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Undiagnosed: Numbness After Consuming Carbohydrates

Discussion in 'Ask A Question' started by ChetRoi, Mar 25, 2018.

  1. ChetRoi

    ChetRoi Researcher · Active Member

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    I briefly discussed my undiagnosed pathology about six weeks ago in response to a poster's question. I am restating the problem in its own thread in great depth for wider review. I am a 70 year old retired scientist. I'd appreciate any input this community may offer.

    A Lay Opinion of the Clinical Picture

    A slowly progressive systemic dysfunction of uncertain etiology has presented for more than ten years. Suggestive of a chronic dysmetabolism syndrome, it is triggered by ingesting even minute amounts of carbohydrates. Its acute symptoms--including most prominently distal numbness--are partially relieved by repletion with Methylcobalamin (MeCbl), a bioactive cofactor of B-12 that provides cellular methylation in addition to B-12 itself.

    The array of clinical manifestations includes the characteristic B-12 deficiency triad of neurological, hematological, and psychiatric symptoms; foamy transformed macrophages; apparent connective tissue inelasticity; Alpha-1 Antitrypsin Deficiency (S-variant allele); a 1.3 cm renal mass cryoablated Nov 2016; and numerous other deficits, many consistent with a B-12 malabsorption or dysmetabolism pathology.

    As has been reported in the scientific literature, high-dose vitamin B-12 can overcome pathway deficits in some patients, perhaps related to the more recent finding that B-12 cofactors MeCbl or Adenosylcobalamin (AdoCbl) may have a significant stabilizing effect on the MMACHC (cobalamin C) protein. In this patient’s case, repletion and ongoing titration with MeCbl and AdoCbl, and B-9 Methylfolate (MeFolate) in therapeutic doses begun in 2014 initially resulted in dramatic biochemical and clinical improvement.

    However, neurologic deficits have progressed to the severe level with a January 2018 Dx of severe sensorimotor polyneuropathy (SMPN) with axonal features and denervation. Nonetheless, in mid-2016, adoption of a fat-oriented very low carb ketogenic diet to bypass the dysfunctional carbohydrate metabolic pathway has further slowed accumulating deficits. Currently, MeCbl is administered subQ: 0.33 cc every other day @ 25 mg/mL. AdoCbl and MeFolate are given orally @ 1.5 mg and 0.8 mg every other day. SAMe, 200 mg, is taken every other day.

    Importantly, a diagnostic clue may be found in the lack of effectiveness of the standard-of-care Cyanocobalamin (CyCbl) and the dramatic therapeutic response to B-12 cofactor repletion (MeCbl, AdoCbl). It may indicate the end stage cobalamin pathway reduction is never realized because from a CyCbl administration for the patient neither the cytoplasm methylation to form MeCbl, nor mitochondrial adenosylation to form AdoCbl occurs. Alternatively, it may suggest the effectiveness of the MeCbl repletion is more a function of the applied cellular methylation by influencing gene expression. For example, methylation is a process now known to improve some systemic diabetes manifestations.

    Current Syndrome of this Metabolic Pathology

    More recently, within just hours now of consuming carbohydrates (and to lesser detrimental effect, food cholesterol), an acutely arising distal numbness presents that can advance into the torso. Thereafter affected are balance, mobility, motor coordination, proprioception, waste elimination, strength, stamina, a burning mouth syndrome, and days later, psych profile alterations and apparent connective tissue inelasticity. A positive Romberg can re-emerge.

    These deficits increase in severity over time (up to three+ days) proportional to the amount of carbohydrates consumed, and then wane with the repletion dosing of MeCbl injections. Over the past eight years, the latency period after carbohydrate consumption and the appearance of distal numbness has closed from days to one hour, and distal neurologic deficits have advanced to severe SMPN with axonal features and denervation. Distal nerve damage is visually apparent with permanent sluggishness in movement and coarseness in lower/upper limb and phalanges articulation. The patient cannot coordinate running; walking is often labored, limited to 100 yards at a time. Unaided stair climbing is impossible beyond ten steps. More specifically,

    1) Hematologic: transient mild pancytopenia; leading thrombocytopenia (105: 160-410); reticulocytopenia (#0.03: 0.05-0.11); transient mild leukopenia, erythropenia, monocytopenia. Abnormal platelets.

    2) Neurologic: progressive, severe SMPN with axonal features and denervation, painless, symmetric, stocking-glove (B-12 deficiency type), entrapment across elbow. Gait, foot-drop, balance, coordination, and stamina deficits worsening within hours of consuming carbohydrates. Moderate proprioception errors; sensory ataxia appears. Walking is stiff, sluggish, weighted, and distance-limited particularly when under carbohydrate dysmetabolism stress. Chronic absent deep tendon reflexes, moderate hand tremor.

    3) Gastroenterologic: NAFLD. Splenomegaly. 2017 liver biopsy showed glycogenated nuclei and trace positive iron stain in macrophages. Portal tracts contained a sparse lymphocytic infiltrate. Until three years ago, periodically explosive diarrhea and abdominal pain largely relieved by a reduction in dietary carbohydrates. Diverticulitis Dx 2005. A 2017 SIBO test (hydrogen only) was negative.

    4) Psychiatric: When under extended challenges from either carbohydrate dysmetabolism stress or a trial reduction in MeCbl repletion: memory loss, brain fog, confusion, depression, anger, paranoia, word searching, presentation anxiety, and combat PTSD symptoms appear or are acutely exacerbated.

    5) Endocrinologic: Enlarged abdominal lymph nodes. Chronically well below RR Alkaline Phosphatase. Lipids: TC 226 (ketogenic dietary necessity of fatty meats). TC/HDL 3.8. Glucose: 112. A1C typically 4.8 but now 5.3 due to periodic carbohydrate consumption challenges.

    6) Physical: Frequent thirst. Foamy transformed macrophages from biopsy preceding 2012 rib resection. Presumed connective tissue inelasticity. Leg muscle atrophy, infrequent calf and tibial bone pain. Chronic mild cubital tunnel syndrome (R arm, dominant) and mild carpal tunnel syndrome (L). Persistent sinusitis during adult life; sinus infections ended after MeCbl repletion began in 2014. Multiple direct exposures to organophosphates (Agents Orange, Blue, White) in Vietnam (1969-1970).

    7) Ophthalmologic: Occasional blurry vision. EBMD corneal dystrophy (Dx prior to 2014), cataracts. Events of wavy, shimmering lights (Dx painless migraines). Sensitivity to light relieved by MeCbl repletion.

    What Happens When Carbs are Consumed?

    Several years ago, when the association between carb consumption and acutely arising distal numbness was first realized, the latency period between the events was about 2-3 days. Since then, the carb consumption to the start of distal numbness period has dropped to about an hour.

    1) Example: 25 carb grams at dinnertime of hamburger potato bun.

    2) About one hour later, soles of feet and foot tops/sides, fingers are beginning to numb; articulation diminishes.

    3) During subsequent sleep period, action of stretching legs usually causes calf muscle cramping.

    4) In morning at wakeup, walking has become stiff, stilted as lower legs and feet have numbed. Seemingly, all neurologic deficits have worsened. Sense of lethargy ensues.

    It may take three or more days for the additional numbness to resolve, often not fully. If the carb consumption has been large enough, ataxia and psychiatric disturbances follow. (B-12 molecules not crossing the BBB to the CSF?)

    ***
     
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  2. Indy51

    Indy51 Type 2 · Expert

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    Why keep on eating carbs if they make you this sick, especially gluten containing carbs like hamburger buns?

    Among all your tests, have you ever been tested for coeliac? What are the state of your microvilli if you've had endoscopic investigations?

    Coeliac is not just an illness of childhood and it is primarily a neurological disease (not all coeliacs have the GI symptoms). I knew someone in their 60s who almost died from undiagnosed coeliac and the associated malabsorption micronutrient deficiencies.
     
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  3. Lamont D

    Lamont D Reactive hypoglycemia · Master

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    Can someone translate the ops post into English that we can all understand!

    However, if like me you are literally carb intolerant, don't eat them!

    My health has improved dramatically since going Keto.

    P.S., asymptomatic similarities persist continuously when ingesting carbohydrates.

    Best wishes
     
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  4. Incyb

    Incyb Type 2 · Well-Known Member

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    ALA might help. And don't eat carbs! Sounds to me like there might be a functional neurological thing going on as well.
     
  5. ChetRoi

    ChetRoi Researcher · Active Member

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    Thanks, Indy51, for responding.

    I've been on a keto diet for two years averaging about 18 carb grams per day.

    I have learned that if you want clinicians to really pay attention to your case, you must provide them with as full a context as possible. That includes periodic stimulus-response testing with the offending substance. Further, my body reaction to carbs has evolved. It is therefore important to show this evolution to physicians who are working to offer a diagnosis.

    I have had a blood test for celiac disease--it was negative and, of course, did not involve examination of microvilli. But your comment of micronutrient malabsorption is interesting. I have heard that testing for celiac can be hit or miss. Do you agree with this assertion?
     
  6. ChetRoi

    ChetRoi Researcher · Active Member

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    Appreciate your responding.

    I have used ALA for quite some time (1200 mg/day) with success in almost eliminating the burning mouth syndrome effect. I am ketogenic, and only eat carbs when testing is necessary. Diet discipline is not a problem for me.
     
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  7. Indy51

    Indy51 Type 2 · Expert

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  8. Lamont D

    Lamont D Reactive hypoglycemia · Master

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    Having a descriptive study on how you react to carbohydrates, should help with diagnosis. If you keep what we simply call a food diary, will help with your daily life, it should help with your medical team, if they are savvy with endocrine conditions.
    I have been in ketosis for over four years now, my health is really good.

    Avoid the carbs.

    Could you have other hormonal issues?

    Have you had the tests other than the ones you have mentioned?
     
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  9. ChetRoi

    ChetRoi Researcher · Active Member

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    LaMont, thanks for responding.

    Sorry for the less-readable post. The verbiage is a cut-and-paste from my monthly medical summary for physicians. I agree that I have sacrificed readability for what I consider to be precision. It is helpful to the medical community; less important for this forum, perhaps.

    As I noted in my original post, I am ketogenic and have been for two years. Carb challenges of about 25 extra carb grams are periodically undertaken about every six months or so to determine how I am responding because this is changing--important information for the diagnostician. The fact is even at an average of 18 carb grams per day, my disease is still progressing although much more slowly since I began the keto program.

    And remember, unlike many of you, I do not yet have a diagnosis. Collecting data on my evolving response to carb intake has been important to the physicians I have seen, and I have seen many. That includes the biochemical geneticist whose Whole Exome Sequencing was not at all enlightening.

    But here's a question for you. Are you aware of anyone who is carb intolerant and also food cholesterol intolerant? I am also cholesterol intolerant but to a much lesser degree than with carbs.
     
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  10. ChetRoi

    ChetRoi Researcher · Active Member

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    Until a few months ago, I used the FatSecret app to track all my food consumption. I did this for almost three years. I have not encountered a single physician who thought it useful to review the reports, although it has helped me.

    I describe the carb reaction at the end of my initial post. Also, here is the rest of that which I tried to post but was denied because the post was too lengthy:

    What We Know

    1) Indications of sub-clinical long-term illness; manifestations are consistent with a prolonged B-12 deficiency.
    a) Congenital heart murmur as a toddler; chronic manual proprioception errors beginning as a toddler and continuing into adulthood.
    b) Recurrent infections since late 1960s: sinusitis has not re-established since MeCbl repletion began.
    c) Severely diminished or absent deep tendon reflexes first noticed by a clinician in the late 1970s.
    d) Presence of B-12 deficiency triad of neurological, hematological, and psychiatric symptoms.
    e) Progressive, painless, severe SMPN with axonal features; B ulnar entrapment across R elbow. EMG/NCV indicates denervation.
    f) Two cobalamin transport genes have heterozygous mutations: TCN1 (rs526934, genotype AG) and TCN2 (rs1801198, genotype CG).
    g) Chronic abnormal platelets; thrombocytopenia for at least five years. Other cytopenias transient.
    h) Enlarged abdominal lymph nodes, splenomegaly, NAFLD, renal cell carcinoma (cryoablated).
    i) 2017 liver biopsy showed glycogenated nuclei and trace positive iron stain in macrophages. Portal tracts contain a sparse lymphocytic infiltrate.
    j) Foamy transformed macrophages, seen in B-12 deficiency, was present in a 2012 tissue biopsy of an exceedingly rare bone xanthoma of the L 10th rib; excised.
    “The lesion of interest is present in the tissue biopsy and comprises cytologically [benign] spindle cells arranged in a somewhat haphazard fashion resembling fibrous histiocytoma. These are in many respects overshadowed by sheets of foamy macrophages resulting in a xanthomatous appearance. Given the relatively nonspecific nature of xanthomatous change, I suspect it likely that this represents an example of fibrous dysplasia given the location.”

    2) Immediate and dramatically effective therapeutic response to MeCbl and AdoCbl repletion; ultra high dosage required; disease progression continues but at a slower pace as long as carb consumption is minimal (target of less than 25 grams/day). Deficits accumulation occurs within days if repletion is interrupted. Standard of care CyCbl is ineffective.

    3) The syndrome defines a progressive disease provoking a metabolic dysfunction.
    a) About an hour or so after consuming carbohydrates, an acutely arising distal-to-proximal numbness begins that can advance into the torso—presumed to be a biochemical interruption of neuronal cellular signaling due to macronutrient dysmetabolism. B-12 is required to metabolize both carbohydrates and food cholesterol.
    b) The glycemic load of the carbohydrates consumed predicts the extent and intensity of the distal numbness and rigidity

    What We are Doing

    1) Treatments. Regardless of the etiology of the disease, two facts have emerged in its management.
    First, as previously discussed, a dramatically positive reaction occurs when taking methylcobalamin and adenosylcobalamin, both methylation cofactors of B12. These benefits are lost if repletion is interrupted. Note that cyanocobalamin--unmethylated B12--is ineffective.
    Second, neurological deficits are acutely exacerbated by any carbohydrate consumption.
    The following are the only treatments known to possibly help this unidentified disease.
    a) Daily ultra high dosage repletion of B12 cofactor vitamins, and the B9 cofactor vitamin.
    b) A very low carbohydrate (less than 25 grams/day), moderate protein, and high fat (Ketogenic) diet.
    c) Light weight lifting to maintain muscle mass given both disease and possible wasting effect of ketogenic diet.
    Bicycle riding to reduce loss of leg strength.

    I am seeing a different endocrinologist in June. Perhaps she will have some ideas.
     
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  11. ChetRoi

    ChetRoi Researcher · Active Member

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  12. Tannith

    Tannith · Well-Known Member

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    My Grandma had B12 deficiency -pernicious anaemia - not because she lacked B12 but because in her older age she lost the ability to absorb it through her stomach. Maybe you have been checked for this.
     
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  13. ChetRoi

    ChetRoi Researcher · Active Member

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    Thanks for responding--

    Yes, not infrequently older folks lose the ability to absorb B12 because of the failure of the protein known as intrinsic factor to do its job. But you have hit on an avenue of investigation I am currently pursuing.

    In my case, intrinsic factor is alive and well. However, the processing of B12 in the body, from ingestion of food containing B12 to cellular absorption, known as the B12 pathway is a highly complex process comprised of over 25 steps. Genetic errors can cause mistakes in this processing.

    As we write, my doctor is looking at whether the biochemical processes which transport B12 within my body are functioning properly. Thanks again.
     
  14. Lamont D

    Lamont D Reactive hypoglycemia · Master

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    No, I have not heard of being cholesterol intolerant.
    That is a new one on me!
    You have a lot of issues with your health.
    It is not surprising that no definitive diagnosis is given.
    I think you would come under, what the specialists would call idiopathic metabolic syndrome. This description would cover many conditions regardless.
    The key thing that I have found and is that the diagnosis itself is not the be all and end all because, even if they could give you one, it is more important to find your own treatment for you, rather than a group of similar patients.
    Finding your own balance of low carb, protein and the fats you eat and cook with.
    I can't use vegetable oils, only animal fats. Even if I low carb and use vegetable oils, I would still feel awful later. I have also learnt that the small things can make big changes in how you cope. Also fasting helps with the imbalances in hormonal issues.
    If you don't eat, the body can and will go into reset mode. You don't need a lot of food.
    I have discovered I can live healthier if I don't eat a lot, just a few bites of the right balance for me, is my new nutritional needs. Sleep and walking is also important.

    I had a battle to get the correct diagnosis for me. Lots of doctors, dsns, two endocrinologists. I was lucky in the end and got a specialist who was very knowledgeable about reactive hypoglycaemia and how to test for it.

    Don't give up. The answer is out there.
     
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  15. ChetRoi

    ChetRoi Researcher · Active Member

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    Lamont,
    Can you tell me a bit about your fasting and caloric need?
    How many calories per day did you consider to be fasting? and how many fasting days?
    What is your daily caloric intake? And what is typical for your weight/height?
     
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  16. Lamont D

    Lamont D Reactive hypoglycemia · Master

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    I don't count calories.
    I don't have a need to because I am always below recommended requirements for calories, I don't have proper meal times either.

    I now only eat as a way to gain sufficient nutrition for an active man like myself.
    A few bites throughout the day, seems to be sufficient.
    My weight hovers around the twelve stone mark, a few days below, a few days above but always around twelve stone.
    Five years ago I was approaching eighteen stone!
    I am five eight in height.
    My approach to fasting can be a day, two days or intermittent, the longest is just over 80 hours. My regular fasting regime whilst in work, is thus,
    Fasting from previous evening until between 11 am. or till 1pm. I only eat in the following six hours as a window of nutrition. A few bites within the window. A balanced approach to my protein, fats with small pieces of fruit to freshen my mouth after protein.
    If I'm travelling or off work, I try and not eat unless I want to.
    I only drink water or black tea.
    I am never hungry and don't miss the unnecessary meal times and amounts of processed rubbish they sell now. Everything is fresh and from scratch. Anything not eaten is frozen, such as curries, soups and stews.
    I can sometimes not think about food for a lot of the time by keeping busy.

    To understand fasting, you do have to be patient, you have to take it in small steps increasing the gap between eating and the eating window smaller to a part of the day to suit you. As an example, for a start miss breakfast, then eat at noon, follow on to missing breakfast and only eat between 6pm to 9pm. Then eighteen hours, then twenty four hours, then as you gain more experience, thirty six.
    Fasting can be really good for you if you can tolerate not eating for a large portion of the day. It helps with a lot of endocrine conditions.
    My specialist endocrinologist has been impressed and encourages me to to use intermittent fasting rather than the longer fasting, the benefits of fasting, is not only healthy but will save on grocery bills!!!

    Hope this helps

    Best wishes
     
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  17. ChetRoi

    ChetRoi Researcher · Active Member

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    Wow, that's hard-won information. I'm going to look more deeply into intermittent fasting. I have seen studies extolling the benefits of fooling the body into thinking starvation is underway.

    Thanks for the help. Best Regards.
     
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  18. ickihun

    ickihun Type 2 · Master

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    Maybe I need testing as I'm not absorbing vit D nor iron at mo, yet my diet hold both these nutrients.
    Who diagnoses coeliac and how?
     
  19. DionneT

    DionneT Other · Member

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    Hello, I just wanted to second Lamont D's suggestion of fasting - I have done several 24 hour fasts recently and feel fantastic in the final few hours. I get a glimpse of the old me - sharp mental focus, abundant physical energy and a sense of calm. Shame that I have to resume eating again! I think fasting is relatively easy after eating a ketogenic diet for almost a year, the hunger pangs are brief and mild, whereas my old carb-eating self would have been struggling after a few hours.
    Although as someone who also gets the ascending numbness after carbs, I will say that fasting seems to decrease my carb tolerance slightly- a meal that would usually cause no problems can trigger symptoms, so my first meal has to be small and very low carb.
    Sorry I only just noticed you had created this new thread, I posted yesterday on the old one. It's fascinating to see more detail on your medical history. I also have had recurrent issues with sinusitis that has dramatically improved since reducing carb intake. Can I ask how does your connective tissue inelasticity manifest? I get very tight feeling hands, like the skin temporarily becomes thick, and stiffness of joints, with muscle spasms that move up my body travelling the same path as the numbness.
    Best wishes,
    Dionne
     
  20. ChetRoi

    ChetRoi Researcher · Active Member

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    From Dionne:

    Unfortunately still no explanation ....


    Hello, I just wanted to second Lamont D's suggestion of fasting....


    Hi Dionne, thanks for the reconnect—

    I have had an initial visit with an immunologist; first-round testing has uncovered no autoantibodies. More testing to follow, perhaps with pre/post carb challenges, which up to this point hasn’t been done.

    Exercise just after eating carbs is not something I have tried but I do know that a prolonged fast of carbs (keto diet) does seem to give me a few meals/days without much numbness after eating carbs.

    I will make note of the channelopathy possibility for my clinicians, and I will read more about this myself.

    With regard to fasting, I am currently 160 pounds (11.4 stone) and 5’ 10”, and I lose weight easily so I must be careful about reduced calorie dieting.

    I have just completed a new round of dietary challenges and learned that food cholesterol still has a significant numbing affect, albeit much less sensitivity than with carbohydrates. So, my eating choices are now even more reduced.

    The apparent connective tissue inelasticity presents as medial (and to lesser extent, lateral) epicondylitis, carpal tunnel, cubital tunnel, and general muscle/ligament inelasticity evidenced by torn L and R medial menisci, torn L biceps tendon, torn L rotator cuff, and easily strained back and shoulder muscles, all in the absence of strenuous exercise. The chronic inelasticity symptoms have been largely relieved with Adenosylcobalamin (bioactive B12) supplements. The connective tissue pain returns when Adenosylcobalamin repletion is reduced or interrupted.

    Some new information:

    My youngest daughter, largely bed-ridden and under pain management for ten years, was just diagnosed with Hypermobile Ehlers-Danlos Syndrome. There are now 14 known subtypes of EDS but this type has not yet had genetic allele errors identified. Hypermobile EDS' inheritance pattern is autosomal dominant meaning each child has a 50% chance of having the defect when just one parent carries the “bad” genes. I will nonetheless be tested for EDS-related genetic defects but judging only by the clinical presentation, it appears to originate from my wife’s side off the family.

    A new round of amino acid testing by a biochemical geneticist revealed nothing except to confirm my body is in a state of ketosis. :-/

    In the next 30 days, more testing to come with the immunologist, an endocrinologist, and the biochemical geneticist.

    With regard to my B12 deficiency/malabsorption/pathway blockage problem, you should be aware that the widely used serum B12 test would not show any pathology as a result of B12 not being absorbed into the cells. This was the case for me.

    Adequate levels of B12 are essential for proper metabolic processing of at least carbs and food cholesterol. The MMA (urine or blood), serum Homocysteine and folate tests will provide this information, allowing one to rule out a B12 cellular-level dysmetabolism connection.

    In my case, the bioactive B12s—both Methylcobalamin and Adenosylcobalamin—demonstrably mitigate the post-carb numbness, and to a significant degree.

    From my latest medical write-up:

    As has been reported in the scientific literature, high-dose vitamin B-12 can overcome pathway deficits in some patients, perhaps related to the more recent finding that B-12 cofactors Methylcobalamin (MeCbl) or Adenosylcobalamin (AdoCbl) may have a significant stabilizing effect on the MMACHC (cobalamin C) protein. In this patient’s case, repletion and ongoing titration with MeCbl and AdoCbl, and B-9 Methylfolate (MeFolate) in therapeutic doses begun in 2014 initially resulted in dramatic biochemical and clinical improvement.

    However, accumulated neurologic deficits have progressed to the severe level with a January 2018 Dx of severe SMPN with axonal features and denervation. Nonetheless, in mid-2016, adoption of a fat-oriented very low carb ketogenic diet to bypass the dysfunctional carbohydrate metabolic pathway has further slowed accumulating deficits. Currently, MeCbl is administered subQ: 0.45 cc every day @ 25 mg/mL. AdoCbl and MeFolate are given orally @ 1.5 mg and 1.6 mg, respectively, every day.

    Importantly, a diagnostic clue may be found in the lack of effectiveness of the standard-of-care Cyanocobalamin (CyCbl) and the dramatic therapeutic response to B-12 cofactor repletion (MeCbl, AdoCbl). It may indicate the end stage cobalamin pathway reduction is never realized because from a CyCbl administration for the patient neither the cytoplasm methylation to form MeCbl, nor mitochondrial adenosylation to form AdoCbl occurs. Alternatively, it may suggest the effectiveness of the MeCbl repletion is also a function of the applied cellular methylation by influencing gene expression. For example, hypermethylation is a process now known to improve some systemic diabetes manifestations.


    Looking ahead toward new investigative paths, here is a list of (my top four) candidates. Again, from my monthly medical summary document:


    Best Lay Differential Assertions on the Pathology

    Over the past several years, in discussion with physicians, four of the most likely disease candidates have driven much of the diagnostic testing.

    1) A late-onset inborn error of B-12 metabolism, subclinical until the 6th decade of life, interrupting the cobalamin pathway before final reduction to its cofactors in the lysosome. This explanation correlates best with the clinical features: the presence of the characteristic B-12 deficiency triad of neurological, hematological, and psychiatric symptoms; dramatic clinical response to B12 cofactors MeCbl and AdoCbl but not standard of care CyCbl; foamy transformed macrophages; connective tissue disturbances; chronic low alkaline phosphatase (may suggest the liver is not storing B-12--a B-12 recycling failure); dysfunctional carbohydrate and cholesterol metabolism due to insufficient B-12 thereby giving rise to interrupted cellular signaling; severe neurological complications upon disease progression; and other manifestations.

    Further, the clinical phenotype is consistent with an error of cobalamin recycling/transport: subacute onset and slow progression; multi-system involvement; a decrease in motor and sensory NCV; distal axonopathy; muscle weakness, fasciculations, ataxia; initially thrombocytopenia, then developing pancytopenia; and psychiatric disturbances.

    2) Paraneoplastic Syndrome (PNS). The PNS effect has likely been present since birth. Initially a cyst perturbing the B-12 and perhaps other nutrient pathways, it evolved into an RCC circa 2010 having multi-system effects due to the secretion of hormones and cytokines by an immune response or from the tumor itself.

    A 1.3 cm renal mass extending from the lower pole of the R kidney, cryoablated in Nov 2016. The mass was observed 10 years earlier on a CT scan as a cyst. Four days after cryoablation, chronic hip dermal lesions spontaneously resolved suggesting a paraneoplastic response, consistent with the patient’s dysmetabolism syndrome. A PET scan of June 2017 for evidence of renal cancer found no indication of neoplasm. A carbohydrate challenge in August 2017 demonstrated a less severe acute dysmetabolic reaction. Of late, chronic thrombocytopenia and transient cytopenias may have stabilized.

    3) A small intestine bacterial overgrowth, inhibiting absorption of B-12. Multiple past infections of Candida Albicans; past stomach parasitic infection from unwashed fruit; one year living in rural Southeast Asia, sometimes consuming local food.

    A carbohydrate dysmetabolism that in this patient introduces a greater systemic disturbance than a food cholesterol dysmetabolism is consistent with a SIBO clinical phenotype. However, a 2017 SIBO test (hydrogen only) was negative.

    4) A storage disease, possibly lysosomal. Cobalamin utilization depends on its efficient transit through the intracellular lysosomal compartment and subsequent delivery to the cytosol and mitochondria. Lysosomal dysfunction may impair lysosomal cobalamin transport. Enzymopathy could result in the improper catabolism of carbohydrates and cholesterol with the resulting accumulation of organelle debris disrupting the cellular uptake of cobalamin.

    Foamy transformed macrophages, typical in lysosomal storage disorders and B12 deficiency, were present in a 2012 rib lesion biopsy of an exceedingly rare bone xanthoma, subsequently resected. However, a hepatic transplant physician expressed the opinion, upon reviewing the results of the liver biopsy, that neither a storage disease nor a primary hepatic condition was a likely cause of the metabolic dysfunction.


    I'll pass on more information after the upcoming consults. Take care.
     
    #20 ChetRoi, Apr 16, 2018 at 4:35 PM
    Last edited: Apr 16, 2018
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