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Metabolic profiles in autism fit "purine-driven cell danger response" theory

natasa778

Senior Member
Messages
1,774
Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism

The metabolic pathways most distinctive of young Italian autistic children largely overlap with those found in rodent models of ASD following maternal immune activation or genetic manipulations. These results are consistent with the proposal of a purine-driven cell danger response, accompanied by overproduction of epileptogenic and excitotoxic quinolinic acid, large reductions in melatonin synthesis, and gut dysbiosis.

...

The “metabolome overview” obtained through metabolic pathway analysis (MetPA) shows tryptophan metabolism, purine metabolism, vitamin B6 metabolism, and phenylalanine-tyrosine-tryptophan biosynthesis as the four most perturbed metabolic pathways in ASD (Fig. 3).

...
Given the relevance of tryptophan-derived compounds in many neural functions, tryptophan metabolism was assessed in greater detail at the level of specific intermediates (Fig. 4):
  • The kynurenine pathway displays increases in xanthurenic acid and especially in quinolinic acid, paralleled by a considerable decrease in kynurenic acid...

  • The serotonin pathway shows a significant decrease in melatonin and its catabolite N-acetyl-5-methoxytryptamine...

  • Bacterial degradation of tryptophan yields in ASD, compared to controls, prominently larger urinary concentrations of indoxyl sulfate and other indole derivatives, including indolyl-3-acetic acid and especially indolyl lactate...
...

Purine metabolites are also well represented in the urines of ASD children, which display a large excess of inosine, hypoxanthine, and xanthosine (Figs. 3 and 5). This pattern bears an interesting resemblance to the excess of urinary inosine and hypoxanthine detected in Fmr1 knock-out mice, an animal model of fragile-X syndrome [35]. Also, mice exposed prenatally to MIA triggered by poly(I:C) injected at E12.5 and E17.5 show an excess of urinary inosine [36].

This excess of urinary purinergic metabolites has been interpreted as part of a “cell danger metabolic response” involving mitochondrial dysfunction, adenosine triphosphate (ATP), and adenosine diphosphate (ADP) release, activation of a variety of purinergic receptors yielding microglial activation, innate, and adaptive immunity responses and leukocyte chemotactics [65]. Inborn errors of purine metabolism are associated with behavioral abnormalities including autistic features [66]. Strikingly, inhibition of purine metabolism by suramin, a competitive antagonist at P2X and P2Y purinergic receptors, reverses behavioral, neurochemical, transcriptional, and metabolomics abnormalities both in the Fmr1 knock-out mouse and in MIA mice exposed to poly(I:C) during pregnancy [35, 36, 37]. Conceivably, this metabolic abnormality, shared between human ASD and genetic/immunological rodent models could thus represent a valuable biomarker to help guide therapeutic interventions.

In addition, the cell danger response also yields relative vitamin B6 deficiency and the enzyme kynureninase is B6 dependent [65]; hence, a cell danger metabolic response in the presence of adequate tryptophan intake could also explain the decreased kynurenine and increased xanthurenic and quinolinic acid observed here (Fig. 4). Interestingly, these abnormalities have been sometimes overcome with vitamin B6 supplementation [67], a therapeutic approach initially proposed for ASD in conjunction with magnesium supplementation [68]. In light of the present data, B6-Mg++ supplementation in ASD may deserve further scrutiny in urinary biomarker-driven therapeutic trials
 
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roller

wiggle jiggle
Messages
775
... purine driven cell danger response ...

with so much purine, tryptophan-failures and surinam, it seems worthwile to test spinal and urogenital fluid for all sort of protozoa (at least), no?

have they tested the children for any?
 

taniaaust1

Senior Member
Messages
13,054
Location
Sth Australia
Are there any studies or personal reports on B6-Mg++ supplementation in CFS/ME?

I did my own personal study on about 34? people here in the past and from that there was people here who were helped by B6 (though not many..I cant remember now it may of only been 2 or 3, half of us though here though are helped by one of the forms of B12 (from my results comparing lots of supplements we are all were on, I found B12 it be the most helpful supplement for ME)..

There was a few here who were helped by B2 or B3. I found that around 75% of us with ME are helped by one of the Bs.

I'm on the autism spectrum (aspergers). Ive had issues though with needing B12 and once the drs at hospital gave me a B3 injection for some reason unknown to me. I haven't found B6 in my case to be helpful, nor magnesium to be helpful at all.
 
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Messages
15,786
Are there any studies or personal reports on B6-Mg++ supplementation in CFS/ME?
There might be something. I think both were prescribed to me by a specialist at a Dutch fatigue clinic right before they went fully BPS. So he probably had some sort of basis for it.

Personally, I find magnesium helpful, but only for avoiding muscle twitches and cramps.
 

Solstice

Senior Member
Messages
641
There might be something. I think both were prescribed to me by a specialist at a Dutch fatigue clinic right before they went fully BPS. So he probably had some sort of basis for it.

Personally, I find magnesium helpful, but only for avoiding muscle twitches and cramps.

Almere?
 

ahmo

Senior Member
Messages
4,805
Location
Northcoast NSW, Australia
Are there any studies or personal reports on B6-Mg++ supplementation in CFS/ME?
Both are important for me. I'd taken B6 for years, before ME. When I finally found and switched to P5P version, there was a big shift, especially in my emotional climate. And these last weeks I've been in a very stressful situation, and have needed extra, large amounts of mg daily. I know I need more when I start getting cramps in hands or feet.
 

PennyIA

Senior Member
Messages
728
Location
Iowa
Very interesting. I didn't understand half of it... but I cannot tolerate any doses of B6 nor magnesium (though Epsom soaks work well from treating the cramping). And I have been diagnosed with gout post-MTHFR treatment where my purine levels keep flaring in uric acid issues.
 

pibee

Senior Member
Messages
304
Naviaux specifically addressed the B6/Mg issue in one of his Q&A noting that ME/CFS patients can't tolerate the doses that babies with normal mitochondrial diseases tolerate easily.

Very interesting. I thought I was the only person on the planet to feel worse from Magnesium even, because I talked to quite a few pwME who dont feel bad and have a deficiency (based on my RBC Mg i dont have it, it was even perfect).
I also dont take absolutely any other supplements, because all make me feel worse, after 2-3 days.

Naviaux:
Q10. If all roads lead to mitochondria in CFS, are there “mito cocktails” or supplements I can take now that could help me while scientists are working out more definitive treatments?

We have learned through hard experience that the answer to this question is not simple. Many patients with CFS have suffered for years or decades. Their metabolic reserves are severely depleted. We have found that if we give the same mito cocktails that we give to patients with genetic forms of mitochondrial disease, the jolt is too much for most people with CFS and they experience a paradoxical flare in their symptoms. Just a simple thing like taking just 25 mg of vitamin B6 and 100 mg of magnesium can send some people into heart palpitations and a feeling of being unwell for hours after a single dose, while a baby with a mitochondrial disease takes twice this much every day without difficulty.

The guiding philosophy to starting any new treatment for CFS is to “Start low, and go slow.” A helpful analogy is to think of metabolism in CFS like a car that has not been used all winter and all the gas and fluids are gone or low. If you try to start the engine before the fuel tank and fluids are topped off you can do damage. I think that effective treatments for CFS will ultimately require a 2-step process. First, we have to refill the metabolic tank, then we need to turn the key. The first step will be guided by personal metabolomics testing. The second step will be based on new discoveries in the lab that have focused on the role of mitokines that maintain the cell danger response in CFS and other disorders. Mitokines are signaling molecules that trace to mitochondria. They have metabolic functions inside the cell, and informational functions outside the cell.