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A rare deficiency cfs/fm patients should consider

Discussion in 'Diagnostic Guidelines and Laboratory Testing' started by Ambrosia_angel, Jan 29, 2014.

  1. Sea

    Sea Senior Member

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    Yes those last two in the chart are the two common ones that I have with 50% and 25% frequency respectively. They are known as secondary mutations and are known to reduce the activity of the enzyme even further if there are primary mutations.

    In one of the studied rare mutations (not the one I have) enzyme activity is reduced to 70% without the common mutation and 30% with. The rare mutation I have reduces the enzyme activity to somewhere between 10% - 20% by itself. I haven't been able to find what effect the common one has with my mutation but I am presuming it will also have some effect.
     
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  2. Sea

    Sea Senior Member

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    To add to Ambrosia's first post with symptoms and clinical picture:

    Researchers are still learning about this as it is very rare. The older literature says this is a recessive disorder that will only manifest in those who are homozygous for a rare mutation. As more cases have been investigated though it has become evident that those who are heterozygous or compound heterozygous can also be affected.

    This was discovered when testing parents of severely affected homozygous infants or children and finding out that their heterozygous parents sometimes had symptoms as well, ranging from mild to quite life altering.

    Also, at first there was a belief that there were "episodes" following various triggers and a complete return to normal in between. That too has been proven not to be the case with some people having chronic symptoms.
     
  3. Pajk

    Pajk

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    I have had had CFS symptoms for 3 years. I am 48 years old. Prior to becoming symptomatic I was a distance runner racing competitively at local level until age 45. Recently it was discovered I was heterozygous for cpt2 c.338c>T [p.Ser113Leu] mutation. I too wonder about how many individuals with sudden onset of symptoms suffer from this mutation. Moreover, I tested very low for GLA enzyme associated with fabry disease but did not have the mutation associated with that illness. I have positive ANA and RNP (both low) as well.
     
  4. Valentijn

    Valentijn Activity Level: 3

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    @Pajk - CPT2 S113L will only have an impact if you're homozygous for it, or compound heterozygous with another pathogenic missense mutation on the same gene.
     
  5. Pajk

    Pajk

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    Valentijn -Thank you for your feedback. Yes - they could not definitively say I have cpt2 deficiency due to single mutation. However, The geneticist who found the mutation explained it's possible that I do have cpt2 deficiency as they simply don't know enough about affects of single mutation, at this point. My father, and his mother, were afflicted with similar symptoms. A biopsy has been recommended. Muscle MRI showed mild myopathy -non specific.
     
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  6. Isaiah 58:11

    Isaiah 58:11

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    A Sun-Scorched Land
    I'm late to this party, but I thought I would toss in that my mother was given a printout of CPT2 because someone thought she may be affected. She has been unable to get any follow-up on that.

    I am intensely interested in this not only for her, but because I have many of the same symptoms and have a lab-confirmed carnitine deficiency (last labs: Esterified/Free 2.3 High Ratio 0.1 - 0.9 Esterified/Free Ratio is a calculated value equal to Total Carnitine minus Free Carnitine divided by the Free Carnitine.) and must take 2 grams acetyl-l carnitine daily. About a year after I first became ill, a trip to the ER revealed that my CPK levels were 2800; it was suggested that I had a neuromuscular degenerative disorder, but the specialist I was referred to only saw muscular dystrophy patients...

    Most doctors never cared, but over the past decade I found two to at least run the CK test since I still had the same symptoms (that do wax and wane) but both times it was normal. In November, however, I had a crash after going to a meditative yoga class (strenuous, right? ;)) and my new neurologist drew my CK the following week: Creatine Kinase 1205 H 29 143 IU/L. Ten years after the first test someone finally caught it high again.

    I am certain it has been as issue the entire time.

    I think there may be something to this... I have had my 23andMe done if someone wants to look at my SNPs for this.
     
  7. Sea

    Sea Senior Member

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    It is common in all the Fatty Acid Oxidation Disorders for the CK only to be high in crisis. That is, when a person is otherwise sick or has exercised at what is a strenuous level for them. The high level indicates some breakdown of muscle tissue. I've seen values in excess of 50 000 being reported in people with metabolic disorders though so even though yours is out of range high it wouldn't be at a level that would typically concern doctors.

    Have you looked at the chart Valentijn put up on this thread with others results for the CPT2 gene and seen how yours compares? Unfortunately 23andme doesn't test for all the pathogenic snps on this gene.

    Unless you want to pay for a complete gene sequencing a first step for getting a doctor interested is to have an Acylcarnitine profile blood test done. It looks at the composition and levels of fatty acids in the blood. Raised levels of various fatty acids point to different metabolic disorders. Unfortunately though, this test will sometimes only show abnormalities when the system is stressed - by illness or fasting
     
  8. Isaiah 58:11

    Isaiah 58:11

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    Thank you for your reply. :) I am sorry that I was not clear. I am not intending to state that I believe I have CPT2 specifically, just that I think that there may be some sort of carnitine issue involved with the possible mitochondrial problems that seem as if they could be connected to this disease. Especially as CPT2 tends to occur severely, at a younger age (I think I recall reading that at least), and in males. (Personally, I see carnitine deficiency as a downstream issue in my illness, but I am far from qualified to make a judgement on that.)

    I don't know what my CK levels are in an actual crash as I have only had them done a week or two following for the ones that showed high, though I am sure they are not that high. (My ER doc said marathoners go up to about 20000 and I can only imagine that a disease state would bring them even higher, like to the 50000 you mentioned.)

    I have had an acrylcarnitine profile done (while on an upswing): that is when I was told to take the 2 grams of carnitine per day, because it was abnormal.

    I don't feel the need for further genetic testing, especially as I don't think that I have this exact disorder and was just suggesting that carnitine is something that may be involved in ME/CFS in some way, at least for some people. (I did see some carnitine abnormalities in posted lab work in the thread about Myhill's mitochondrial testing after writing my above comment, so at least I am not alone in this.) I was just offering up the information if someone wanted to look further for their own investigations. I did check the specific SNP first mentioned on page 1 of this thread out of curiosity, but that was not on the test chip used for my sequencing. As I looked over CPT2 I noticed that I had a handful of +-, but not any that were known pathogenic alleles (I think these are recessive problems anyway?) and I did not check any of the homozygous ones to see if they were the rare allele rather than the ancestral.

    I hope that clears up my first comment, but my brain is muddled, so it is probably as clear as mud. So, just in case, a recap: I have a carnitine deficiency, I think they may be more common than most people realize, but I do not think I have CPT2.
     
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  9. Sea

    Sea Senior Member

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    @Isaiah 58:11 There are also genetic mutations that are a primary cause of carnitine deficiency that might be worth your while looking into seeing as you say that you have similar symptoms to your mother.

    With regards to the severity and age of onset of metabolic disorders it is clear that there are some mutations which cause an infantile onset and can be quickly fatal without medical intervention but there are others which may not show up until adulthood or until a serious illness overwhelms the body's capacity to function normally. Many people now diagnosed as infants through newborn screening may previously have died for unknown reasons or not ever been diagnosed if they had a mutation with a mild effect.

    Research on these disorders really still is in its infancy. Individually they are rare, but realistically with so many rare disorders it is not so unlikely to find you have one.
     
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  10. out2lunch

    out2lunch Senior Member

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    My concerns involve the other side of the coin, i.e., carnitine being increased. My latest lab work came back with serum carnitine, both total and free, being elevated (Total: 100 umol/L, range 25 - 69; Free: 62 umol/L, range 16 - 60).

    I don't supplement carnitine and I don't have cardiovascular disease such as cardiomyopathy, which is a common cause of elevated carnitine.

    I read about CPT2 deficiency on several med sites and elevated carnitine was listed as an indicator.

    So I'm not sure why a carnitine deficiency would be connected to a CPT deficiency. :confused:
     
  11. Sea

    Sea Senior Member

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    Usually it is acylcarnitines which are elevated rather than free carnitine. It changes the normal ratio which is one indicator that is looked for.
     
  12. out2lunch

    out2lunch Senior Member

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    Well, it turns out that CPT2 deficiency does not increase serum carnitine. Just the opposite. It's CPT1 (primarily CPT1a) deficiency that causes serum carnitine to increase. I got them mixed up in reading an article about CPT deficiency in general.

    So I'm still stuck as to why my serum carnitine is so high. I do eat meat, including the darker flesh types like beef and buffalo, and small amounts of dairy. But it's not like I'm eating an 8 oz sirloin steak every night. Diet alone doesn't explain these numbers.

    The only three causes I can pin down for elevated carnitine are cardiomyopathy, renal disease, and CPT1 deficiency. First two were ruled out last year through extensive testing, but not the third. However, CPT1 deficiency is genetic and expresses itself in early childhood. If this was a deficiency of CPT1, why would someone my age (late 50s) be having these problems now? :confused: Doesn't make any sense.
     
  13. Sea

    Sea Senior Member

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    Google CPT1 deficiency adult onset and you will find it is not necessarily only discovered in childhood. Some of the milder mutations (ie higher percentage of enzyme activity) don't show up until the body is no longer functioning optimally in other areas.
     
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  14. out2lunch

    out2lunch Senior Member

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    Nope. You're making the exact same mistake I did. You're retrieving info on CPT II instead of CPT I.

    There is no milder adult variant for CPT I. And CPT II creates a deficiency of carnitine, not excess.

    The only causes of elevated carnitine are congestive heart failure and cardiomyopathy, stage 3 -5 chronic kidney disease, and a deficiency of the CPT I enzyme. That's it.

    I don't have heart disease; echo stress test ruled that out less than a year ago.

    I don't have stage 3 CKD; creatinine levels remain normal.

    And I don't have any of the symptoms associated with CPT I deficiency, which are pretty severe.

    So either Labcorp screwed up and gave me some other patient's test result (it's happened before), or my liver is starting to lose its ability to produce the CPT I enzyme. Given the other problems I have with severe drug and chemical sensitivities, I wouldn't rule out the latter. But my past experience with Labcorp tells me it's probably the former. Guess I need to retest.
     
  15. Sea

    Sea Senior Member

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  16. out2lunch

    out2lunch Senior Member

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    Yes, I saw the reference. But the authors didn't even know if the genetic variant was responsible for the symptoms found in one individual of a particular ethnic origin:
    • Adult-onset myopathy. In a single individual of Inuit origin who was homozygous for the p.Pro479Leu pathogenic variant, the presenting feature was a history of exercise-induced sudden-onset muscle cramping with no indication of hypoglycemia or hepatic failure. There is some doubt as to whether this myopathic presentation is related to the genetic alteration.

    One lone Inuit adult was found to have the genetic variant. No other record exists anywhere of adults being diagnosed decades beyond childhood with this disorder. So the likelihood of this being my problem is far greater than the odds of winning the lottery.

    Sorry for snapping, but this is the kind of cherry-picking of medical info that drives me crazy! Homozygous adults not diagnosed in childhood do not exist. Heterozygous adults are asymptomatic carriers, which means they don't have elevated carnitine levels like the homozygous children. But more to the point… no way any insurance will cover CPT I genetic testing for someone pushing 60. So why bother dwelling on something that statistically does not exist?
     
  17. out2lunch

    out2lunch Senior Member

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    Also from the link:

    Testing
    Hypoglycemia, absent or low levels of ketones, elevated liver transaminases, elevated serum ammonia concentration, and elevated total serum carnitine are typical laboratory findings.

    Hypoketotic hypoglycemia. In most cases, hypoketotic hypoglycemia is defined as low blood glucose concentration (<40 mg/dL) in the absence of ketone bodies in the urine.

    Hepatic encephalopathy includes liver enzymes AST and ALT that are two- to tenfold the upper limit of normal and hyperammonemia (i.e., plasma ammonia concentrations usually 100-500 µmol/L [normal: <70 µmol/L]).

    Elevated total serum carnitine. The total serum carnitine concentration may be elevated, in the range of 70-170 µmol/L (normal total serum carnitine: 25-69 µmol/L). The elevation of total carnitine hypoketotic hypoglycemia should increase suspicion specifically for CPT1A deficiency.​


    Yes, my elevated total serum carnitine falls within the reported range for this disease. However…

    I don't have hypoglycemia. I don't have low levels of ketones. I don't have elevated liver transaminases. And I don't have elevated serum ammonia. Just the elevated total serum carnitine.

    I don't know why I have the elevated carnitine. But CPT I deficiency is obviously not the cause.
     
  18. Valentijn

    Valentijn Activity Level: 3

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    Ethnicity is really not relevant to how a SNP acts. Pathogenic is pathogenic.

    You are correct that there are often errors made in genetic associations based entirely upon a single case for a disease. But a proline/leucine swap scores -3 on a BLOSUM62 chart, on a scale of -4 to +4, with -4 being the worst. So those are two amino acids which behave very very differently from each other, which increases the risk that the altered protein breaks down at a very different rate, or otherwise doesn't function normally.

    They seem to exist for many diseases, where they were previously thought not to exist. Usually it is a different, less severe mutation. Because it is typically a slow onset in those cases, it's not as apparent as newborns dropping dead, and is probably then very unlikely to be investigated as a genetic issue.

    Again, not always, according to other diseases where something happens and a subclinical reduction in function suddenly becomes very pronounced. Some known triggers in other diseases include hypoxia, infection, prolonged infection, and other types of severe biological stress. And in some cases a small percentage of carriers for a disease will have very mild symptoms of the disease.

    Anyhow, keep in mind that genetic research is very much in its infancy. Thanks to emerging technology, it is growing rapidly. But knowledge gaps are likely to remain for a while, especially for less-common diseases, and for manifestations of those diseases which are less deadly or less clear-cut.
     
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  19. out2lunch

    out2lunch Senior Member

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    So if I want to see if I'm a carrier with mild symptoms of the disease, I'm going to have to pay for the gene testing myself. Not sure it's worth the expense at this time, since there's no cure and the treatment regardless of genetic defect or not is the same: consume less carnitine, i.e., more carbs, less meat.
     

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