A rare deficiency cfs/fm patients should consider

[Valentijn]

Another that I am Hetero for , and that seems to explain a lot.
AMPD1.
AMPD rs17602729 Alleles CT +- Hetero
Adenosine monophosphate deaminase deficiency type 1.

That mutation is pretty common when heterozygous (17% of Caucasians have it) and only pathogenic when homozygous.

 

[Loachi]

That mutation is pretty common when heterozygous (17% of Caucasians have it) and only pathogenic when homozygous.

The strange thing is that eg Wiki says that one of the options when having AMPD1 is to take D-Ribose (a mono-sacharide) that is one of the key components for making ATP....
On the other hand I read some reviews from CFS sufferers saying they notice a difference in energy .
Off course these reviews are worthless, ...
But then I find even a pubmed art. reporting positive results with CFS and Fibro patients.
https://www.ncbi.nlm.nih.gov/pubmed/17109576
While other statements that it would benefit athletic performance are broken down by studies that show no results on athletic performance on healthy people.
From one side, you could see a link........But if you stay objective , off course all this proves nothing. After all Ribose is a sugar, and pure candy gives energy to everybody.

 

[MrME/CFS++]

Here is a link that propose that heterozygous for CPT2 S113L and R503C may render individuals with symptoms.

https://www.ncbi.nlm.nih.gov/pubmed/10090476

I am hetero for rs74315294 (S113L), have ME/CFS and have all the symptoms in the article.

@Valentijn , this snp is showing in your rare mutations program, but not as pathogenic. Should it not? And the Rs shown in the rare mutation report for this allele is the old one. Just for your interest.

 

[Valentijn]

I am hetero for rs74315294 (S113L), have ME/CFS and have all the symptoms in the article.

The available research indicates it's only having an impact when homozygous or compound heterozygous.

@Valentijn , this snp is showing in your rare mutations program, but not as pathogenic.

Pathogenic status comes from the NIH database, which changes from time to time as entries get updated. Likely there was an update for that SNP which isn't in our program's database yet.

 

[MrME/CFS++]

The available research indicates it's only having an impact when homozygous or compound heterozygous.

I find a lot of research proposing for clinical possibility of symptoms with hetero (not compound) for S103R.

"CPT II deficiency may manifest clinically even in a person heterozygous for the S113L mutation"

found in research: http://www.nature.com/labinvest/journal/v83/n11/full/3780745a.html

wich again points to these three research articles:

https://www.ncbi.nlm.nih.gov/pubmed/9309694?dopt=Abstract&holding=npg
https://www.ncbi.nlm.nih.gov/pubmed/8358442?dopt=Abstract&holding=npg
and the one I mentioned in post above: https://www.ncbi.nlm.nih.gov/pubmed/10090476?dopt=Abstract&holding=npg

One other article says it this way:
"Heterozygous carriers for CPT2 mutations are generally asymptomatic; however, a few symptomatic heterozygotes have been reported."

https://www.genedx.com/wp-content/uploads/2013/01/info_sheet_cpt2.pdf

Here is an article that gives some evidence for two specific cases when other mutation in the gene was not found:

https://www.researchgate.net/public...ine_palmitoyltransferase_II_CPT_II_deficiency

...and what about all other incidences that is not reported because of loss of knowledge...

This article is a good one, wich shows with numbers that single mutation S113L also shows impaired fat oxidation under exercise. In the discussion part I find this:

"The primary findings of this investigation are that patients with CPT II deficiency are unable to increase longchain FAO (fat acid oxidation) during long-term, low-intensity cycle exercise, and that carriers of single CPT2 gene mutations also can have impaired fat oxidation during exercise, which may explain milder symptoms of CPT IIdeficiency in these subjects."

http://www.academia.edu/18753108/Fu...rnitine_palmitoyltransferase_2_gene_mutations

So not every available research indicate what you write.

It would certainly be great to check out this mutation with your doctor if you have heterozygous for it, and symptoms related to this disease.

 

[MrME/CFS++]

I am currently being investigated for this as my 23andme results turned up a rare genetic mutation that can be a cause of CPT2 deficiency. My doctor hasn't heard of it but was willing to pursue testing for it. Because it is so rare the pathology lab didn't know what to do with the doctor's request so it is taking a little while to get sorted.

@Sea, what came out of your personal investigation regarding CTP2 deficiency? And are you heterozygous for S113L only? I asume that will require you to perform some exercise before some bloodwork to be done? Just curious how I should present this for my personal doctor...

 

[Valentijn]

When all of the heterozygous family members of the homozygous patients have no symptoms, it usually means that other heterozygous cases are really compound heterozygotes for which the 2nd mutation has not yet been found.

At the very least, testing would be needed to confirm the disease. The heterozygous mutation simply cannot be assumed to be causing the symptoms.

 

[MrME/CFS++]

As I said, I discovered my hetero for S113L through your rare SNP's software. Because it did not report back pathology in your software, I did not catch it. What made me invest it yesterday was that it reported a frequency of 1 percent (this was a 10% report). Further investigation on this gene today (23andme) shows that I am also homo for V368I (Rs 1799821) and hetero for Rs 1157883. Last one is intronic, and I dont know if it matters at all. Since 23andme data for most of CPT2 SNP's have internal numbers (not rsID), I have to studie further to see if there is more interesting in there.

From wiki I see that V368I have no impact alone, but with other mutation around it might worsen things. Also here they say that S113L hetero have reported cases with CPT2 deficiency.

https://en.wikipedia.org/wiki/Carnitine_palmitoyltransferase_II_deficiency

"Ser113Leu (338C>T) is the most common mild mutation observed in adult cases, it has an observed allelic frequency of 65% in adult cases, and both homozygous and heterozygous cases have been documented."

"Val368Ile and Met647Val are polymorphisms have been linked to CPT II deficiency. These genetic abnormalities alone do not directly cause the disorder, but they seem to exacerbate the reduction in enzymatic efficiency when combined with one or more primary CPT2 mutations."

It is well known to science that in some rare cases hereditary heterozygous mutations could develope disease in a milder way than homozygous for the same mutation. For CPT2 mutation S113L it looks like this could be the case.

But of course, until proven otherwise we dont know for sure. What we do know is that there are reported several CPT2 pasient cases of what researchers believe is hetero only for S113L.

 

[Sea]

@Sea, what came out of your personal investigation regarding CTP2 deficiency? And are you heterozygous for S113L only? I asume that will require you to perform some exercise before some bloodwork to be done? Just curious how I should present this for my personal doctor...

I had an Acylcarnitine profile done (blood test) while I was not ill with a virus or in pem from overdoing. It was mostly normal although my carnitine/acylcarnitine ratio was a little outside normal range. It would be worth doing again when in pem or otherwise not well or fasting.

I took some simple literature with me from the FOD website when I asked for the test. I had already shown my doctor my 23andme results for haemachromatosis when he had suggested having me tested for that so I didn't have the hurdle of trying to prove anything there.

I've just ordered a Genos whole exome sequencing test so it will be interesting to see what that turns up. 23andme doesn't test all the known pathological snps on the CPT2 gene.

I am also homozygous for the Val368Ile and hetero for Met647Val (or the other way around, I can't remember :thumbdown: )

For all the FODS they used to say only homozygous were affected, but as further investigations have been done they now say heterozygotes can also be affected, but to a lesser degree. As Val said, it could be because of another unknown mutation adding to the affect.

I also have a mutation on the ACADS gene known to cause problems with short chain fatty acid oxidation so I don't know whether that too makes a difference overall.

I haven't found a doctor who knows anything about CPT2 yet and it's been a bit lower on my priority list the last year while I've been busier with appointments for my daughter. It is still something I would like to follow up.

 

[Sea]

When all of the heterozygous family members of the homozygous patients have no symptoms, it usually means that other heterozygous cases are really compound heterozygotes for which the 2nd mutation has not yet been found.

At the very least, testing would be needed to confirm the disease. The heterozygous mutation simply cannot be assumed to be causing the symptoms.

While that is true, also, every patient can be affected differently even with the same mutations. Geneticists have moved away from classifying someone as mild or severe simply on the basis of which mutations are found and instead patients are categorised by testing percentage of enzyme function.

 

[Valentijn]

While that is true, also, every patient can be affected differently even with the same mutations. Geneticists have moved away from classifying someone as mild or severe simply on the basis of which mutations are found and instead patients are categorised by testing percentage of enzyme function.

Yeah, but testing is still required ... having the heterozygous mutation alone would be a very small "maybe". There's typically dozens of such "maybes" in genetic results, any of which could more or less explain symptoms. And given the tenuous connection for all of those, it's a bad idea to assume the puzzle is solved without appropriate diagnostic testing for that disease.