes which are thought to be ‘associated’ with MS. There seems to be over a hundred. The word ‘associated’ is used, since there is no causal link to any ‘MS genes’ yet. Pick up any textbook on MS, and there will usually be a statement to the effect that whilst it is thought that persons with MS must have a genetic susceptibility to the disease, one or more environmental factors are thought to play a greater part. The genes they have isolated so far seem to work to increase people’s susceptibility to developing MS, but just because someone has some of these genes does not mean they will get MS. The understanding of the complexities of genetic susceptibility to MS is also in its infancy. Even in identical twins, if one twin falls ill with MS, the risk to the other twin is only about 30%.
This page is not about the so called MS genes. It is about some of the now well-known genes which can negatively impact on neurological function, because of errors in the way the body handles B group vitamins, and mainly the gene known as MTHFR. This is because B group vitamin deficiencies (especially B12 can look exactly like MS), and some of these genes are common in the population.
In a nutshell:
- Amongst other things, B group vitamins are responsible for a properly functioning nervous system
- Deficiencies in some B group vitamins can cause catastrophic neurological damage, such as B12 deficiency and B1 (thiamine) deficiency (Beri Beri)
- Even when diets are replete with B group vitamins, and the digestive system is working correctly, the body may not be able to process the vitamins properly, leading to a practical deficiency
- This can be caused by the genes that are involved in the complex biochemistry of B group vitamin metabolism
- Variations from the usual expression of a gene can cause that gene to malfunction
- These gene variations are called Single Nucleotide Polymorphisms, or SNPs (pronounced “snips”), and they occur normally throughout a person’s DNA. It is thought that there are about 10 million SNPs in the human genome and most have no effect on health or development. However, scientists are finding some SNPs that may help predict a health risk
- The main gene thought to control a B group vitamin metabolic pathway with implications for MS is called MTHFR, but there are others that relate to this process
- A test for your MTHFR status is a straightforward blood test but this won’t show any other genes that may be involved in the same metabolic pathway
- You can have your DNA analysed to detect your MTHFR genetic variations, including a wider panel of SNPs related to the metabolism of B group vitamins. This is relatively inexpensive and you can then refer your data to a specialist for analysis and advice.
- If you have one or more variations that affect your metabolism of B group vitamins, expert advice can help you to correct any imbalances
More detail:
For information on how B12 Deficiency can affect the nervous system and be related to errors of B12 metabolism, please see the page ‘Vitamin B12 deficiency’.
The main gene thought to control a B group vitamin metabolic pathway with implications for MS is called MTHFR, but there are others that relate to this process
MTHFR is short for methylenetetrahydrofolate reductase. Found on chromosome 1, it is responsible for making the enzyme methylenetetrahydrofolate reductase (MTHFR), so the gene is named after the enzyme it makes. The purpose of the enzyme is to take dietary folate and turn it into the active form that can be used by the body (methylfolate).
Methylation is a bodily chemical process where a carbon and three hydrogens atoms (a methyl group) is attached to an enzyme so that the enzyme can perform its task. If the gene is a variant (once a mutation and now common in the population) the gene will not make the enzyme as it should be made. There is said to be a disruption in the methylation pathway.
This is a problem, because the MTHFR enzyme is a key enzyme for metabolising homocysteine. It does this by converting homocysteine into methionine which is an amino acid the body needs for growth and metabolism, and also to produce glutathione, the body’s master antioxidant. So people with this genetic variation may not be able to detoxify heavy metals, toxins, and other wastes as efficiently. Methionine is converted in the liver to SAM-e which is needed for its anti-inflammatory properties, immune support, and the proper growth and maintenance of our cells and the proper functioning of our neurotransmitters.
If you have variants in this gene, you may find high levels of homocysteine in the blood, which has been recognised as a risk for heart disease, high blood pressure, clotting, stroke, micro strokes, complications in type 1 and 2 diabetes, osteoporosis, irritable bowel syndrome, obesity, foetal neural tube defects, multiple miscarriage, stillbirths, cognitive fog, dementia, Alzheimer’s, anxiety, depression, autistic spectrum disorders, epilepsy and more.
An under functioning thyroid gland (hypothyroidism) may also compound the effects of MTHFR defect, because the thyroid produces hormones needed by the MTHFR gene. Vitamin B12 deficiency will be accelerated in the body if there is untreated hypothyroidism or low Vitamin B2. In these cases, the function of people with MTHFR and MTRR variations are both compromised. The MTRR protein is responsible for regenerating inactivated B12 and so when it doesn't work, or there are low levels of B2, then B12 consumption goes up dramatically.
Caution! If your homocysteine is high, your doctor may prescribe ‘folate’. Many authorities suggest that 'folate' is contraindicated for people with MTHFR genetic variations, who may need the active form of folate, or an active form of B12, or both, or indeed, input from an expert who understands the complex interplay of biochemical reactions that are involved, and is able to monitor your supplements and your response to them.
Most commonly, MTHFR gene mutations are found at position 677 and/or position 1298 on the MTHFR gene. One copy comes from the mother and one copy comes from the father. So if you have your blood tested and no variations are found (that is, your MTHFR 677CC and MTHFR 1298AA are normally functioning MTHFR genes) then the report will come back as something like ‘not detected’.
If you get one copy from one parent, it is called a heterozygous variation. If you get a copy from each parent, it is called a homozygous variation. So here are the possible combinations:
•Normal/Normal for both 677 and 1298
•Heterozygous 1298 / Normal 677 (a 1298 mutation from one parent)
•Homozygous 1298 / Normal 677 (a 1298 mutation from both parents)
•Heterozygous 677 / Normal 1298 (a 677 mutation from one parent)
•Homozygous 677 / Normal 1298 (a 677 mutation from both parents)
•Heterozygous 677 / Homozygous 1298 (a 677 mutation from one parent; a 1298 mutation from both parents)
•Homozygous 677 / Heterozygous 1298 (a 677 mutation from both parents; a 1298 from one parent)
•Heterozygous 677 / Heterozygous 1298 (Compound Heterozygous: a 677 mutation from one parent, a 1298 mutation from another parent)
•Homozygous 677 / Homozygous 1298 (Compound Homozygous, a 677 mutation from both parents, and a 1298 mutation from both patients)
As noted earlier, these variations can cause a disruption in the methylation pathways, the way in which a methyl group is attached to an enzyme so that the enzyme can perform its task. Estimates vary, but the combinations of these MTHFR variants are thought to produce the following levels of impairment in the methylation pathway;
MTHFR A1298C Heterozygous: 20% impairment
MTHFR C677T Heterozygous: 40% impairment
MTHFR C677T & MTHFR A1298C heterozygous (compound heterozygous): 50% impairment
MTHFR A1298C Homozygous: 50-70% impairment
MTHFR C677T Homozygous: 70% impairment
Whilst the MTHFR gene is crucial to this methylation pathway there are many other genes involved, so it is not a simple matter of supplementing with methylfolate. This compound has side effects and it may be that a person can over methylate. It may well be that an active form of B12 is called for, and ultimately it may be wise to see a professional who understands the multitude of genes involved and the complex biochemical interactions, particularly where a severe neurological condition is involved.
A test for your MTHFR status is a straightforward blood test but this won’t show any other genes that may be involved in the same metabolic pathway
In Australia the two main MTHFR mutations can be analysed via a simple blood test ordered by your doctor and organised through a local pathology lab. However, the results may only refer to a risk for clotting, pregnancy loss and neural tube defects. The other relationships are unlikely to be mentioned, nor the interrelationship with B12 deficiency, and folate may be recommended to reduce high homocysteine. Your doctor may not be aware of the neuropsychiatric implications of this gene defect, or the need to check other genes related to this impaired methylation cycle, in order to assess what compound effects are being experienced by the patient.
You can have your DNA analysed to detect your MTHFR genetic variations, including a wider panel of SNPs related to the metabolism of B group vitamins. This is relatively inexpensive and you can then refer your data to a specialist for analysis and advice.
Companies like 23andme (which is based in America) will send you a kit and analyse your DNA for a fee which at the time of writing is $99 US. At the time of writing the only analysis they do is to provide you with ancestry data and a raw data file. Health reports have been suspended by the FDA, but may be reinstated in the future. https://www.23andme.com/?
If you have one or more variations that affect your metabolism of B group vitamins, expert advice can help you to correct any imbalances
Once you have your raw data file, various organisations can assist you in running reports, and you can have your data analysed by an appropriate professional. MTHFR Support Australia is one organisation dedicated to unravelling the complexities of the gene interactions and their biochemical effects surrounding MTHFR variations (LINK). http://www.mthfrsupport.com.au/
The effect of an MTHFR variation and associated defects on MS - like symptoms:
Even low to moderate levels of homocysteine is thought to be neuroexcitatory, promoting nerve cell destruction, and it is also thought that having the genetic defect interferes with the body’s capacity to properly form the myelin sheath and nerves. Impaired production of the master antioxidant glutathione is also thought to contribute to oxidative stress and impaired excretion of toxins in the central nervous system, causing harm.
This link notes the association with the C677T mutation and multiple sclerosis http://www.ncbi.nlm.nih.gov/pubmed/21190091
The following link notes the association of MTHFR mutations and neurological, MS – like symptoms and MRI findings
http://www.jrheum.com/subscribers/07/02/341.html
MTHFR mutations are now common. Estimates vary, but it is thought that up to 60% of the population could be at risk of the effects of these variations.
Given the potentially catastrophic consequences of poor metabolism of B group vitamins on neurological function (not to mention other disease risks), and given that there is yet no known cause for MS, people with MS may consider investigating their MTHFR gene status, together with associated genes involved in the methylation pathway, with a view to optimising their health in as many dimensions as possible.
Links:
Folate Metabolism and MTHFR
http://www.seekinghealth.com/media/MTHFR-Introduction-Basic.pdf
Active Folate - 5-methyltetrahydrofolate (5-MTHF)
http://www.anaturalhealingcenter.com/documents/Thorne/monos/5mthf_mono_11.4.pdf
INTRACELLULAR INFECTIONS: