Friday, December 3, 2010

Brain Efficiency, Pediatric Edition

Back in November, I wrote a post titled Brain Efficiency that detailed some of the links between mitochondrial dysfunction and Parkinson's Disease.  The mitochondria are the energy powerhouses of the cells, cranking out ATP (cell gasoline) to keep pace with all our cells need to do. 

Classically, mitochondrial dysfunction was felt to be relatively rare, and it was usually investigated in cases of chronic fatigue, unexplained muscle weakness, that sort of thing - we medical types are a literal lot.  "Goodness, you have no energy?  Maybe we should see if your cells can make energy."   

However, my readers know that that pile of gelatin quivering between your ears is one of the most energy hungry parts of the human body.  It is 5% of our body weight, but comprises 20% of our metabolism.  Therefore, any genetic predisposition to dysfunctional mitochondria may show up was a brain problem.

Earlier this week, this article was published in JAMA, "Mitochondrial dysfunction in autism." This is the first study to examine the function of mitochondria in a well-defined population of children with autism, which is a disorder that strikes in infancy to early childhood and can result in poor social skills, developmental delay, and stereotypical repetitive movements among other symptoms.  It was a small study, 10 children diagnosed with full spectrum autistic disorder and 10 controls, but they examined everything soup to nuts, as it were.

The children and their cells were examined for problems with mitochondrial DNA, the actual energy-generating capacity of their actual mitochondria (lymphocytes* were put on ice and immediately taken to a lab to measure the respiration!), and for signs of leftover metabolic garbage hanging around.  The results were pretty remarkable. 


Cell respiration (mitochondrial capacity to take glucose (or ketones!) and oxygen and turn it into energy) can be measured by the amount of input of fuel and output of the byproducts of respiration.  I'm not the most mechanical of people, but I imagine measuring cell respiration has the automotive equivalent of measuring horsepower.  Some of us have Ferraris, others Ford Festivas, and most will be somewhere in between.  The autistic kids had lower average NADH oxidase activity - their average was 4.4 (95% CI, 2.8-6) as opposed to 12 (95% CI, 8-16) in the control kids, and the majority of the autistic kids had levels that were below the range of the control kids.  The mitochondria of the autistic kids seemed to putter along, compared to the more zippy mitochondria of the control kids. 

Now let's look at some metabolic byproducts of slow or inefficient cell respiration.  Higher pyruvate levels were found in the autistic kids (pyruvate levels should be relatively low if your mitochondria are efficiently processing oxygen and glucose) than in controls (0.23 vs 0.08), and 8 out of the 10 autistic kids had pyruvate levels higher than any of the controls.  This finding matched the decreased amount of pyruvate dehydrogenase activity found in the autistic kids.   Levels of hydrogen peroxide were also higher in autistic kids.  

At a genetic level, the kids with autism had a lot more copies of mitochondrial DNA in their cells.  (Our mitochondria are probably evolved from energy-producing bacteria that another ingenious and cheeky cell gobbled up long, long ago to create its own internal power plant.  Therefore our mitochondria, within our big old animal cells, have their own DNA called "mitochondrial DNA."  This mDNA (also sometimes called mtDNA) is inherited from our mother, and her mother, and her mother etc. etc. back to that first precocious gobbling cell, as we get all our cell organelles from our mother's egg, and only a bit of good old human DNA from Dad.).  An average human cell mitochondria has 2-10 copies of its DNA hanging around.  5 of the autistic kids had more mDNA than expected.  2 of the autistic kids also had deletions of certain areas of their mitochondrial DNA.

So what does all this data mean?  It was felt, all told, that the autistic children had cells that were in a state of chronic oxidative stress.  This would explain not only the respiration issues, but also the higher copies of mitochondrial DNA, made either due to errors from free radical damage, or to compensate for the inefficient mitochondria.  But don't jump to conclusions.  We don't know if mitochondrial dysfunction is the cause of autism, or one of the myriad effects.  Maybe the kids were born with Ferraris, but adulterants in the fuel causes it to run like a Ford Festiva.  It also make sense, as we know the brain needs  efficient mitochondria motoring along to keep all those ion gradients that power thinking online, that inherited defects in mitochondria could leave one more vulnerable to developmental insults and problems as the brain forms.

This finding could relate to modern diets and habits in all sorts of ways.  It occurs to me that one stand-out epidemiologic link to increased rates of autism is in kids whose moms had gestational diabetes, so presumably higher glucose, insulin, and other neuronal hardships for the developing baby.  We also know that ketosis helps mitochondrial efficiency and promotes neurogenesis and neuronal repair - vitamin D also has a role in promoting neuronal repair.    And inflammation in general would require mitochondria to be in tip top shape to keep up with the metabolic requirements and clean-up. 

I love it when a little more information comes along in real time to add a piece to the puzzle.

*lymphocytes are cells of the immune systems and easily sampled from a simple blood test, compared to painful muscle biopsies or scary brain biopsies.  Since lymphocytes use equal amounts glycolysis and oxidative phosphorylation to make energy, it was felt they would be a fair tissue to use to measure oxidative capacity of the cells of the autistic children versus the control children.

9 comments:

  1. Awesome post! Your statement "It is 5% of our body weight, but comprises 20% of our metabolism. Therefore, any genetic predisposition to dysfunctional mitochondria may show up was a brain problem." reminds me of what Seth Roberts says about how simple mental functioning tests can be so telling about our metabolic health.

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  2. Fascinating study. However, the authors seem to infer that the mutations causing autism might be in mDNA (maybe I'm wrong). I have my doubts, as the vast majority of traits seem to be coded for (i.e., influenced) by nuclear DNA. In fact, the structure and function of the mitochondria themselves are largely coded by nuclear DNA, not mDNA.

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  3. Ned, the authors hemmed and hawed a bit over the reasoning behind the extra mitochondrial DNA - I think they felt it was more a sign of the oxidative stress than a cause of the problem. Poorly functioning mitochondria => lots of free radicals => errors in DNA replication of any DNA that is hanging around. The deletion they found was for cytochrome b in both the kids who had a deletion. Not sure if that has any meaning whatsoever.

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  4. remember the recent (first) court case a mother of an autistic son won against a vaccination company? iirc the finding was that the vaccines caused massive damage to the immune system because the child had defective mitochondria (or somethign like that). autism in this magnitude is a rather recent phenomenon and we should ask us what has changed in the last 100 years. i'd day its a combination of vitamin D deficiency of the mother (and later, of the child), a ridiculous number of vaccinations very early in life, environmental toxins (mainly mercury, Pb), food allergies, food quality, gut problems. see dr hymans approach for example: http://is.gd/i9rLO

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  5. That is properly cool. Thanks Emily... I'm going to have several rereads of this to spark up my thinking a bit more. But put petrol into a diesel engine and see what happens. That might be the case here!

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  6. Thanks Emily - interesting stuff.

    Have you read Dr Kenneth Bock's book "Healing the New Childhood Epidemics, Autism, ADHD, Asthma and Allergies"?
    His approach looks at all these contributing factors and tries to rectify them: modern toxins, nutritional deficiencies, metabolic imbalances, genetic vulnerabilities, assaults on immune and gastrointestinal systems.

    I wondered what your thoughts are on his approach.
    http://www.rhinebeckhealth.com/rhc/bio_kbock.php

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  7. Qualia - yes that was a special case. I know that a recent study showed that children who later became autistic had differences in eye gaze patterns as early as 4 weeks. I really don't think vaccines are to blame in the vast majority of cases, and there are a number of large studies where vaccines were looked at very carefully. I just don't see vaccines as being that stressful on the mitochondria unless you have a 1 in a million reaction.

    Jamie - they had a robust result!

    Julianne - I haven't looked at that but I will. My general rule is as follows - for a disease without known cure, if you have an alternative treatment that won't hurt and could possibly help, why not give it a try, as long as the parents know that it can be a long shot sometimes. I feel the same way about gluten-free diets and schizophrenia. It's probably not going to help (the psychosis, leaving aside the other gluten issues at the moment - gluten free trials helped 2 in 17 people in a small study?), but given the other case studies in the literature and the antibody studies, it seems wrong not to give the families the information and talk about a gluten-free trial for a few months.

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  8. I had a client with Schizophrenia (fairly well controlled on meds) last year who took my recommendation to try paleo eating (her mother had Hashimotos, so I thought about the gluten connection, she also supported her eating change) She had been eating complete junk, lots of energy drinks, smoked, had awful indigestion, and constipation. And slept a lot of the day and felt unable to work.
    To my surprise, she went full paleo, stopped smoking, stopped all the junk food and sugar, - indigestion gone, constipation gone, slept more normally, went back to work part time, - all in one week! Was I amazed. Not sure where she is at now, but might see if I can contact her and see if she is still paleo and if so what difference it made.

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  9. Have you had a look at natasha campbell mc bride's book, The Gut and Psychology Syndrome? She tracks the pathogenesis of autism back to the mother's gut and vaginal flora and to a (possibly concurring) lack of breastfeeding which would harm the child's gut and make it permeable. Thus the problems with gluten and casein. She explains that a "simple" gluten- free and casein free diet won't help per se, without a lengthy protocol to correct disbiosis and heal the gut by populating with the good flora.
    What do you think?
    By the way, i find your blog simply amazing!

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