Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)

[Valentijn]

@Valentijn

Did you have a Lyme treatment before you got CFS?

No, I had a virus at onset.

 

[PinkPanda]

I don't know much about the medical/drug stuff.

I've been looking into choline/acetylcholine because I think it might be an issue in ME/CFS. I'm unsure wether it's better to improve body-own choline production (requires SAM-e) via more methylation with folate, B12 or to take choline directly.
I've started supplementing choline again a few days ago. It's not bad but I sometimes develop a feeling of hypoglykemia/weakness without actually having low blood-sugar.

The biochemical stuff:

Acetylcholine regulates insulin secretion in the pancreas (Study1). It activates the enzyme phospholipase C in pancreatic cells which leads to calcium release which triggers insulin secretion.
There is another study that also finds acetylcholine to increase somatostatin release, an inhibitor of insulin. They say acetylcholine 'regulates' insulin excretion (Study2). So I'm unsure where that leaves acetylcholine effects on insulin on the whole, but there also definitely seems to be some stimulatory action.

Also, choline can reduce alanine transaminase activity and improve liver function. Wikipedia says one sign of choline deficiency is elevated ALT.
Choline deficiency causes reversible hepatic abnormalities in patients receiving parenteral nutrition: proof of a human choline requirement: a placebo-controlled trial.
If lower ALT activity reduces alanine levels, then choline might be helpful.


I think the form I tolerate best is the watersoluble choline bitartrate. I take extremely low doses though, because of this hypoglykemia feeling. Here is also a list of choline forms found in foods. It seems spices and herbs as well as some fruit and vegetables have higher levels of free choline in comparison to other forms.

So maybe choline/acetylcholine (synthesis) might be something to look into on the side, in addition to drugs etc.
https://www.ncbi.nlm.nih.gov/pubmed/11531217

 

[Jenny TipsforME]

Or I could get whole exome testing done, which is down to US$400 now

I wonder if this is just worth doing for the long run (as in I'm also considering). Then whenever a possible issue is raised we could quickly check for relevant SNPs (I think better than a fishing expedition with that amount of data).

I'm actually a bit furious that the urine testing was only for a single SNP

Because yes healthcare systems are very frustrating at either avoiding genetic testing or only partially testing by picking out a couple of SNPs.

 

[Nickster]

You have been thru a lot of testing (I completely understand they just want one more test and on and on). Have they given any advice on treatments? Do they have anything to help?
Wishing you the best @Valentijn

 

[Jenny TipsforME]

@Valentijn btw how do you get direct-to-consumer exome sequencing for $400? I know I've read about it but can't find now.

 

[Valentijn]

@Valentijn btw how do you get direct-to-consumer exome sequencing for $400? I know I've read about it but can't find now.

http://forums.phoenixrising.me/index.php?threads/new-exome-testing-400.48137/

 

[Jenny TipsforME]

@Valentijn thanks

 

[Jenny TipsforME]

Oh it's $499 now I wonder if it was on an offer before?

 

[pattismith]

Did your mitochondrial clinician give you a reason for why he/she was ruling out MELAS despite your elevated alanine and lactate levels?

The negative result for 3243 in the genetic urine test, and my height and weight not being below average. Also that my lactate didn't get sky high from walking up and down the stairs, and he didn't seem to be interested in it staying high for at least 6 hours afterward.

@Valentijn ,

I'm sorry that your mito specialist didn't take seriously into account this possibility.

Would you explain to me what is the genetic urine test?

I just wonder, when you were to the mito specialist, did you stop all your supplements a long time before in order not to interfer with the blood tests?

 

[Valentijn]

Would you explain to me what is the genetic urine test?

According to their website, it tests for the most common MELAS mutation, 3243. It indicates how much of the mutated form is present compared to the non-mutated form, so I expect it's primarily used in research to track progression or remission in response to interventions. Since it's the most common, it's pretty much the only mutation used in research.

So testing that way would catch many MELAS cases, but it wouldn't rule it out. Deletions, insertions, replications, and many other known and unknown mutations are also capable of causing MELAS, and that test would not catch any of them. The letter from the mitochondrial clinician to my endocrinologist said:

mDNA: geheel beoordeeld, geen mutaties gevonden

That translates to "mitochondrial DNA: fully reviewed, no mutations found". Perhaps the test was fully reviewed, but the mitochondrial DNA was not. And it seems deliberately misleading to phrase it as "no mutations found" when "mutation not found" would be more accurate for a test of a single mutation.

Maybe they have a different urine test which is more comprehensive and isn't listed anywhere, but that seems unlikely.

 

[pattismith]

@Valentijn , it doesn't sound that your mitochondrial clinician was really interested in finding new mitoD genetic mutations...to say the least...
I won't go to a mito specialist if they are all that kind...

What surprises me is that urine doesn't seem to be the sample were you can find lot's of cells and genetic material...
Mostly a few bladder/uretral cells !
I suppose that genetic specialists found it more acurate than blood, and less invasive than muscle biopsy......

 

[Nickster]

My son is seeing a Mito specialist in November for the first time. So we will see where that goes.

 

[Valentijn]

I finally found the study which included the weight of adult mitochondrial disease patients, from Newcastle University:

Habitual Physical Activity in Mitochondrial Disease

Shehnaz Apabhai , Grainne S. Gorman , Laura Sutton, Joanna L. Elson, Thomas Plötz, Douglass M. Turnbull, Michael I. Trenell

• Published: July 22, 2011
• https://doi.org/10.1371/journal.pone.0022294

Abstract
Purpose
Mitochondrial disease is the most common neuromuscular disease and has a profound impact upon daily life, disease and longevity. Exercise therapy has been shown to improve mitochondrial function in patients with mitochondrial disease. However, no information exists about the level of habitual physical activity of people with mitochondrial disease and its relationship with clinical phenotype.

Methods
Habitual physical activity, genotype and clinical presentations were assessed in 100 patients with mitochondrial disease. Comparisons were made with a control group individually matched by age, gender and BMI.

Results
Patients with mitochondrial disease had significantly lower levels of physical activity in comparison to matched people without mitochondrial disease (steps/day; 6883±3944 vs. 9924±4088, p = 0.001). 78% of the mitochondrial disease cohort did not achieve 10,000 steps per day and 48%were classified as overweight or obese. Mitochondrial disease was associated with less breaks in sedentary activity (Sedentary to Active Transitions, % per day; 13±0.03 vs. 14±0.03, p = 0.001) and an increase in sedentary bout duration (bout lengths / fraction of total sedentary time; 0.206±0.044 vs. 0.187±0.026, p = 0.001). After adjusting for covariates, higher physical activity was moderately associated with lower clinical disease burden (steps / day; rs = −0.49; 95% CI −0.33, −0.63, P<0.01). There were no systematic differences in physical activity between different genotypes mitochondrial disease.

Conclusions
These results demonstrate for the first time that low levels of physical activity are prominent in mitochondrial disease. Combined with a high prevalence of obesity, physical activity may constitute a significant and potentially modifiable risk factor in mitochondrial disease.

Twenty-eight per cent of the mitochondrial disease group were overweight (BMI 25–29.9 kg/m2) and 20% were obese (BMI ≥30 kg/m2); only 4% were underweight (BMI<18.5 kg/m2).

And a study from Japan which compares the characteristics of adult-onset with juvenile-onset patients:

MELAS: A nationwide prospective cohort study of 96 patients in Japan

Shuichi Yatsuga, Nataliya Povalko, Junko Nishioka, Koju Katayama, Noriko Kakimoto, Toyojiro Matsuishi, Tatsuyuki Kakuma, Yasutoshi Koga
and Taro Matsuoka for MELAS Study Group in Japan

ABSTRACT
Background: MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) (OMIM 540000) is the most dominant subtype of mitochondrial myopathy. The aim of this study was to determine the prevalence, natural course, and severity of MELAS.

Methods:
A prospective cohort study of 96 Japanese patients with MELAS was followed between June 2003 and April 2008. Patients with MELAS were identified and enrolled based on questionnaires administered to neurologists in Japan. MELAS was defined using the Japanese diagnostic criteria for MELAS. Two follow-up questionnaires were administered to neurologists managing MELAS patients at an interval of 5 years.

Results:
A prevalence of at least 0.58 (95% confidential interval (CI), 0.54–0.62)/100,000 was calculated for mitochondrial myopathy, whereas the prevalence of MELAS was 0.18 (95%CI, 0.02–0.34)/100,000 in the total population. MELAS patients were divided into two sub-groups: juvenile form and adult form. Stroke-like episodes, seizure and headache were the most frequent symptoms seen in both forms of MELAS. Short stature was significantly more frequent in the juvenile form, whereas hearing loss, cortical blindness and diabetes mellitus were significantly more frequent in the adult form. According to the Japanese mitochondrial disease rating scale, MELAS patients showed rapidly increasing scores (mean±standard deviation, 12.8±8.7) within 5 years from onset of the disease. According to a Kaplan–Meier analysis, the juvenile form was associated with a higher risk of death than the adult form (hazard ratio, 3.29; 95%CI, 1.32–8.20;p=0.0105).

Conclusions and General Significance:
We confirmed that MELAS shows a rapid degenerative progression within a 5-year interval and that this occurs in both the juvenile and the adult forms of MELAS and follows different natural courses. This article is part of a Special Issue entitled: Biochemistry of Mitochondria

 

[Creachur]

I had my followup appointment over a month ago, and I fear that I'm getting a bit of a brush off, considering the circumstances.

The mitochondrial clinician also seems to think that being of normal height (for an American, not a Dutchie) makes MELAS very unlikely, and that MELAS patients are typically underweight, not overweight. But research of adult mixed mitochondrial disease patients showed half were overweight, so I think he was making some inappropriate assumptions based on how MELAS presents in infancy or early childhood, versus in adults.

So he's saying MELAS is ruled out, and won't recommend a muscle biopsy and genetic test of it, but due to the alanine and fatty acids being elevated, he's ordered CPT2 genetic testing (blood) for a possible carnitine deficiency.

Hello Valentijn. Sorry your recent tests were not productive. I think it is relatively common for MELAS not to be diagnosed directly but for the diagnosis to be done on what might be called "circumstantial symptoms". It seems that gene problems such as m.3243A>G are not present in everyone with MELAS.

Your lab tests could lead on to other tests and so on. For this reason I would not aim to do these privately unless it's necessary. The carnitine deficiency they mention is useful because there are several conditions which can lead to secondary carnitine deficiency. Some say MELAS does but others (such as researcher Tarnopolsky) don't agree.

One thing I have found about my condition may be of interest to you. I had all the symptoms of MELAS but when I took supplements for MELAS I wasn't ever particularly well. To cut a long story short, I may have Propionic Acidemia or Methlymalonic Acidemia which causes a difficulty processing certain amino acids from protein in food or certain food additives. These conditions almost always lead to raised ammonia and raised lactate. One knock-on effect of PA/MMA is impaired function in Complex IV of the Electron Transport Chain which would essentially be a secondary form of MELAS. So the symptoms of PA/MMA can include symptoms associated with MELAS but which, unlike MELAS, are caused by a dietary problem. So, it really seems to be worth testing for other conditions.

 

[Creachur]

I also had elevated alanine in a blood amino acid test. In a urine test I had elevated unmetabolized fatty acids and they recommended vitamin B2 and carnitine.

Do you know how high alanine levels relate to alanine transaminase activity (ALT)? I guess high ALT activity would cause high alanine by conversion from glutamate+pyruvate? I just don't read it anywhere explicitly and am unsure because the enzyme goes in both directions..

As I understand it, ALT is a classic liver function test and is often a marker of liver inflammation perhaps from having a fatty liver. However the lab value has to be several times higher than normal for it to be significant. In other words mild elevation is not normally significant.

As an aside, if I had unmetabolised fatty acids in my urine I would want to know the cause rather than patch up the symptoms with supplements.

 

[Valentijn]

Your lab tests could lead on to other tests and so on. For this reason I would not aim to do these privately unless it's necessary. The carnitine deficiency they mention is useful because there are several conditions which can lead to secondary carnitine deficiency. Some say MELAS does but others (such as researcher Tarnopolsky) don't agree.

CPT2 has been ruled out now, and the doctor has already said he has no further recommendations for any other investigations. So that's it as far as the Dutch system is concerned, unless I can find another angle to start over from.

When the doctor called on Monday, I asked him about the urine test and he insisted it's one which tests for all mitochondrial genetic problems, not just 3243. I've asked him to send me all of my test results in the mail, since they aren't on the hospital's online patient site. I'm hoping that seeing all of the results (including normal ones) might help a bit more in ruling things out or indicating likely suspects. I should get those within two weeks.

I'm still not really trusting him. If they have an awesome urine test which can test for all mutations, deletions, etc, why do they not list it anywhere? Why do they recommend muscle biopsy testing as the gold standard for the paying (non-Dutch) customers instead? But the hardcopy of the test results should include enough information for me to figure out what test was really used.

 

[Creachur]

CPT2 has been ruled out now, and the doctor has already said he has no further recommendations for any other investigations. So that's it as far as the Dutch system is concerned, unless I can find another angle to start over from.

CPT2 is just one of many conditions which can cause carnitine deficiency. If your doc was testing for CPT2 then presumably they have established a carnitine deficiency exists. There are many other important conditions other than CPT2 in which carnitine becomes severely depleted.

If you want to read up on these diseases from a clinical point of view then the books I was going back to repeatedly include these titles (which can be browsed on Google Books):

(1) Inborn Metabolic Diseases: Diagnosis and Treatment ~ Saudubray (5e, 2012)
(2) Physician’s Guide to Diagnosis, Treatment & Follow-Up of Inherited Metabolic Diseases ~ Blau (2014)
(3) Inherited Metabolic Diseases: A Clinical Approach ~ Hoffman (2010)

 

[Valentijn]

CPT2 is just one of many conditions which can cause carnitine deficiency. If your doc was testing for CPT2 then presumably they have established a carnitine deficiency exists. There are many other important conditions other than CPT2 (such as my own PA/MMA) in which carnitine becomes severely depleted.

I don't think carnitine was measured directly, since it wasn't mentioned as an abnormal result. So he was probably just going off of the raised alanine and certain fatty acids. This is why I need to see my full results

 

[merylg]

Just came across this link about MELAS
http://discovery.ucl.ac.uk/135344/1/135344_MELAS Final Draf.pdf

 

[pattismith]

Just came across this link about MELAS
http://discovery.ucl.ac.uk/135344/1/135344_MELAS Final Draf.pdf

Many interesting points! I didn't know that MELAS could be associated with hypothyroid, and that thyroid supplementation may be detrimental to people with defective mitochondria!

It's important to notice the variability of the clinical aspect of the disease!

"The A3243G mutation of MTTL1 is manifest in four main syndromes:
(1) classical MELAS syndrome, as i llustrated in the current cases;
(2) maternally - inherited hereditary sensorineural deafness, diabetes mellitus, ataxia and deafness, but without stroke - like episodes;
(3) progressive external ophthalmoplegia; and
(4) limb weakness and exercise intolerance (5) . The highly variable clinical presentation, age at presentation and progression may be due to differences in the degree of heteroplasmy between tissues, due to variations in the threshold levels of mutant mtDNA required to cause cellular or organ malfunction, and perhaps due to the influence of the nuclear genome"


"We would therefore suggest that patients with MELAS syndrome should be monitored for the development of hyperthyroidism and aggressively treated, as this may precipitate a ‘bioenergetic crisis’ (32) . The introduction of levothyroxine in the treatment of hypothyroidism should likewise be carefully introduced. To protect against the development of oxidative stress, a combination of antioxidants, such as coenzym e Q10 and vitamins C, E an d K (33) , plus beta - blockade may be useful. Carvedilol may be an especially promising agent in this context, as it has alpha and beta - blocker properties, and as it has been shown to protect against mitochondrial oxidative stress in vitro and in vivo (34, 35) ."