The “Subpopulation” of Mitochondrial Autism

From an op-ed in today’s Atlanta Journal-Constitution by neurologist Jon S. Poling, the father of Hannah Poling, with a proposal for more research in the “mitochondrial autism”:

Emerging evidence suggests that mitochondrial dysfunction may not be rare at all among children with autism. In the only population-based study of its kind, Portuguese researchers confirmed that at least 7.2 percent, and perhaps as many as 20 percent, of autistic children exhibit mitochondrial dysfunction. While we do not yet know a precise U.S. rate, 7.2 percent to 20 percent of children does not qualify as “rare.” In fact, mitochondrial dysfunction may be the most common medical condition associated with autism.
……
Although unlikely, if the Portuguese studies are incorrect and mitochondrial dysfunction were found to be a rarity occurring in less than 1 percent of all autism, it would still impact up to 10,000 children (250,000 worldwide), based on current estimates that 1 million people in the U.S. (25 million worldwide) have autism. If, on the other hand, the research showing that 7.2 percent to 20 percent of children with autism have mitochondrial dysfunction is correct, then the implications are both staggering and urgent.

Autism researchers do not currently understand whether mitochondrial dysfunction causes autism or is simply a secondary biological marker. Autism clearly has many different causes, and should really be separated into multiple autism(s). I propose that we clearly identify and research the subpopulation term of “mitochondrial autism,” which is distinguished by its unique biological, but not genetic, markers.

Dr. Poling also calls on the CDC and the American Academy of Pediatrics to reaccess the current schedule of vaccines being given to children, and notes that the government’s concession in the case of his daughter Hannah has opened up a sort of “Pandora’s Box” of questions and concerns about the safety of that current vaccine schedule, and of a causal link to autism.

From a statement issued by the United Mitochondrial Disease Foundation on the connection between mitochondrial disease and autism:

“Recent published reports about the potential links between mitochondrial disorders and autism demonstrate the urgent need for more research into mitochondrial disease, a devastating and often fatal illness.

“Mitochondrial dysfunction has also been implicated in Alzheimer’s Dementia, Parkinson’s disease, Huntington’s disease, heart disease and diabetes.

“Mitochondrial disease is not rare. Researchers estimate that every 15 minutes a child is born with mitochondrial disease or will be diagnosed with mitochondrial disease by the age of 10. Most affected children do not live beyond their teenage years.

While my son Charlie has struggled to talk and communicate and with his academics and behavior, it has never seemed that he had some sort of “fatal illness,” or that he would not make it into his teenage years. We have repeatedly asked Charlie’s pediatric neurologist about the possibility of him having seizures and, so far, Charlie does not seem to have these. Our concern has been about how to help Charlie achieve his full potential into his teenage years and beyond—-because whatever the causes of autism, and whatever questions (or woes, or evils, in keeping with the Greek myth) unleashed by the case of Hannah Poling, there is always hope about what our children can do and learn as they grow up.

Because, in the myth, that’s what is at the bottom of Pandora’s Box: Hope, and hope thanks to our kids themselves.

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    • passionlessDrone

      Hi Kristina -

      I believe a critical distinction to be made in this discussion is the subtlties between ‘disorder’ and ‘dysfunction’. This is a big difference; at a very high and jerk parent researcher level, I think you could say the relationship could be described as a system that is broken very badly, and one that is not functioning as intended, but is much more lenient in the way it is not working.

      Luke did not have elevated lactic acid if I remember correctly; but several of his Krebs cycle metabolites, which are involved with the production of energy on a cellular level, were very skewed.

      Take care!

      - pD

    • MarĂ­a Luján

      Hi Kristina
      Such as pD said, disorder and dysfunction are not the same.
      J Autism Dev Disord. 2004 Dec;34(6):615-23.
      Relative carnitine deficiency in autism.Filipek PA, Juranek J, Nguyen MT, Cummings C, Gargus JJ.

      A random retrospective chart review was conducted to document serum carnitine levels on 100 children with autism. Concurrently drawn serum pyruvate, lactate, ammonia, and alanine levels were also available in many of these children. Values of free and total carnitine (p < 0.001), and pyruvate (p = 0.006) were significantly reduced while ammonia and alanine levels were considerably elevated (p < 0.001) in our autistic subjects. The relative carnitine deficiency in these patients, accompanied by slight elevations in lactate and significant elevations in alanine and ammonia levels, is suggestive of mild mitochondrial dysfunction. It is hypothesized that a mitochondrial defect may be the origin of the carnitine deficiency in these autistic children.
      This manuscript is worth the reading.

    • http://www.autismvox.com Kristina Chew, PhD

      the distinction recalls that between “being” and “becoming”—-

    • MarĂ­a Luján

      Hi Kristina
      The point of how a mitochondrial dysfunction can be present after a certain trigger probably is the point you are considering- even when predisponent biochemistry/metabolic conditions are present before the exposure to the trigger.
      More research is needed on this- and including triggers in combination.

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    • alyric

      pd, if there were significant problems with the Krebs cycles, lactic acid levels would be high – the energy has to come from somewhere and the alternate pathway (leading to the production of lactic acid) is the only other possibility.

    • http://daedalus2u.blogspot.com/ daedalus2u

      The notion of a “trigger” causing a mitochondrial disorder or dysfunction is problematic. Mitochondria have limited lifetimes in the body and are being turned over on a regular basis. In rats mitochondria with the longest lifetime are in the CNS where they have a lifetime of about a month.

      After 6 months or so, essentially all of the mitochondria have turned over. There are essentially none of the old ones left. Cells that can’t turn over and replace their mitochondria have no alternative but to die when those mitochondria wear out.

    • http://autismnaturalvariation.blogspot.com Joseph

      I’ve searched the literature to see what the nature of the evidence is that says vaccines or fever can trigger mitochondrial disorder, and I haven’t found much of anything. Initially I thought, these HHS guys must know what they are talking about. But now I’m left wondering why it is that they conceded. Maybe it was the credentials of Dr. Poling or a well-written case report.

    • MarĂ­a Luján

      I do think that the concession from the HHS was done because of the strenght of the clinical evidence they showed.

    • MarĂ­a Luján

      Joseph
      There are several studies published on the issue of mitochondrial dysfunction and environmental collaborators (drugs, inflammation,impact of fever, etc). The research is ongoing on the issue.

    • http://autismnaturalvariation.blogspot.com Joseph

      Is there anything of higher quality than case reports ? Specifically, is there epidemiology?

    • MarĂ­a Luján

      Joseph
      Because of the nature of the research, there are epi on the mito DISORDERS, but less on mito dysfunctions associated to other medical conditions. Even more the need of clinical data to complete the characterization of the medical condition with concomitant mitochondrial dysfunction makes difficult the classical epi and more needed the genetic epi plus clinical data-because of the heterogeneity plus the relative individual importance of geneticss/epigenetics/envronment. The field is complex.
      Ann Rheum Dis. 2008 Apr 3
      Abnormal expression of the genes involved in cytokine networks and mitochondrial function in systemic juvenile idiopathic arthritis identified by DNA maicroarray analysis.
      Ishikawa S, Mima T, Aoki C, Yoshio-Hoshino N, Adachi Y, Imagawa T, Mori M, Tomiita M, Iwata N, Murata T, Miyoshi M, Takei S, Aihara Y, Yokota S, Matsubara K, Nishimoto N.

      OBJECTIVES: Systemic juvenile idiopathic arthritis (sJIA) is a rheumatic disease in childhood characterized by systemic symptoms and a relatively poor prognosis. Peripheral leukocytes are thought to play pathological roles in sJIA although the exact cause is still obscure. In this study, we aimed to clarify the cellular functional abnormality in sJIA. METHODS: We analyzed the gene expression profile in peripheral leukocytes from 51 patients with sJIA, 6 patients with poly-articular type JIA (polyJIA) and 8 healthy children utilizing DNA microarrays. Gene ontology analysis and network analysis were performed on the genes differentially expressed in sJIA to clarify the cellular functional abnormalities. Result: A total of 3,491 genes were differentially expressed in patients with sJIA compared to healthy individuals. They were functionally categorized mainly into a defense-response group and a metabolism group according to gene ontology, suggesting the possible abnormalities in these functions. In the defense-response group, molecules predominantly constituting IFN-gamma and TNF network cascades were up-regulated. In the metabolism group, oxidative phosphorylation-related genes were down-regulated, suggesting a mitochondrial disorder. Expression of mitochondrial DNA-encoded genes including cytochrome c oxidase (MT-CO) 1 and MT-CO2 were suppressed in patients with sJIA but not in patients with polyJIA or healthy children. However, nuclear DNA-encoded cytochrome c oxidases were intact. CONCLUSION: Our findings suggest that sJIA is not only an immunological disease but also a metabolic disease involving mitochondria disorder.
      Eur Radiol. 2008 Apr 4
      Neuroradiologic findings in children with mitochondrial disorder: correlation with mitochondrial respiratory chain defects.Kim J, Lee SK, Kim EY, Kim DI, Lee YM, Lee JS, Kim HD.

      Mitochondrial disorders are a heterogeneous group of disorders affecting energy metabolism that can present at any age with a wide variety of clinical symptoms. We investigated brain magnetic resonance (MR) findings in 40 children with defects of the mitochondrial respiratory chain (MRC) complex and correlated them with the type of MRC defects. Enrolled were 40 children with MRC defects in biochemical enzyme assay of the muscle specimen. Twenty-one children were found to have classical syndromes of mitochondrial disorders and 19 children presented nonspecific mitochondrial encephalomyopathies. Their brain MR imaging findings were retrospectively reviewed and correlated with the biochemical defect in the MRC complex. Children with MRC defects showed various neuroradiologic features on brain MR imaging that resulted from a complex genetic background and a heterogeneous phenotype. Rapid progression of atrophy involving all structures of the brain with variable involvement of deep gray and white matter are the most frequent MR findings in children with MRC defects in both classical syndromes of mitochondrial disorder and nonspecific mitochondrial encephalomyopathies. The type of biochemical defect in the MRC complex enzyme did not correlate with brain MR findings in child patients.
      [Autism, epilepsy and mitochondrial disease: points of contact]
      http://www.ncbi.nlm.nih.gov/pubmed/18302129?ordinalpos=8&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

      There is a group of researchers that are looking at Mitochondria as part of the innate immune system and important in cell death signaling
      Physiology (Bethesda). 2008 Apr;23(2):84-94. Links
      Mitochondria: the hub of cellular Ca2+ signaling.Szabadkai G, Duchen MR.

      Mitochondria couple cellular metabolic state with Ca(2+) transport processes. They therefore control not only their own intra-organelle [Ca(2+)], but they also influence the entire cellular network of cellular Ca(2+) signaling, including the endoplasmic reticulum, the plasma membrane, and the nucleus. Through the detailed study of mitochondrial roles in Ca(2+) signaling, a remarkable picture of inter-organelle communication has emerged. We here review the ways in which this system provides integrity and flexibility for the cell to cope with the countless demands throughout its life cycle and discuss briefly the mechanisms through which it can also drive cell death.

      “Mutations caused by ROS to mitochondrial DNA, its inability to repair it completely and creation of a vicious cycle of mutations along with role of Bcl-2 family genes and proteins has been implicated in many diseases where mitochondrial dysfunctions play a key role”
      from
      .http://www.ncbi.nlm.nih.gov/pubmed/17562131?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_Dis

      “Mitochondrial antiviral signaling protein (MAVS) is an essential component of virus-activated signaling pathways that induce protective IFN responses. Its localization to the outer mitochondrial membrane suggests an important yet unexplained role for mitochondria in innate immunity.”

      http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17438296

    • http://autismnaturalvariation.blogspot.com Joseph

      I know there’s mito epidemiology, but what I mean is whether there’s epidemiology on suspected mito triggers. It doesn’t look like there are, and I realize it’s not very easy to study a rarely diagnosed disorder. It appears that some things stated as fact about mitochondrial disorder are simply plausible but not yet demonstrated.

    • MarĂ­a Luján

      Joseph
      There are enough clinical biomarkers in many medical conditions to suspect mitochondrial involvement
      J Autism Dev Disord. 2004 Dec;34(6):615-23.
      Relative carnitine deficiency in autism.
      Filipek PA, Juranek J, Nguyen MT, Cummings C, Gargus JJ.
      A random retrospective chart review was conducted to document serum carnitine levels on 100 children with autism. Concurrently drawn serum pyruvate, lactate, ammonia, and alanine levels were also available in many of these children. Values of free and total carnitine (p < 0.001), and pyruvate (p = 0.006) were significantly reduced while ammonia and alanine levels were considerably elevated (p < 0.001) in our autistic subjects. The relative carnitine deficiency in these patients, accompanied by slight elevations in lactate and significant elevations in alanine and ammonia levels, is suggestive of mild mitochondrial dysfunction. It is hypothesized that a mitochondrial defect may be the origin of the carnitine deficiency in these autistic children.
      This manuscript is worth the reading because of the careful approach of the authors.. 83 % of the autistic children demonstrated to have abnormal values of carnitine. Exclusionary criteria from this study was existing seiuzure disorder, chromosomal abnormality, concomitant genetic disorder, medications, focal abnormality on neurological examination or special diets. Confounders such as valproate therapy were carefully considered and excluded-because valproate has been linked to hyperammonia and carnitine defficiency. They also mentioned specifically that the children did not present classic beta oxidation fatty acid disorders- mainly the medium chain acyl CoA dehydrogenase defficency-even when some markers were present. The children did not present the particular kind of hypoglycemia that characterize this condition.
      From the same authors

      http://www.scipub.org/fulltext/ajbb/ajbb42198-207.pdf

      an analysis of biochemical findings and potential genetic links plus the clear focus on clinical research.
      Besides the aspect of causation, the issue of adequate testing/diagnosis/treatment as a CMP to an ASD diagnosis is for me important.
      More research is needed to clarify a very complex issue such as the role of mitochondrial dysfunction in a subgroup of children with ASD to clarify the following aspects
      a- May xenobiotics received the first 2 years of live ( combination of antibiotics plus vaccines plus food introduction and other illness management in modern pediatrics) produce mitochondrial dysfunctions in susceptible children?
      b- May this dysfunction be reversed if properly tested/detected and diagnosed? May be prevented in a susceptible population?
      c-How this mitochondrial dysfunction may be related to glycolysis, beta oxidation of fatty acids and urea cycle problems- including sugar levels control? There are several manuscripts published on glycemia control, fatty acids management and levels and urea cycle problems in ASD.
      d-What role this mitochondrial dysfunction- and its consequences has in the symptomatology that is used under the DSMIV to diagnose ASD?
      I consider that we have clues but not definitive answers-such as in many other aspects. I do not consider that some things are considered as facts, especially looking at the wording of the manuscripts on the issue.

    • MarĂ­a Luján

      About mito triggers perhaps you can find here some manuscripts on partial aspects related to environmental contribution
      http://www.autismweb.com/forum/viewtopic.php?t=14855&start=0
      and
      http://www.autismweb.com/forum/viewtopic.php?t=14974&start=20

    • MarĂ­a Luján

      An interesting piece
      http://student.bmj.com/issues/08/02/education/078.php
      References
      Schaefer AM, Taylor RW, Turnbull DM, Chinnery PF. The epidemiology of mitochondrial disorders—past, present and future. Biochim Biophys Acta 2004;1659:115-20.
      McFarland R, Taylor RW, Turnbull DM. Mitochondrial disease—its impact, etiology, and pathology. Curr Top Dev Biol 2007;77:113-55.
      Taylor RW, Turnbull DM. Mitochondrial DNA mutations in human disease. Nat Rev Genet 2005;6:389-402.
      Some quotes
      “In addition to monogenic disorders, scientists are also discovering that mitochondria have a secondary role in many more diseases. One of the most common, and potentially most important, presentations of mitochondrial dysfunction is diabetes, which is after all a disorder of altered fatty acid and carbohydrate metabolism. How mitochondria contribute to the disease is not entirely clear, but some mutations in mitochondrial DNA are associated with type 2 diabetes, as are some changes in genes regulating mitochondrial biogenesis—the process of organelle growth, maintenance, and replication”.

      “In many major diseases people are now looking at mitochondria,” said Mervyn Singer, professor of intensive care medicine at University College London

      “Many changes that occur in acute critical illness switch off mitochondria, such as the release of inflammatory mediators like nitric oxide”

      “He points out that antibiotics are among the most potent inhibitors of mitochondrial biogenesis. Perhaps this is hardly surprising considering the organelle’s prokaryotic origins, but he adds that perhaps this means the way infections are treated may also be delaying recovery”.

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    • MarĂ­a Luján

      Neuropharmacology. 2008 Mar 8
      Endogenous neuroprotection: Mitochondria as gateways to cerebral preconditioning?Dirnagl U, Meisel A.
      Department of Experimental Neurology, Center for Stroke Research Berlin, Berlin, Germany; Department of Neurology, Center for Stroke Research Berlin, Berlin, Germany.

      From single to multicellular organisms, protective mechanisms have evolved against endogenous and exogenous noxious stimuli. Preconditioning paradigms, in which stimulation below the threshold of injury results in subsequent protection of the brain, have played an important role in elucidating such endogenous protective mechanisms. Consequently, over the past decades numerous signaling pathways have been discovered by which the brain senses and reacts to such insults as “neurotoxins, substrate deprivation, or inflammation”. Research on preconditioning is aimed at understanding endogenous neuroprotection to boost it, or to supplement its effectors therapeutically once damage to the brain has occurred, such as after stroke or brain trauma. Another goal of establishing preconditioning protocols is to induce endogenous neuroprotection in anticipation of incipient brain damage. Currently several endogenous neuroprotectants are being investigated in controlled clinical trials. In the present review we will give a short overview on the signals, sensors, transducers, and effectors of endogenous neuroprotection. We will first focus on common mechanisms, on which pathways of endogenous neuroprotection converge, and in particular on mitochondria, which may be considered master integrators of endogenous neuroprotection. We will then discuss various applications of preconditioning, including pharmacological and anesthetic preconditioning, as well as postconditioning, and explore the prospects of endogenous neuroprotective therapeutic approaches.

    • http://autismnaturalvariation.blogspot.com Joseph

      Maybe I wasn’t clear. I wasn’t questioning that mitochondrial disorder is associated with other disorders. I’m sure it is. What I don’t see any evidence of is that environmental triggers cause mitochondrial disorder, other than expert assertions, case reports and evidence of about that same level.

    • MarĂ­a Luján

      Environmental triggers have been linked to oxidative stress. Oxidative stress are being more and more studied related to mitochondrial dysfunction.
      Apoptosis. 2007 May;12(5):913-22. Links
      Mitochondria, oxidative stress and cell death.Ott M, Gogvadze V, Orrenius S, Zhivotovsky B.
      Institute of Environmental Medicine, Karolinska Institutet, S-171 77 Stockholm, Sweden.

      In addition to the well-established role of the mitochondria in energy metabolism, regulation of cell death has recently emerged as a second major function of these organelles. This, in turn, seems to be intimately linked to their role as the major intracellular source of reactive oxygen species (ROS), which are mainly generated at Complex I and III of the respiratory chain. Excessive ROS production can lead to oxidation of macromolecules and has been implicated in mtDNA mutations, ageing, and cell death. Mitochondria-generated ROS play an important role in the release of cytochrome c and other pro-apoptotic proteins, which can trigger caspase activation and apoptosis. Cytochrome c release occurs by a two-step process that is initiated by the dissociation of the hemoprotein from its binding to cardiolipin, which anchors it to the inner mitochondrial membrane. Oxidation of cardiolipin reduces cytochrome c binding and results in an increased level of “free” cytochrome c in the intermembrane space. Conversely, mitochondrial antioxidant enzymes protect from apoptosis. Hence, there is accumulating evidence supporting a direct link between mitochondria, oxidative stress and cell death
      Curr Vasc Pharmacol. 2008 Apr;6(2):84-92.Links
      Mitochondrial MMP Activation, Dysfunction and Arrhythmogenesis in Hyperhomocysteinemia.Moshal KS, Metreveli N, Frank I, Tyagi SC.
      Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, KY 4020, USA. s0tyag01@louisville.edu.

      Chronic volume/pressure overload-induced heart failure augments oxidative stress and activates matrix metalloproteinase which causes endocardial endothelial-myocyte (EM) uncoupling eventually leading to decline in myocardial systolic and diastolic function. The elevated levels of homocysteine (Hcy), hyperhomocysteinemia (HHcy), are associated with decline in cardiac performance. Hcy impairs the EM functions associated with the induction of ventricular hypertrophy leading to cardiac stiffness and diastolic heart failure. Hcy-induced neurological defects are me-diated by the NMDA-R (N-methyl-D-aspartate (NMDA) receptor) activation. NMDA-R is expressed in the heart. However, the role of NMDA-R on cardiac function during HHcy is still in its infancy. The blockade of NMDA-R attenuates NMDA-agonist-induced increase in the heart rate. Hcy increases intracellular calcium and activates calpain and calpain-associated mitochondrial (mt) abnormalities have been identified in HHcy. Mitochondrial permeabilization and uncoupling in the pathological setting is fueled by redox stress and calcium mishandling. Recently the role of cyclophilin D, a component of the mitochondrial membrane permeability transition pore, has been identified in cardiac-ischemia. Mechanisms underlying the potentiation between NMDA-R activation and mitochondrial defects leading to cardiac dysfunction during HHcy remain to be elucidated. This review addresses the mitochondrial mechanism by which Hcy contributes to the decline in mechano-electrical function and arrhythmogenesis via agonizing NMDA-R. The putative role of mitochondrial MMP activation, protease stress and mitochondrial permeability transition in cardiac conduction during HHcy is discussed. The review suggests that Hcy increases calcium overload and oxidative stress in the mitochondria and amplifies the activation of mtMMP, causing the opening of mitochondrial permeability transition pore leading to mechano-electrical dysfunction.
      Mitochondrial Oxidative Stress and Dysfunction in Rat Brain Induced by Carbofuran Exposure.
      http://www.ncbi.nlm.nih.gov/pubmed/18340526?ordinalpos=32&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

      Pharmacogenomics. 2008 Apr;9(4):383-97. Links
      Analysis of the adult human plasma metabolome.Lawton KA, Berger A, Mitchell M, Milgram KE, Evans AM, Guo L, Hanson RW, Kalhan SC, Ryals JA, Milburn MV.
      Metabolon, Inc, 800 Capitola Dr. Suite 1, Durham, NC 27713, USA.

      OBJECTIVE: It is well established that disease states are associated with biochemical changes (e.g., diabetes/glucose, cardiovascular disease/cholesterol), as are responses to chemical agents (e.g., medications, toxins, xenobiotics). Recently, nontargeted methods have been used to identify the small molecules (metabolites) in a biological sample to uncover many of the biochemical changes associated with a disease state or chemical response. Given that these experimental results may be influenced by the composition of the cohort, in the present study we assessed the effects of age, sex and race on the relative concentrations of small molecules (metabolites) in the blood of healthy adults. METHODS: Using gas- and liquid-chromatography in combination with mass spectrometry, a nontargeted metabolomic analysis was performed on plasma collected from an age- and sex-balanced cohort of 269 individuals. RESULTS: Of the more than 300 unique compounds that were detected, significant changes in the relative concentration of more than 100 metabolites were associated with age. Many fewer differences were associated with sex and fewer still with race. Changes in protein, energy and lipid metabolism, as well as oxidative stress, were observed with increasing age. Tricarboxylic acid intermediates, creatine, essential and nonessential amino acids, urea, ornithine, polyamines and oxidative stress markers (e.g., oxoproline, hippurate) increased with age. Compounds related to lipid metabolism, including fatty acids, carnitine, beta-hydroxybutyrate and cholesterol, were lower in the blood of younger individuals. By contrast, relative concentrations of dehydroepiandrosterone-sulfate (a proposed antiaging androgen) were lowest in the oldest age group. Certain xenobiotics (e.g., caffeine) were higher in older subjects, possibly reflecting decreases in hepatic cytochrome P450 activity. CONCLUSIONS: Our nontargeted analytical approach detected a large number of metabolites, including those that were found to be statistically altered with age, sex or race. Age-associated changes were more pronounced than those related to differences in sex or race in the population group we studied. Age, sex and race can be confounding factors when comparing different groups in clinical studies. Future studies to determine the influence of diet, lifestyle and medication are also warranted.
      It would be difficult to perform the kind of studies you consider evidence due to the heterogeneity of the population, the concomitant medical problems and the individual variability of the mtDNA.
      I consider that more clinical/genetic/epigenetic combined studies are needed-including impact of xenobiotics to adequately identify subrgroups in ASD.
      J Expo Sci Environ Epidemiol. 2008 Apr 9 [Epub ahead of print]Links
      Separation of uncertainty and interindividual variability in human exposure modeling.Ragas AM, Brouwer FP, BĂĽchner FL, Hendriks HW, Huijbregts MA.
      aDepartment of Environmental Science, Radboud University Nijmegen, Nijmegen, The Netherlands.

      The NORMTOX model predicts the lifetime-averaged exposure to contaminants through multiple environmental media, that is, food, air, soil, drinking and surface water. The model was developed to test the coherence of Dutch environmental quality objectives (EQOs). A set of EQOs is called coherent if simultaneous exposure to different environmental media that are all polluted up to their respective EQOs does not result in exceeding the acceptable or tolerable daily intake (ADI or TDI). Aim of the present study is to separate the impact of uncertainty and interindividual variability in coherence predictions with the NORMTOX model. The method is illustrated in a case study for chlorfenvinphos, mercury and nitrate. First, ANOVA was used to calculate interindividual variability in input parameters. Second, nested Monte Carlo simulation was used to propagate uncertainty and interindividual variability separately. Lifetime-averaged exposure to chlorfenvinphos, mercury and nitrate was modeled for the Dutch population. Output distributions specified the population fraction at risk, due to a particular exposure, and the reliability of this risk. From the case study, it was obtained that at lifelong exposure to all media polluted up to their standard, 100% of the Dutch population exceeds the ADI for chlorfenvinphos, 15% for mercury and 0% for nitrate. Variance in exposure to chlorfenvinphos, mercury and nitrate is mostly caused by interindividual variability instead of true uncertainty. It is concluded that the likelihood that ADIs of chlorfenvinphos and mercury will be exceeded should be further explored. If exceeding is likely, decision makers should focus on identification of high-risk subpopulations, rather than on additional research to obtain more accurate estimates for particular parameters.Journal of Exposure Science and Environmental Epidemiology advance online publication, 9 April 2008; doi:10.1038/jes.2008.13
      ns Am Ophthalmol Soc. 1998;96:881-923. Links
      Acquired mitochondrial impairment as a cause of optic nerve disease.Sadun A.
      Doheny Eye Institute, Department of Ophthalmology, University of Southern California School of Medicine, Los Angeles, USA.

      BACKGROUND: Blindness from an optic neuropathy recently occurred as an epidemic affecting 50,000 patients in Cuba (CEON) and had clinical features reminiscent of both tobacco-alcohol amblyopia (TAA) and Leber’s hereditary optic neuropathy (Leber’s; LHON). Selective damage to the papillomacular bundle was characteristic, and many patients also developed a peripheral neuropathy. Identified risk factors included vitamin deficiencies as well as exposure to methanol and cyanide. In all 3 syndromes, there is evidence that singular or combined insults to mitochondrial oxidative phosphorylation are associated with a clinically characteristic optic neuropathy. PURPOSE: First, to test the hypothesis that a common pathophysiologic mechanism involving impairment of mitochondria function and, consequently, axonal transport underlies both genetic optic nerve diseases such as Leber’s and acquired toxic and nutritional deficiency optic neuropathies. According to this hypothesis, ATP depletion below a certain threshold leads to a blockage of orthograde axonal transport of mitochondria, which, in turn, leads to total ATP depletion and subsequent cell death. Second, to address several related questions, including (1) How does impaired energy production lead to optic neuropathy, particularly since it seems to relatively spare other metabolically active tissues, such as liver and heart? (2) Within the nervous system, why is the optic nerve, and most particularly the papillomacular bundle, so highly sensitive? Although there have been previous publications on the clinical features of the Cuban epidemic of blindness, the present hypothesis and the subsequent questions have not been previously addressed. METHODS: Patients in Cuba with epidemic optic neuropathy were personally evaluated through a comprehensive neuro-ophthalmologic examination. In addition, serum, lymphocytes for DNA analysis, cerebrospinal fluid (CSF), sural nerves, and eyes with attached optic nerves were obtained from Cuban patients, as well as from Leber’s patients, for study. Finally, we developed an animal model to match the low serum folic acid and high serum formate levels found in the CEON patients, by administering to rats low doses of methanol after several months of a folic acid-deficient diet. Optic nerves and other tissues obtained from these rats were analyzed and compared with those from the Cuban patients. RESULTS: Patients from the Cuban epidemic of optic neuropathy with clinical evidence of a selective loss of the papillomacular bundle did much better once their nutritional status was corrected and exposure to toxins ceased. Patients with CEON often demonstrated low levels of folic acid and high levels of formate in their blood. Histopathologic studies demonstrated losses of the longest fibers (in the sural nerve) and those of smallest caliber (papillomacular bundle) in the optic nerve, with intra-axonal accumulations just anterior to the lamina cribrosa. Our animal model duplicated the serologic changes (low folic acid, high formate) as well as these histopathologic changes. Furthermore, ultrastructural examination of rat tissues demonstrated mitochondrial changes that further matched those seen on ultrastructural examination of tissues from patients with Leber’s. CONCLUSION: Mitochondria can be impaired either genetically (as in Leber’s) or through acquired insults (such as nutritional or toxic factors). Either may challenge energy production in all cells of the body. While this challenge may be met through certain compensatory mechanisms (such as in the size, shape, or number of the mitochondria), there exists in neurons a threshold which, once passed, leads to catastrophic changes. This threshold may be that point at which mitochondrial derangement leads to such ATP depletion that axonal transport is compromised, and decreased mitochondrial transport results in even further ATP depletion. Neurons are singularly dependent on the axonal transport of mitochondria.

    • MarĂ­a Luján

      http://toxsci.oxfordjournals.org/cgi/content/full/92/1/186
      Investigation of Drug-Induced Mitochondrial Toxicity Using Fluorescence-Based Oxygen-Sensitive Probes
      http://physrev.physiology.org/cgi/content/full/87/1/99
      Mitochondrial Membrane Permeabilization in Cell Death
      Look please at IX
      IX. MITOCHONDRIAL MEMBRANE PERMEABILIZATION IN MAJOR HUMAN DISEASES
      A. Ischemia/Reperfusion
      B. Intoxication
      C. Neurodegeneration
      D. Viral Infection
      1. Vpr from HIV-1
      2. HBx from hepatitis B virus
      3. Influenza virus PB1-F2
      E. Cancer

    • http://autismnaturalvariation.blogspot.com Joseph

      In other words, Maria, you are confirming that there are no group or population studies that demonstrate environmental factors trigger mitochondrial disorder. There are only plausible hypotheses and likely mechanisms, plus proposals on how future research should be conducted.

      As I’m sure you know, there are levels of evidence in evidence-based medicine. It would appear to me that the science around environmental causes of mitochondrial disorder has not moved beyond the lowest levels of evidence quality thus far.

    • MarĂ­a Luján

      Joseph
      I was not confirming the point you mentioned. I disagree. Clinical measurements have been reported in many cases-and including animal models that resemble the clinical findings found in some known mito disesase.

      About EBM, I have read a lot of pro and contras. Acad Med. 2008 Mar;83(3):268-73.
      Viewpoint: Envisioning the Successful Integration of EBM and Humanism in the Clinical Encounter: Fantasy or Fallacy?
      Smith DG.
      Dr. Smith is director, Graduate Medical Education, Abington Memorial Hospital, Abington, Pennsylvania, and clinical associate professor of medicine, Temple University School of Medicine, Philadelphia, Pennsylvania.
      Some authors challenge the dominance of evidence-based medicine (EBM) in current medical practice because of its tendency to disregard the patient in the clinical process and thus distort the clinician’s view of the patient as the primary focus. This tendency to “scientize” the clinician-patient encounter threatens to seriously reduce the role of humanistic elements in medicine. Although the pendulum shift toward the epistemology of EBM is worrisome, it is only one aspect of the problems facing modern medicine in the process of discovering-or rediscovering-the human dimension in medical care.The author uses his own and others’ interpretation of the philosophy of an underappreciated thinker, Michael Polanyi, as a springboard to envision the research required for the development of models of medical education and clinical practice that appropriately acknowledge both EBM and humanism. Striking the right balance between these two elements will require much additional research, but those who simply demonize EBM as the major barrier to humanistic practice fail to appreciate the essential role for critical thinking in responding to the demands of patient safety and health care quality. All may agree that the current medical landscape needs immediate attention but this author argues that such work needs to use the available tools such as EBM and Polanyi’s Theory of Tacit Knowing as well as products of future research efforts. Failure to do less will prevent us from reaching the ideal of a truly humanistic encounter firmly embedded in practices that maximize patient safety and health care quality.
      Acad Med. 2007 Mar;82(3):292-7.
      Viewpoint: Moving beyond evidence-based medicine.
      Henry SG, Zaner RM, Dittus RS.
      University of Michigan Health System,
      The evidence-based medicine movement has remained both well known and controversial since its inception. The authors reframe the evidence-based medicine debate by pointing out an underappreciated epistemological deficiency: evidence-based medicine as currently conceptualized cannot accommodate concepts that resist quantitative analysis and therefore cannot logically differentiate human beings from complex machines. The authors use Michael Polanyi’s philosophy of tacit knowing (which refers to the taken-for-granted knowledge at the periphery of attention that allows persons to understand the world and discern meaning in it) as a starting point for rectifying this deficiency and for working towards an improved, person-centered epistemology of medical practice. The authors demonstrate that not only evidence-based medicine but also most traditional theories of medical practice need a concept such as tacit knowing to account for the kinds of knowledge human beings actually use. Polanyi’s philosophy of tacit knowing is defined and briefly explained. A medical epistemology that can account for the tacit dimension of human knowledge and recognize physicians and patients as persons requires a revised conception of medical uncertainty and a recognition that clinician-patient interactions are central to medicine. The authors discuss practical implications of tacit knowing for medical practice, education, research, and health care policy and suggest ways for moving beyond evidence-based medicine towards a comprehensive epistemology of medical practice.
      Blood Purif. 2008;26(1):73-6.
      Guidelines have done more harm than good.
      Amerling R, Winchester JF, Ronco C.
      Division of Nephrology and Hypertension, Beth
      Practice guidelines have proliferated in medicine but their impact on actual practice and outcomes is difficult, if not impossible, to quantify. Though guidelines are based largely on observational data and expert opinion, it is widely believed that adherence to them leads to improved outcomes. Data to support this belief simply does not exist. If guidelines are universally ignored, their impact on treatment and outcomes is minimal. The incorporation of guidelines into treatment protocols and performance measures, as is now common practice in nephrology, increases greatly the likelihood that guidelines will influence practice and hence, outcomes. Practice patterns set up this way may be resistant to change, should new evidence emerge that contradicts certain recommendations. Even if guidelines are entirely appropriate, a ‘one-size-fits-all’ approach is likely to benefit some, but not all. Certain patients may be harmed by adherence to specific guidelines. Guidelines certainly do not encourage clinicians to consider and treat each patient as an individual. They are unlikely to stimulate original research. They are created by a process that is artificial, laborious and cumbersome. This all but guarantees many guidelines are obsolete by the time they are published. Guidelines are produced with industry support and recommendations often have a major impact on sales of industry products
      Perspect Biol Med. 2005 Autumn;48(4):477-89.
      Looking for rules in a world of exceptions: reflections on evidence-based practice.
      Upshur RE.

      After more than a decade, evidence-based medicine (EBM) is well established as an important influence in health care. EBM has engendered a wide range of responses from near-evangelical fervor to angered rejection, with supporters convinced of its scientific superiority and detractors of its needless reductionism. EBM is not a philosophical doctrine, and its originators and proponents have, for the most part, ignored critics and foresworn theorizing. However, EBM claims to be a normative guide to being a better physician. The theoretical, practical, and philosophical dimensions of EBM are intimately intertwined. This essay is a sustained reflection on the issues raised by EBM as experienced by a clinician/teacher who has tried to apply the tenets of EBM in clinical care and teaching over the past decade, and who has sought to expand the borders of EBM from a philosophical point of view.

      ‘Better than numbers…’ A gentle critique of evidence-based medicine.
      Little M.
      Centre for Values, Ethics and the Law in Medicine, University of Sydney, Sydney, New South Wales, Australia.
      Evidence-based medicine (EBM) has achieved cult status in the last 10 years or so. It is an altogether admirable movement in medicine, capable of a great deal of good. Its privileged status, however, has prevented critics from being heard, and there are problems with EBM. Eight features need further discussion if EBM is not to be discredited and superseded. They are its reductionism; its unwitting paternalism; its privileging of restricted kinds of evidence; its dependence on the questionable concept of equipoise; the instability of the ‘truths’ it produces; its capacity to eliminate individuals in favour of categories; its historical arrogance; and its contempt for the wisdom and integrity of our predecessors. Evidence-based medicine is here to stay; for the moment, at least. It is sufficiently well established to withstand critique. It needs criticism if it is to survive and flourish.

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