Martyn Hooper

Pernicious Anaemia Society

Nitrous Oxide – let’s have a laugh!

by on Aug.22, 2015, under Other, Pernicious Anaemia Society, Personal

My next book addresses the problem of a growing cause of Vitamin B12 Deficiency – the use of Nitrous Oxide (N2O) as a recreational drug.  Baloon N2O

Nitrous Oxide, or ‘laughing gas’ is now the second most common recreational drug after cannabis in the UK.  Users can easily buy balloons of the gas at festivals or in nightclubs where they are readily and legally available or they can make their own using ‘whippits’ – small compressed gas cannisters that are used to whip cream.  Readily available from cook shops these small gas containers are attached to larger cannisters containing unwhipped cream and then discharged – the gas passes through the cream and on the depression of a lever out pops some freshly whipped cream.  Users leave out the cream and attach a balloon over the aperture where the whipped cream would have appeared – the balloon fills with N2O and the user can then inhale it.  It is laughing gas and so it causes uncontrollable laughter – it also deactivates any B12 the user has in his or her body.

This is a serious problem as it is both legal and growing in popularity.  It’s not new as Victorians used to hold WippitLaughing Gas Parties (well they had to make their own entertainment didn’t they) and it is readily available and very cheap.  Before this year’s Glastonbury festival an appeal was made to stop revellers using the sacred space of the King’s Meadow as the preferred gathering point for N2O users – the previous year over 2 tonnes of the small cannisters were recovered by hand.  If each used cannister weighs say 100gms that means there were over 20,000 cannisters recovered from one field alone, in just one festival – in a long summer of festivals.

And just one more time – N2O deactivates the bodies stores of Vitamin B12……

And just one other thing to take into consideration – N2O is a greenhouse gas which is 298 times more polluting than carbon dioxide

You’re having a laugh surely!

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Five Cases of Mistreatment in One Hour

by on Aug.20, 2015, under Pernicious Anaemia Society

Yesterday morning started normally enough.  The lady who looks after the e-bay site had left me a note asking me to take a look at some comments from a lady who had purchased some of our wristbands.  The member had written that she was in a terrible mess and had been told that because her B12 levels were high she could only have an injection once a year.  She was diagnosed twenty years ago and had been managing, but only just, on the three monthly injections but four years ago she was told she can only have an injection every year.  I replied and asked her to call the office.

When I reached the office she had already left a message and I telephone her.  As in all these cases I told her to go and talk to her doctor and mention that she had spoken to us and that we were extremely concerned and would become actively involved unless things were changed.  I have to refer patients back to their doctor as a matter of course – before we get actively involved we have to give the patient’s physician to correct any shortcomings in treatment.  I suspect that we will end up writing to the practice manager and the Medical Director of the Regional Health Board but first we must give the physician to order the correct treatment.

Ten minutes later I had another call from a middle-aged man who had all the symptoms but whose serum B12 was one point over the threshold.  Following a previous telephone call with me he had convinced his doctor to allow him a therapeutic trial of weekly injections for four weeks.  He reported an immense improvement in both his physical and mental state.  But now – you guessed it – those injections have been stopped and he is experiencing a return of his symptoms two months after his last injection.

Ten minutes later it was a similar story.  This time a 21 year old lady with all of the symptoms including numbness in her toes and ankles.  Again she was given a therapeutic trial of four weekly injections as her serum B12 was exactly on the threshold used to determine any deficiency.  She experienced a marked improvement but now they have been stopped again and she is going back to how she was.

I could also tell you about the university student who cannot manage the three months between injections and is really struggling (last week I had a 22 yr old medical student in the same position though in her case her two uncles with PA were injecting themselves monthly – they were both doctors) or the lady in her mid thirties with all of the symptoms who took along our summary of the new guidelines to show her doctor that she should be ignoring the test and treating her – she too had numbness in her feet; unfortunately the doctor told her that we, as a society, were ‘scaremongering’ and that we were ‘non-medical’.

All of these conversations took place within one hour.

I had no alternative but to refer them to doctors in the private sector or to alternative supplementation methods – and I shouldn’t have to; there is a serious shortfall in how the NHS is diagnosing and treating patients that we will continue to campaign to get this rectified.

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by on Aug.20, 2015, under Pernicious Anaemia Society

Some people have read my previous post and have unfortunately misinterpreted what I have said.  Here is my post regarding new treatments of Pernicious Anaemia in point form:

1. The UK’s Medicines, Pharmacy and Industry Group (MPIG) is going to start persuading pharmaceutical companies to look at new ways to treat Pernicious Anaemia.

2.  These ‘new formulations’ may well include a high dosage (1-2mg) oral tablet which would be the strength required to potentially treat Pernicious Anaemia (I know that some of our members take high dosage tablets rather than have injections). Around 300 of our members in the UK opt for this particular treatment even though the new Guidelines from the BCSH state that injections are the best way of treating the condition. 

3.  If patients want to treat themselves using tablets they have to buy their own as high dose B12 tablets are not available on the NHS – but I suspect this will change soon.

4. There are other delivery methods that have been developed but have not been evaluated.  Before the introduction of these new methods I am asking for a full evaluation of their efficacy be carried out.

5.  The problem lies in evaluating the effectiveness of the treatment.  We know that some patients need much more frequent injections than others in order to feel benefit – and the PAS is working with a team of researchers to investigate why this is so as most doctors will immediately jump on the ‘it’s a placebo’ explanation even though there is no evidence of this. We know that using different forms of B12 delivery methods increases serum B12 – that is evidenced and yes, that includes tablets of B12 even for those with Pernicious Anaemia.  But that does not in itself mean that the patient will immediately feel better.  Simply raising B12 serum levels doesn’t always mean the patient feels better – some patients need enormous amounts of B12 to feel any benefit and that is why evaluating the effectiveness of the treatments needs to take into consideration how the patient feels rather than simply measuring their serum B12.

6.  The Pernicious Anaemia Society has, and has always had, one of its objectives that states we want patients with Pernicious Anaemia to have a choice of treatments made available to them (there isn’t any in choice in the UK at this time) and for the patient to be able to access this treatment according to their individual needs. There’s no reason why patients cannot be taught to self administer small, daily or thrice daily sub-cut injections but again this hasn’t been looked at.

7.  I anticipated the reaction to my blog – as I wrote in my blog

There will be those, I’m sure, who will now take what I have read as evidence that I support the withdrawal of injections as a form of treatment.  That is not what I am saying; rather I am just pointing out that the treatment used for Pernicious Anaemia today is the same as it was 70 years ago and there must be a more effective delivery method of B12 – and there are, but they haven’t been evaluated. 

And one of these alternative delivery methods will be self-injecting.

8.  The British Committee for Standards in Haematology recognises that currently injections are the most sure-way of treating pernicious anaemia and that the use of tablets (even though some of the members of the PAS use them) needs to be evaluated before being introduced:

‘However the efficacy and cost–effectiveness of oral treatment in wider population-based settings has yet to be established. There are arguments against the use of oral cobalamin in initiation of cobalamin therapy in severely deficient individuals who have poor absorption, especially due to pernicious anaemia’.

and then again:

‘On the other hand, some patients may prefer intramuscular injection therapy in order to assure effective treatment


To sum up then – the Dept of Health in the UK is actively seeking pharmaceutical companies to develop new treatment methods.  That can’t be stopped.  The way in which Pernicious Anaemia is treated is 70 years old and is, unfortunately expensive – not in the cost of the injection but in nurse time (estimated at a quite convenient £10 per injection).  The treatment is invasive, not without risk and often not centred on the individual needs of the patient.  New delivery methods such as sub-lingual sprays, nasal drops, infusions etc need to be thoroughly evaluated – and that means that any evaluation must take into consideration how the patient feels on that particular treatment – not just on rectifying any serum B12 deficiency.

Things are moving on and we cannot stop these developments.  What I’m saying is that we, as a society need to be vigilant and have a say in what is going on.  By far the biggest concern of our members relates to them getting an individual based treatment regime.  This causes all manner of problems five of which manifested themselves within one hour yesterday (see new post).  New delivery methods hold out the promise for better treatment based around the needs of the individual patient.  Either we get actively involved in this or we keep our heads down and do nothing.  I think playing an active role is a much better option.  Don’t you?

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New Treatments

by on Aug.15, 2015, under Pernicious Anaemia Society

Yesterday I replied to the Chairman of the Welsh Assembly’s Petition Committee who had now had two letters from the Minister for Health in Wales.j0182630

The second of these letters mentioned the fact that the UK’s Under Secretary of State for Health, Jane Ellison MP had been contacted and there are a few words of hope in her reply to the Minister.  Tucked away in the letter is the following sentence:

‘The Department of Health Medicines, Pharmacy and Industry Group (MPIG) is looking at the possibility of persuading pharmaceutical companies to introduce new formulations. I have been given no indication of when these discussions will be undertaken and it is likely to take some time’.

These ‘new formulations’ may well include a high dosage (1-2mg) oral tablet which would be the strength required to potentially treat Pernicious Anaemia (I know that some of our members take high dosage tablets rather than have injections) but it probably also means the introduction of less invasive, and potentially suitable products such as nasal sprays, nasal drops, sub-lingual lozenges, sprays and drops and even trans-dermal patches.  Whilst all of these are available and used by some of our members either instead of replacement therapy injections or as a supplementation in between injections.  The problem is that it is up to the manufacturer of the products to get them licensed for use as a treatment for Pernicious Anaemia.  At present they are sold as ‘food supplements’.

Getting the products licensed would need that they would have to meet the strict compliance regulations of the Medical and Healthcare Products Regulatory Agency and it would take a lot of money and a lot of time.  The benefits in financial terms would not be great and so I don’t see a whole host of product manufacturers rushing to the MHRA anytime soon.

This is a pity because the Pernicious Anaemia Society has had as it’s vision a world where patients are given a choice of treatments at diagnosis.  And when you think about it, a twice daily spray or drop of high potency B12 is a far more natural form of treatment as a normal healthy person will be getting regular hits of B12 throughout the day.  Receiving an injection every three months and hoping that that will suffice to treat the Pernicious Anaemia rather than regular doses suddenly feels very old fashioned.

There will be those, I’m sure, who will now take what I have read as evidence that I support the withdrawal of injections as a form of treatment.  That is not what I am saying; rather I am just pointing out that the treatment used for Pernicious Anaemia today is the same as it was 70 years ago and there must be a more effective delivery method of B12 – and there are, but they haven’t been evaluated.  And there lies the rub – how do you evaluate the efficacy of any treatment, including injections?  Current thinking among medical professionals is that the efficacy of the treatment can be evaluated by examining whether the B12 had raised serum B12 levels in the patient and consequently any anaemia has disappeared.  But this is only half of the story – any evaluation of the efficacy of any treatment must take into consideration how the patient feels.  Do different types of delivery methods of B12 yield differing levels of feelgood in patients?  We know that all of the different delivery methods will increase the patient’s B12 – but that only seems to be one aspect that needs to be considered when analysing the effectiveness of the treatment.

For those in the UK who are worried that injections are going to be replaced by oral supplementation you can seek solace in the words of the new Guidelines issued by the British Committee for Standards in Haematology – here’s what they have to say about injections:

‘However the efficacy and cost–effectiveness of oral treatment in wider population-based settings has yet to be established. There are arguments against the use of oral cobalamin in initiation of cobalamin therapy in severely deficient individuals who have poor absorption, especially due to pernicious anaemia’.

The guidelines also point out that whilst there has been some research to suggest that oral supplementation ‘should’ work the guidelines state that some patients prefer injections (including myself) because I know they work so why should we take a chance on a treatment method that ‘should’ work:

‘On the other hand, some patients may prefer intramuscular injection therapy in order to assure effective treatment



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Patient Advocate

by on Aug.05, 2015, under Pernicious Anaemia Society

I’ve attended consultations between members and consultants – usually consultant Haematologists in the past.  I’m doing so again tomorrow.  A lady who lives not very far from here is aged 62.  She was diagnosed as having Pernicious Anaemia when she was forty and, for twenty years, she had a two-monthly injections.  Two and a half years ago her doctor told her that she no longer needed the injections because her B12 “was fine” and when she questioned this with the nurse she was told that “people just use B12 like a drug”.

She has fought a two and a half year battle to get her treatment reinstated.  Tomorrow she has an appointment with a Haematologist at her local hospital and she has asked if I can go with her.  In fact she asked more than that.  She asked if I could take her in my car.  You see, for the past 6 months the numbness in her legs has become worse and for the past 6 weeks she has been unable to walk unaided.


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Response from the Dept of Health to Parliamentary Questions

by on Aug.04, 2015, under Pernicious Anaemia Society

Our thanks go to the Countess of Mar for her support in trying to get the Dept of Health to address the problems faced in getting a timely and accurate diagnosis of Pernicious Anaemia.images

Following previous questions Lady Margaret tabled the following questions in mid July:

1. To ask Her Majesty’s Government upon what scientific evidence they rely to show that there need be no concern for the health of pregnant women or the foetus exposed to fume events on aircraft.
2. To ask Her Majesty’s Government what action they are taking to address the problems associated with the late diagnosis of pernicious anaemia following the publication of the results of a survey published in the British Nursing Journal in April 2014.
3. To ask Her Majesty’s Government how they propose to alert medical practitioners to the severe and irreversible nerve damage that can occur if pernicious anaemia is misdiagnosed as ME/CFS, depression, hypochondria or multiple sclerosis

The first question was nothing to do with PA but the second two were and the first of these mentions the results of our survey.  Here is the reply from the government who, in this instance, is represented by Lord Prior of Brampton who is a minister of health

Lord Prior of Brampton, the Department of Health, has provided the following answer to your written parliamentary question (HL1540):
To ask Her Majesty’s Government how they propose to alert medical practitioners to the severe and irreversible nerve damage that can occur when pernicious anaemia is misdiagnosed. (HL1540)
Tabled on: 16 July 2015
This question was grouped with the following question(s) for answer:
1. To ask Her Majesty’s Government what action they are taking to address the problems associated with the late diagnosis of pernicious anaemia, in the light of the results of the survey published in the British Nursing Journal in April 2014. (HL1539)
Tabled on: 16 July 2015
Lord Prior of Brampton:
It is important that patients suffering from pernicious anaemia, the result of a vitamin B12 (cobalamin) deficiency, receive a prompt and appropriate diagnosis. Pernicious anaemia develops gradually, and can cause a range of symptoms, including fatigue, lethargy, feeling faint and headaches, which vary from patient to patient. Because of the gradual progression of the condition, the variety of symptoms, which are shared with a range of other conditions, diagnosis at early onset can be challenging.
To support the diagnosis of pernicious anaemia, the British Committee for Standards in Haematology (BCSH) has published Guidelines for the diagnosis and treatment of Cobalamin and Folate disorders, which sets out that cobalamin status is the recommended first line diagnostic test. However, the guidance states that there is no gold standard test for the condition and makes it clear that the clinical picture of a patient is the most important factor in assessing the significance of the test results. This means clinicians should take into account all of the symptoms the patent is experiencing, their medical history, age and other relevant factors when considering the implications of a patient’s cobalamin status. The BCSH guidance highlights the risk of neurological impairment if treatment is delayed.

The BCSH operates independently of Department and NHS England and produces evidence based guidelines for both clinical and laboratory haematologists on the diagnosis and treatment of haematological disease, drawing on the advice of expert consultants and clinical scientists practicing in the United Kingdom. It would be for the BCSH, not the Department, to consider whether any adjustments to current best practice in the diagnosis and treatment of patients with pernicious anaemia were needed, including whether any new or additional tests were appropriate. A copy of the BCSH guidance document has already been placed in the Library and is attached.

More general clinical guidance on the diagnosis and management of pernicious anaemia can also be found on the National Institute for Health and Care Excellence (NICE) Clinical Knowledge Summaries website. This is a freely accessible online resource that covers the causes, symptoms, diagnosis and treatment of pernicious anaemia, as well as potential complications of the condition. In addition to this, NHS Choices provides similar, though less technical, information on pernicious anaemia for the public.

So what does this all mean.  Well it means that it is back to the drawing board – well, sort of.  What the reply is very good at doing is pointing out that the Dept. of Health is not responsible for telling doctors what they should be doing.  The Guidelines produced by the British Committee for Standards in Haematology (BCSH) were the result of a long-term diplomatic lobby of various bodies and they are very good; no, they are exceptionally good at identifying, or rather verifying what a growing number of physicians know – that the current tests to determine B12 Deficiency and whether that deficiency is caused by lack of Intrinsic Factor (Pernicious Anaemia) are next to useless and that physicians should listen to the patient’s symptoms rather than rely on the tests.  So – that was a wonderful achievement especially when you consider how many other issues Haematologists are having to address and that the guidelines were written by volunteers who all have an interest and expertise in B12 related issues.

So now what?  Well we could just throw up our hands and say “I give up” or we could take a good look at what the reply from the Dept of Health says – and hidden in among the politic speak is a very good sentence:

‘It would be for the BCSH, not the Department, to consider whether any adjustments to current best practice in the diagnosis and treatment of patients with pernicious anaemia were needed, including whether any new or additional tests were appropriate’.

Passing the buck?  No – most definitely not – what they are doing is stating that the experts have identified the problem but have offered no solution to the problem of making primary care physicians aware of what they recommend.  Or so I thought.  Last Friday I had a short meeting with the lead author of the Guidelines and asked how they were going to make GPs aware of the new guidelines.  It seems that the British Society for Haematology are working on this and may even be developing an app that GPs can download and complete in order to gain Continuous Professional Development credits.  I asked the haematologist what we could do to help and he suggested that maybe we (that’s me) could produce a short 30 minute presentation that marries in the results of our survey of patients’ experiences in getting diagnosed with what the new guidelines state.  But that would mean being invited along to GP training sessions to present the talk.  And so guess what I will be working on in September?  Now where to start?

My thanks go to Lady Mar for her support and I would like to wish Dr Vinod Devalia the best of luck as he takes up his now post ‘over the bridge’ in England.  Dr Devalia has been a great supporter of the society and hopefully he will continue to work and advise us.

But what of the Treatment of PA – the guidelines make it perfectly clear that this is a matter for the British National Formulary (BNF) which is a joint undertaking by the Royal Society of Medicine and the Royal Pharmaceutical Society.  I’ve already had one meeting with the Director of the BNF who told me that if I could provide evidence that some doctors are treating some patients more often than the guidelines state then they could “change the wording” in the BNF.  Guess what – I’ve got the evidence (see my next book) and, perhaps just as importantly, the Dept of Health states quite categorically that the treatment a patient receives should be based on discussion between the physician and the patient and it is not for the Dept of Health to interfere with this.  So I have some ammunition to put our case when I next meet with the BNF representatives.

I’ve started the ball rolling with a letter to the Chairman of the BCSH asking if they are able to do anything to make GPs aware of the recommendations of the new guidelines and if the society can do anything to help disseminate them.  Onwards and upwards.

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Katie’s Tough Mudder Success

by on Aug.04, 2015, under Pernicious Anaemia Society

Well done to Katie McMullin in completing the Yorkshire Tough Mudder Challenge on behalf of the society.  Thanks go to all who sponsored her.  Unfortunately the running vest that the society ordered for her arrived a day too late but I’m sure there will be a next time – eh Kate?

You can see how much fun she had here:


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Leicestershire/East of England Support Group

by on Aug.04, 2015, under Pernicious Anaemia Society

The number of people planning to attend the Leicester Support Group has grown steadily and Frank the organiser of the event has been asked several times if it is open to members of the PA Society who live outside Leicester or Leicestershire – the answer is most definitely.  I will be there.

The Church

The Church

Members who are prepared to travel from outside the immediate area are most welcome – in fact it’s fast turning into the Leicester/East of England Support Group.  Please let Frank know if you are planning to attend as we may need a bigger room at the same venue which is Bishop Street Methodist Church on Saturday 8th August 2015 between 10 – 12
The venue is in the middle of Leicester and is easily accessible by public transport.
For directions see the Church’s website. If you are thinking of attending please let Frank Chafer know so we know how many to expect on 07526 237998

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Leicestershire Support Group

by on Jul.22, 2015, under Pernicious Anaemia Society

The first meeting of the Leicestershire Support Group will take place at Bishop Street Methodist Church on Saturday 8th August 2015 between 10 – 12
The venue is in the middle of Leicester and is easily accessible by public transport.
For directions see the Church’s website.
More information from Frank Chafer on 07526 237998 or by email:
replace the ‘at’ with the @ sign

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Summary of B12 Conference, Nancy, France, July 2015

by on Jul.11, 2015, under Pernicious Anaemia Society

There were over 240 delegates to the 10th International Conference on One Carbon Metabolism, B Vitamins and Homocysteine at the Medical School at the University of Lorraine.

Whilst most of the subjects were way over my head (and over the heads of some of the professionals there) I have included below the titles of the papers presented and a short summary of the research.  Please don’t leave messages asking for further clarification – I am not scientifically qualified and won’t be able to answer you.

The title of the speaker is given and not all of the authors of the individual papers.


Session 1: Enzymes and co-enzymes of the one carbon metabolism: the mechanistic interplay and alternative reactions
Chairs: J.P. Kraus and W. Kruger

1.Lessons in biology from patients with inherited disorders of vitamin B12 metabolism; D. S. Rosenblatt, (Montreal, Canada)

“We have been able to define steps in intracellular cobalamin metabolism and to identify five novel complementation groups…and the first patients with a defect in the transcobalamin receptor.  In addition, we have described the first patient with mutations in the MTHFD1 Gene which is involved in the interconversion of folate coenzyme forms, resulting in the altered flux of single carbon units into thymidine, and severe combined immunodeficiency”.

2. CBS News; Structure, Regulation and Enzyme Replacement Therapy; J. P. Kraus (Aurora, USA)

CBS* upon SAM**binding undergoes a large structural movement of its regulatory regions to allow substrate access to the catalytic sites. Our results strongly suggest that CBS ERT*** is a viable alternative to the existing therapies for homocystinuria”.

*Cystathionine beta-synthase


***Enzyme Replacement Therapy

3.Promiscuity of enzymes in sulfur amino acid metabolism: hydrogen sulfide production in homocystinurias; V. Kozich (Prague, Czech Republic)

“This study implies that deficient CBS activity results in decreased H2S* production, which is in vivo compensated by enhanced synthesis of hydrogen sulfide from homocysteine by CTH**”

*Hydrogen Sulfide


4.  Investigations focused on the methionine synthase intercactome provide novel mechanistic insights about the intracellular metabolism of vitamin B12; D. Coelho (Nancy, France)

“…moreover our data suggest that a potential innovative treatment of patients with acquired or inherited disorders of Cbl metabolism could be based on SIRT1 agonists”

5.  Allosteric regulation of cystathionine beta-synthase and ligand-mediated stabilization of its regulatory domain; T Majtan (Aurora, United States).

“Results indicate that independent pharmacological targeting of regulatory and stabilizing sites in CBS may represent a feasible approach for development of CBS-specific kinetic stabilizers and thus rescue CBS activity”.
6. Visualization of a B12-dependentenzyme with its G-protein chaperone indicates molecular mechanisms of methylmalonic aciduria; M. Jost, D. Born (Cambridge, United States)
“The lcmF crystal structures reveal how G-protein chaperones associate with adenosylcobalamin-dependent enzymes to regulate cofactor delivery and indicate a molecular mechanism of pathogenicity for five methylmalonic adicuria-causing mutations”.
Session 2: Metabolic, molecular and cellular consequences of hyperhomocysteinemia and folate and vitamin B12 deficiencies
Chairs: J.L. Guéant and V. Kožich
1. Influence of folate deficiency on brain development and function: the rat model of folate receptor autoantibodies; E.V. Quadros. (New-York, United States)
“…Testing for FR autoantibodies and folinic acic supplementation could have a major impact in preventing and treating autism”.
2.   Understanding the role of vitamin B12 deficiency in de novo thymidylate biosynthesis.
A.M. Palmer. (New York, United States):
“These studies will enable us to establish the role of B12 deficiency in nucleotide biosynthesis and genome stability”.
3. Metabolomics reveals new pathways and candidate biomarkers of vitamin B12 status, effects of B12 on myelinated peripheral nerve conduction and interaction with folate status.
A. Brito (California, United States)
“Metabolomics reveals new pathways and candidate biomarkers of B12 status and effects of B12 on myelinated peripheral nerve conduction.  The interaction with folate status is under assessment.  The combined indicator of B12 status had the highest capacity to identify associations with metabolomics as compared with any single biomarker”.


4. Impact of elevated levels of plasma homocysteine and impaired DNA repair in a mouse model of vascular cognitive impairment
N.M. Jadavji, (Berlin, Germany)
“The results suggest that a combination of hyperhomocysteinia, chronic hypoperfusion or impaired DNA synthesis is required for memory impairments, whereas MTHFR deficiency alone has no effect on learning.  Additionally, cortical choline metabolism is disrupted in MTHFR deficient mice with chronic hypoperfusion”.
5. Methyl donor deficiency impairs differentiation of pre-osteoblasts through disruption of functional interaction between peroxisome proliferator-activated receptor-gamma coactivator-1 alpha and vitamin D receptor
E. Feigerlova (Nancy, France):
“The data presented here provide new mechanistic insights into regulation of human osteoblast differentiation demonstrating for the first time crucial role of PGC-1α-VDR functional interaction, dramatic effect of MDD on the nuclear action of 1,25(OH)2D3 through hypomethylation of PGC-1α and sequestration of VDR in a form of the HSP90-VDR complex. This prevents the hormone binding to PGC-1α and leads to impaired expression of target genes ultimately directing cell differentiation toward a more adipogenic phenotype.”

Session 3: Metabolic, Cellular and Tissular Compartments of the One Carbon Metabolism

Patrick J Stover (Ithaca, New York)

“The results from these studies suggest a convergence of the NTD-associated risk factors to a single pathway responsible for folic-acid responsive NTDs.”

  1. MPV17 Mitochondrial Inner Membrane Protein Loss-of-Function Causes MDS and Altered One-Carbon Metabolism

J Alonzo (New York, USA)

“Mutations in the human MPV17 gene are known to cause Mitochondrial DNA depletion syndrome (MDS). Our results suggest that MPV17 may play an important role in mitochondrial one-carbon metabolism and maintaining mtDA integrity. Understanding the mechanism by which MPV17 affects mtDNA and causes changes in one-carbon metabolism may provide insight into better medical treatment and prognosis for MDS patients.”

 2. Methyl deficient diet promotes colitis and SIRT1-mediated endoplasmic reticulum stress

H Melham (Nancy, France)

“Adding either vitamin B12, S-adenosylmethionine, or a SIRT1 activator (SRT1720) reduced the unfolded protein response (UPR) in vitro. In rats, SIRT1 activation by SRT1720 prevented colitis by reducing acetylation of HSF1 and increasing the expression of BIP, HSP27 and HSP90. Immunohistochemistry showed impairment of SIRT1 in the colonic epithelium of IBD patients. SIRT1 is a master regulator of ER stress and severity of experimental colitis in cases of methyl donor deficiency (MDD). It could deserve further interest as a therapeutic target of inflammatory bowel disease.”


3. S-Adenosylhomocysteine promotes endothelial activation through NF-KB activation

M Barroso (Lisbon, Portugal. Boston, USA)

“Our results show that S-Adenosylhomocysteine (SAH) accumulation leads to the activation of NF-KB canonical and ono-canonical pathways. NF-KB activation induced the expression of adhesion molecules and cytokines that promote pro-inflammatory activation of endothelial cells and leukocyte recruitment, important steps in atherogenesis. Here we demonstrate a new association between SAH and NF-KB that may promote cardiovascular diseases.”

4. Interplay between folate, S-adenosylhomocysteine and protein methylation in human endothelial cells: the importance of methionine availability

R Castro (Lisbon, Portugal)

“In endothelial cells, methionine excess constrains the ability of folate to restore the intracellular methylation potential. Interestingly, our findings may explain why in randomised trials folic acid lessened plasma tHcy, but failed to reduce cardiovascular risk, suggesting that folate interventions will be vascular-protective only within a context of low methionine availability.”


1. Strategies to correct homocystinuria in mouse models of CBS deficiency

 WD Kruger (Philadelphia, USA)

 “Our findings indicate that while betaine supplementation does have some beneficial effects, it is not as effective and methionine restriction for reversing the phenotypes associated with severe CBS deficiency in the Tg-I278T Cbs-/- mouse model of CBS deficiency.”

 2. Correction of cognitive impairment in a model of hyperhomocysteinemia due to cystathionine beta synthase

 Nathalie Janel (Paris, France)

 “We conclude that specific hepatic Dyrk1A gene transfer restores the molecular mechanisms altered by Dyrk1A overexpression in brain of CBS deficient mice.”

 3. Does hyperhomocysteinemia affect collagen and elastin cross-links in a mouse model of cystathionine 􀀁-synthase deficiency?

 J Perla-Kaján (Poznan, Poland)

 “Although susceptible to N-homocysteinylation in vivo, elastin and collagen do not show significantly affected cross-linking in Cbs-deficient mice.”

 4. Body composition, lipid metabolism and SCD-1 activity in patients with classical homocystinuria

S Poloni (Porto Alegre, Brazil)

 “This study suggests that, in classical homocystinuria, altered SAA metabolism suppresses SCD-1 activity also in humans. The reduction of leptin, a major regulator of SCD-1 expression, is in agreement with the findings in animal models of hyperhomocysteinemia.”

5. Methylation imbalance in a mouse model of CBS deficiency induces liver phospholipids remodelage

 A Imbard (Paris, France; Chatenay-Malabry, France)

 “Accumulation of satured PC and unsaturated PE and decrease in unsaturated PC suggest an inhibition of the PEMT pathway which uses preferentially unsaturated PE for PC synthesis1. Moreover the increased CHPT1 expression and increased saturated PC might suggest an induction of the Kennedy pathway to maintain the PC synthesis.”

Session 5: Absorption, Blood and Cellular Transport of B Vitamins

1. Absorption and blood/cellular transport of B vitamins involved in one-carbon metabolism

David H Alpers(St Louis)

 “the intestinal transporters for folate and cobalamin differ greatly in their structure. The compartmentalization of folate and cobalamin within the body is determined in part by these specific features, and can be understood in terms of classical pharmacokinetics. Because of these complexities it is not surprising that the bioavailability of folate and cobalamin can be variable in health and disease.”

 2. Lysosomal transport of cobalamin: What we know and what we don’t know?

Frank Rutsch (Munster, Germany)

“Preliminary experiments so far have failed to prove transmembrane transport of cobalamin by either one or both of the identified proteins. While most recent data suggest an interaction of LMBD1 with ABCD4 and with the cytosolic protein MMACHC, the exact mechanism of lysosomal cobalamin export is still mysterious.”

3. Transcytosis in the vascular endothelium recycles uncommitted vitamin B12
L Hannibal (Ohio, United States; Erlangen, Germany)
“Our results suggest a mechanism whereby the vascular endothelium recycles uncommitted intracellular cobalamin for downstream usage.”

4. Proteomics and Genomics approach to understand mechanism of Cysteine induced toxicity in yeast
Ajay Bhat (New Delhi, India)
“Leucine plays an important role in survival during cysteine induced stress. By overlapping the proteomics and genomics data we found that cysteine affects the expression of ribosomal proteins and protein degradation pathways and expression of amino acid metabolism serve as a response for survival during high cysteine levels.”

5. Stable isotope dilution assays for clinical analyses of folates and other one-carbon metabolites
M. Kopp (Freising, Germany)
“The miniaturized methods using sample volumes as low as 50 µL and weighed portions of 5-20 mg will allow to assess the status of folates and further biomarkers of an impaired one-carbon metabolism.”


1. Intracellular cobalamin partitioning, advances and unanswered questions
B. Fowler (Zürich, Switzerland)
“Current knowledge points to a role of MMADHC in at the branch point of Cbl delivery to the mitochondrial and cytoplasmic target enzymes. Emerging studies have shown that MMADHC does not bind Cbl itself but can interact with MMACHC. In spite of these advances much regarding the exact molecular function and interactions of these intriguing proteins remains to be explained and key to this will be knowledge of the 3-D structure of the MMADHC protein.”

2. Search for the molecular basis of two complementationconfirmed atypical mut patients
Jordan Chu (Quebec, Canada)
“It is unexpected that two mutations in MUT were not found in these two patients, considering the high reliability of complementation analysis in diagnosing inborn errors of cobalamin metabolism. Regulatory or deep intronic mutations not assessed by the gene panel may be causative of the mut phenotypes. Alternatively, the patient with heterozygous mutations in MUT and MCEE could be an instance of synergistic heterozygosity. For the patient with no currently identified mutations, there may be mutations in unexpected genes controlling the expression of MUT, as has recently been shown for HCFC1 and MMACHC.”

3. Investigating a novel inborn error of cobalamin metabolism
Mihaela Pupavac (Quebec, Canada)
“These data suggest that the cellular defect in that patient’s fibroblasts affects internalization of the TC-Cbl complex after binding to its cell surface receptor, but before degradation in the lysosome.”

4. New generation sequencing (NGS) identifies digenism in two families, with MTHFR/POLG and MTHFD/GIF mutations, respectively
Guéant JL (Nancy, France)
“NGS found digenism, with POLG mutation in adult twins with MTHFR inherited deficiency and unusual clinical presentation of spastic paraparesis. NGS led us also to find a MTHFD compound mutation in two siblings with GIF mutation and severe immunodeficiency.”

5. Loss of LMBD1 protein results in gastrulation defects during mouse embryogenesis
I Buers (Muenster, Germany)
“Crossbreeding of the Lmbrd1flox3/neo-mice with Credeleter mice resulted in the deletion of the third exon of the Lmbrd1 gene and the loss of the LMBD1 protein. Our results show that loss of function of Lmbrd1 leads to early embryonic lethality in mice due to gastrulation defects. We conclude functional LMBD1 plays an essential role in early developmental processes in mice.”

6. Excessive Folic Acid (FA) Intake and Relation to Adverse Effects
Jacob Selhub (Boston, USA)
“We have shown that the for unilateral retinoblastoma in offspring is higher in mothers who were homozygotes for the 19bp deletion in the DHFR gene and took FA supplement. Elderly with this polymorphism had lower memory and executive scores, both being significantly worse in those with high plasma folate.”


1. Epigenomic Dysregulations in Vitamin B12 and Folate Deficiencies
Jean-Louis Guéan (Nancy, France)
“In conclusion, the deficiency in folate and vitamin B12 influences cell proliferation, differentiation, reticulum stress and energy metabolism through epigenomic mechanisms related to imbalanced acetylation/methylation. Some but not all of these effects reflect their key role in SAM synthesis.”

2. Maternal vitamin B12 deficiency leads to altered DNA methylation in genes involved in fatty acid metabolism as revealed by whole genome methylation analysis using MeDIP-Seq
Shantanu Sengupta (New Delhi, India)
“Maternal Vitamin B12 deficiency leads to altered methylation in the offsprings, which leads to conditions like dyslipidemia in adult pups. This alteration can be partially reversed by supplementation of the vitamin B12 either at conception or parturition.”

3. Effect of MTHFR 677C>T on genome-wide DNA methylation: A meta-analysis
Pooja R Mandaviya (Rotterdam, Netherlands)
“Genome-wide meta-analysis of homocysteineassociated SNPs showed significant meQTLs. In the coming months, the results from this discovery analysis will be replicated in additional studies and presented at the meeting.”

4. B12 Intervention Influences Methylation of Genes Associated with Type 2 Diabetes and Its Intermediate Traits
DK Yadav (Hyderabad, India)
“We demonstrate that B12 supplementation alters the methylation of genes influencing intermediate traits of T2D like obesity (FTO), insulin resistance and secretion (TCF7L2). Our study provides a novel ‘epigenetic’ explanation for the association between one-carbon metabolism and risk of adiposity, insulin resistance and diabetes.”

5. Global and MTHFR gene specific methylation and its role in Preeclampsia
MP Sachdeva (Delhi, India)
“The study highlights the importance of global methylation in the causation of PE i.e. hypermethylation at global levels among PE cases. The study also suggests that MTHFR C677T polymorphism in heterozygous condition along with hyper global methylation is posing a risk for pre-eclampsia.”


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