New Meta Study: One Third of Autism Patients have Mitochondria Dysfunction

kurt

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A consensus is emerging, this is a very clever review of the literature, looking at multiple angles of proposed mitochondria dysfunction in Autism.

Source Article: http://www.prnewswire.com/news-releases/study-shows-link-to-mitochondrial-dysfunction-in-children-with-autism-114594789.html

Study Shows Link to Mitochondrial Dysfunction in Children With Autism


MELBOURNE, Fla., Jan. 25, 2011 /PRNewswire/ -- According to a study published in Molecular Psychiatry by Dr. Daniel Rossignol (International Child Development Resource Center, Melbourne FL, Aid for Autism) and Dr. Richard Frye (University of Texas), children with autism are more likely to have abnormal function of a key part of the cell called the mitochondria (http://www.nature.com/mp/journal/vaop/ncurrent/full/mp2010136a.html). Mitochondria are best known for producing energy for the cell from oxygen and food. Because of its role in energy production, children with mitochondrial disease are known to have dysfunction in high energy organs, such as the brain. The investigators found that 1 out of 20 children with autism have been found to have severe mitochondrial disease, compared to approximately 1 out of 10,000 individuals in the general population. In addition, the study points out that a much wider number of children with autism, possibly one-third of children with autism, might have milder mitochondrial dysfunction.
So, according to this article there is a mitrochondria dysfunction 'spectrum' for autistic children.
 

Dolphin

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Cort

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Autism is just more and more interesting....I always thought they were just too different to have anything really in common with CFS...but

The prevalence of developmental regression (52%), seizures (41%), motor delay (51%), gastrointestinal abnormalities (74%), female gender (39%), and elevated lactate (78%) and pyruvate (45%) was significantly higher in ASD/MD compared with the general ASD population.
Look at this compared to CFS.......I imagines the rate of seizure is higher (altho not nearly as high), gastrointestinal abnormalities (Check), elevated lactate (check)....

Indeed, it is becoming apparent that many children with ASD have associated underlying medical comorbidities, such as epilepsy, sleep disruption, mitochondrial dysfunction and gastrointestinal (GI) abnormalities.8, 9, 10, 11, 12, 13
Common outcomes of mitochondria dysfunction

We identified a total of 11 commonly reported clinical characteristics of mitochondrial dysfunction (ataxia, cardiomyopathy, fatigue/lethargy, GI abnormalities, growth delay, hypotonia, male-to-female ratio, motor delay, myopathy, regression and seizure
Some of them fit and others do not.
 

Cort

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Mitochondrial Dysfunction

This is worth it just for its overview of mitochondrial dysfunction

Mitochondria are the only organelle in mammalian cells with their own genome. The ETC is coded by both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA).30 mtDNA contains 37 genes that code for 13 subunits of complexes I, III, IV and V, as well as the machinery required to translate and transcribe the mtDNA genes into ETC complex subunits. The remainder of the ETC complex subunits are coded by over 850 nDNA genes.31 nDNA also codes for mitochondrial enzymes that participate in carbohydrate and fatty acid oxidation. Thus, mutations in either genome can impair mitochondrial function and cause ETC complex deficiencies.32

The ETC is the predominant source and the major target of reactive oxygen species (ROS)20, 33 and is protected from damage caused by ROS by a mitochondrial-specific superoxide dismutase and antioxidants such as glutathione (GSH).33 Mitochondria lack the enzymes to synthesize GSH and therefore are dependent on cytosolic GSH production.34, 35 The depletion of GSH in mitochondria makes cells more vulnerable to oxidative stress and damage from ROS originating from the mitochondria.36 Additionally, factors that increase ROS production (such as, environmental toxicants, infections and autoimmune disease) can directly and indirectly lead to impairments in ETC activity,27, 37, 38 deplete GSH,37 and activate mitochondrial and non-mitochondrial-dependent biochemical cascades that result in programmed cell death (apoptosis).39

Certain mammalian cells, such as neuronal and non-neuronal brain cells, are very vulnerable to oxidative stress (for example, damage caused by ROS). The high rate of oxygen delivery and consumption in the brain provides the oxygen molecules necessary to generate ROS. The brain's ability to withstand oxidative stress is limited because of: (a) a high content of substrates that are easily oxidized, such as polyunsaturated fatty acids; (b) relatively low levels of antioxidants, such as GSH and antioxidant enzymes; (c) the endogenous generation of ROS via several specific reactions; and (d) the endogenous generation of nitric oxide (NO), a compound that readily transforms into reactive nitrogen species. Furthermore, the brain is very vulnerable to oxidative damage because it contains non-replicating cells which, once damaged, may be permanently dysfunctional or committed to apoptosis.37, 39

The number of mitochondria in each cell depends on the cellular energy demands. For example, low energy cells, such as skin cells, have fewer mitochondria, while cells that require high energy demands, such as muscle, liver, brain, cerebrovascular endothelium and GI cells, have many mitochondria. Neural synapses are areas of high energy consumption40 and are therefore especially dependent on mitochondrial function.41 Mitochondria are concentrated in the dendritic and axonal termini where they have an important role in ATP production, calcium homeostasis and synaptic plasticity.42, 43 Mitochondrial dysfunction can lead to reduced synaptic neurotransmitter release, and neurons that have high firing rates, such as GABAergic interneurons, may be the most adversely affected.27 Mitochondria also have an important role in cellular lipid metabolism, signaling and repair.44, 45

MD was once thought to be uncommon but is now considered the most recognized cause of metabolic disease.30 Despite increased recognition, the prevalence of MD is probably underestimated.46 The minimum birth prevalence of an ETC defect with onset at any age has been estimated at 1 in 7634 individuals (~0.01%).47 More than 100 mtDNA deletions and over 150 mtDNA point mutations have been described in individuals with MD.29 MD has a broad phenotypic presentation: children with MD can have normal intelligence, mental retardation or developmental delay.48 Stressors, such as dehydration, fever and infection can lead to a functional decline and neurodegenerative regression in individuals with MD.49, 50

The diagnosis of MD can be challenging, and is based on several objective clinical, histological, biochemical, molecular, neuroimaging and enzymatic findings. Several major diagnostic criteria are used51, 52, 53, 54, 55 to classify the probability of MD into: not likely, possible, probable or definite; individuals reaching the criteria for probable or definite are typically considered to have MD. The diagnostic criteria recognize several types of clinical presentations. These include primarily muscular or central nervous system presentations or multisystem presentations.54, 55 In addition, patients can present clinically with one of the well-characterized mitochondrial syndromes.55

Other important diagnostic features include abnormal histology (such as, ragged-red or blue fibers in skeletal muscle, or skeletal muscle with reduced cytochrome c oxidase or succinate dehydrogenase staining, or electron microscopy demonstrating abnormal mitochondria or subsarcolemmal mitochondrial accumulations), abnormal enzymology (significantly impaired ETC activity), identification of an mtDNA or nDNA mutation, abnormal neuroimaging and abnormal biochemical markers.54, 55

No reliable biomarker exists to identify all cases of MD.29 Biochemical markers of mitochondrial dysfunction described in the literature include direct (lactate, pyruvate, lactate-to-pyruvate ratio, ubiquinone, alanine, alanine-to-lysine ratio and acyl-carnitine) and indirect markers (creatine kinase (CK), carnitine, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and ammonia).25, 29, 54, 56, 57 These markers can be abnormal for several reasons. For example, mitochondrial dysfunction impairs aerobic respiration, leading to a reduction in TCA cycle function resulting in an elevation in pyruvate (see Figure 1). Pyruvate is metabolized to lactate and alanine, leading to elevations in these metabolites when pyruvate metabolism is impaired.30, 56 Inhibition of the TCA cycle may result in an elevation of TCA cycle intermediates. Inhibition of aerobic respiration also impairs fatty acid β-oxidation, leading to elevations in the concentrations of acyl-carnitines. Furthermore, anaerobic respiration increases when aerobic respiration is insufficient to meet cellular energy demands. As lactate is one of the end-products of anaerobic respiration, deactivation of aerobic respiration further elevates lactate. As a result of this, the measurement of plasma lactate can be helpful in the initial workup of mitochondrial dysfunction.30, 54 However, lactate may be elevated only during illness, or not at all, in children with MD.48, 57 In fact, normal cerebrospinal fluid or serum lactate levels do not rule out MD.48, 58

Indirect markers of mitochondrial function can also be abnormal in MD. For example, depletion in total and free carnitine can occur as a consequence of excessive unprocessed fatty acids.56 Ammonia may be elevated for at least two reasons. First, under anaerobic conditions, ammonia is produced when adenosine monophosphate is broken down into inosine monophosphate in order to replenish ATP. Second, as the urea cycle is partially located in the mitochondria, mitochondrial dysfunction can result in secondary urea cycle dysfunction and an elevation in ammonia. In addition, the integrity of certain high-energy tissues, such as muscle and liver, can be compromised from mitochondrial dysfunction, resulting in elevations in indicators of tissue damage such as CK, AST and/or ALT.

Mitochondrial dysfunction can be classified as either primary or secondary.29 Primary mitochondrial dysfunction generally refers to mitochondrial dysfunction caused by a defect in a gene directly involved in the function of mitochondrial systems responsible for producing ATP, whereas secondary mitochondrial dysfunction refers to other metabolic or genetic abnormalities that impair the ability of mitochondria to produce ATP.

For example, metabolites produced by toxic substances (for example, environmental toxicants) or by the dysfunction of other metabolic systems that are not specifically involved in producing ATP (for example, increased oxidative stress because of dysfunctional antioxidant pathways) can interfere with the ability of mitochondria to make ATP and lead to secondary mitochondrial dysfunction. Other reported causes of secondary mitochondrial dysfunction include: certain medications;29, 59, 60 enteric short chain fatty acids, such as propionic acid;61, 62, 63, 64, 65 elevated concentrations of tumor necrosis factor-α;66, 67, 68 cerebral folate deficiency;69, 70 malnutrition;71 heme, vitamin B6, or iron deficiencies;72 elevated NO;73, 74, 75 GSH deficiency;73 oxidative stress;36 or exposure to environmental toxicants, such as heavy metals,76, 77, 78, 79 chemicals,80 polychlorinated biphenyls81 or pesticides.82, 83 Some individuals have findings consistent with MD but do not have an identifiable genetic defect and/or do not meet full criteria for definite or probable MD. It is possible that these individuals have secondary mitochondrial dysfunction9, 25, 84, 85 or may have an as yet unidentified genetic abnormality. In this review article, we collate evidence of both primary and secondary mitochondrial dysfunction in ASD.
 

richvank

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Hi, Kurt, Cort and the group.

Pasted below is something I wrote about the connection between autism and CFS five years ago, that was published in the Townsend Letter. (Note that most of the internet links cited in it have since been changed.) For later developments, see www.cfsresearch.org or http://www.aboutmecfs.org/Trt/TrtGSHIntro.aspx

Also, note the paper by Myhill et al. on mito dysfunction in CFS: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680051/pdf/ijcem0001-0001.pdf

It's nice to see the pieces continuing to fit together.

Best regards,

Rich


February 21, 2006



Chronic Fatigue Syndrome and Autism

by
Richard A. Van Konynenburg, Ph.D.
(richvank@aol.com)


For the past ten years I have been studying chronic fatigue syndrome as an independent researcher. Over the course of several years I developed a hypothesis for the pathogenesis of this disorder that prominently featured the depletion of glutathione. I presented a poster paper on this hypothesis at the AACFS (now the International Association for Chronic Fatigue Syndrome) meeting in October, 2004, in Madison, Wisconsin. This paper can be found at the following url:

http://phoenix-cfs.org/GluAACFS04.htm

Anecdotal experience of people with CFS who acted upon my hypothesis suggested that while some were able to raise their glutathione levels by various means and experienced benefit from doing so, others were not able to do so. At the time I wrote my poster paper, I was aware of this, and I acknowledged in the conclusions of the paper that there appeared to be factors that were blocking the raising of glutathione in CFS. At that time, I was not sure specifically what they were. I also knew that there was evidence for a genetic predisposition in CFS, but I did not know the details of the genetic variations involved.

Shortly after that, I became aware of the work of S. Jill James et al. in autism (American Journal of Clinical Nutrition 2004 Dec; 80(6):1611-7). They found that glutathione was also depleted in autistic children, that this was associated with a partial block in the methylation cycle (also called the methionine cycle), that this partial block was associated with genetic variations in the genes for certain enzymes and other proteins associated with the sulfur metabolism, and that it interfered with the synthesis of glutathione. They also found that by using certain supplements (methylcobalamin, folinic acid and trimethylglycine) they could lift the block in the methylation cycle and restore the glutathione level.

Upon learning of this work, I became very interested in possible parallels between chronic fatigue syndrome and autism. I attended the conference of the Defeat Autism Now! (DAN!) project in Long Beach, California in October, 2005, sponsored by the Autism Research Institute, headed by Dr. Bernard Rimland. As a result I became convinced that the genetic predisposition found in autism must be the same or similar to that in a major subset of chronic fatigue syndrome, and that the resulting biochemical abnormalities were also the same or similar. As far as I know, the genetic variations in people with chronic fatigue syndrome have not yet been studied in detail or published, but I am optimistic that this will occur soon, because of the rapid advances in the technology for doing so, and because of the current active interest of at least three groups in the U.S. and the U.K. in genomic aspects of CFS.

There are obviously major differences between chronic fatigue syndrome and autism. I believe that these result primarily from the different ages of onset. Autistic children experience onset early in life, before their brains are fully developed. I believe that this gives rise to the very different brain-related symptoms seen in autistic children from those seen in adults with CFS. However, there are many similarities in the biochemistry and symptoms of these two disorders as well, including oxidative stress, buildup of toxins, immune response shift to Th2, and gut problems, for examples.

The triggering factors for autism and chronic fatigue syndrome are also largely different. Although this subject remains controversial, there appears to be substantial evidence that vaccinations (containing either a mercury-based preservative or live viruses, many given within a short period of time) were responsible for triggering many of the cases of autism in genetically-susceptible children (D. Geier and M.R. Geier, International Journal of Toxicology 2004 Nov-Dec; 23(6):369-76; and A.J. Wakefield, several publications beginning in 1997).
In CFS, a variety of triggering factors (physical, chemical, biological, or psychological/emotional) have been found to be involved in various cases, as reviewed in my poster paper, cited above. All these factors have in common that they place a demand on glutathione.

It appears that genetically susceptible persons are unable to maintain normal glutathione levels when the total demand for it is high, and that once glutathione drops sufficiently in a genetically susceptible person, the sulfur metabolism becomes disrupted. In many cases the methylation cycle (part of the sulfur metabolism) becomes partially blocked, and the result can be a depletion of some or all of several important sulfur-containing metabolites, including S-adenosylmethionine (SAMe), cysteine, glutathione, taurine and sulfate. A vicious circle is thus formed, and the depletion in these metabolites causes an avalanche of pathogenesis, since they all have very important functions in the body. I think that much of this pathogenesis is common between autism and CFS. In autism, the loss of methylation capacity because of the drop in SAMe appears to be responsible for much of the interference with normal brain development.

There is also a major difference in the sex ratio between autism and
CFS. In the book mentioned below, Dr. Jon Pangborn discusses possible
reasons why autism is more prevalent in boys. In my poster paper, cited
above, I suggested a hypothesis to explain the female dominance in the
prevalence of CFS in adults.

I think that the reason why the people who have developed CFS as adults did not develop autism as children (even though I suspect that they have the same or a similar genetic predisposition) is that when they were children, not as many vaccinations were required. The schedule of vaccinations required for children in the U.S. has grown substantially over the past two or three decades, as has the incidence of autism. This is also true in the U.K.

Shortly after attending the DAN! conference, I also learned of the work of Dr. Amy Yasko, primarily in autism, but extending to a number of other disorders as well. Working independently of the DAN! project, Dr. Yasko develops her treatment recommendations by analyzing the specific gene variations in each patient. In addition to studying effects on the methylation cycle, Dr. Yasko has gone on to consider the effects on associated biochemistry, including folate metabolism, biopterin, the urea cycle and the synthesis of neurotransmitters.

My main message is that a great deal has already been worked out in autism by the researchers and clinicians associated with the Defeat Autism Now! project, and also by Dr. Yasko, and that I believe that the CFS community would benefit greatly by looking carefully at what they have already done. The doctors associated with the DAN! project treat autism by the use of nutritional supplements that compensate for genetic mutations in the sulfur metabolism. These include such supplements as magnesium sulfate, taurine, molybdenum, vitamin B6 and its active form P5P, magnesium, methylcobalamin, folinic acid, trimethylglycine, and dimethylglycine. They also use certain diets, and they perform chelation treatments to remove heavy metals. The results in many autistic children have been astounding, as can be seen in the webcast cited below, where several are interviewed.

Dr. Yasko, in cooperation with Dr. Garry Gordon, uses many of the same supplements as are used by the DAN! project doctors as well as some additional ones, including RNA supplements, and she is also reporting great success.

So I want to encourage everyone who has an interest in CFS to look at the results of the DAN! project and of Dr. Amy Yasko in autism.

To view videos of the talks given at the latest two DAN! conferences on the internet at no cost (unless you are paying for the internet time!), go to this site:

http://www.danwebcast.com

You can choose the more recent Long Beach conference or the earlier Boston conference. They cover much of the same material, but both are worthwhile to watch. If you want to see and hear a good explanation of the methylation cycle research, go to the Boston meeting first, so you will be able to view the talk by Jill James, who did not attend the Long Beach meeting.

After selecting one of the conferences, go to the lower left and register. This is free. They will email a password to you right away, and then you can choose a talk to watch.

Beyond this, I also want to recommend a book entitled Autism: Effective Biomedical Treatments. This is a new book (Sept. 2005). It is by Jon Pangborn, Ph.D. and Sydney Baker, M.D., a biochemist and an autism clinician, respectively. It is available on Amazon for people within the U.S. For people outside the U.S., it can be obtained from the following website by means of PayPal:

http://www.autismresearchinstitute.com

The cost for the book is $30 U.S.

This is an excellent book. It is a reference book, full of good information and good science, explained clearly. This book deals very practically with developing a treatment program for an individual child. I think that most of it will turn out to apply directly to adults with CFS as well.

In addition, I want to recommend the book by Amy Yasko entitled Genetic ByPass. It is available from the website

http://www.longevityplus-rna.com/store/product.php?productid=49

as part of the "Nutrigenomics Educational Starter Packet." The price is $49.95. This is also an excellent book. It discusses treatments specifically tailored to the particular combinations of genetic variations found in different patients.

I think these two books complement each other. I would recommend reading the Pangborn and Baker book first, as it provides a good basis for understanding the technical aspects of the genetics found in the Yasko book.

Although I have been suggesting consideration of the DAN! treatments and the Yasko testing to people with CFS for only a short time, and it is too soon to draw conclusions, early feedback is very encouraging. While I am going out on a limb to some extent in announcing this now, I don't want to wait any longer, because I think this could help a lot of people. Of course, we should all keep in mind that with the current case definition of CFS we have a very heterogeneous population, and the autism treatments will very likely not help everyone who has CFS, but I am convinced that they will help a substantial subset. So I want to encourage those who have CFS and those who treat it to look into this in the strongest way I can. It could be the answer for many of you.

[Disclaimer: I have no financial interest in anything recommended in this article.]