Magnetic therapy for Autism is now a reality using Pulsed Electromagnetic Field therapy (PEMF) in the form of rTMS or repetitive Transcranial Magnetic Stimulation. In this review, we learn about the true nature of Autism and how magnetic stimulation using PEMF devices has proven to be very effective.

During the past few years there has been growing interest in rTMS (repetitive transcranial magnetic stimulation) as a therapeutic tool in autism. We believe you can do better at home with PEMF that is far less intense longer duration exposures without the time and much of the expense if you are lucky enough to find them at all.

It has long been known that autistic children have positive behavioral response to dolphin therapy. It has been the author’s belief that in addition to inter-species communication there was a nearly immediate “grounding” of the child as it had probably never been immersed in sea water before. The combination of the two effects is somewhat miraculous, but unfortunately fleeting.

General knowledge regarding use of magnetic therapies is the need of the hour for child and adolescent psychiatrists and is much more ethical than using captive dolphins to achieve the “grounding” effect that is responsible for healing the autistic neurophysiology.

While frequency specific pulsed electromagnetic field therapy PEMF and rTMS doesn’t “ground” body, it will have other significant effects that will work in synergy with grounding.

pulsed electromagnetic field therapy research for autism and ADHD

Now due to results reported to us by a research partner we believe that pulsed electromagnetic field therapy (PEMF) delivered in form of repetitive Transcranial Magnetic Stimulation (rTMS) particularly in combination with a Earthing / Grounding mat can enhance performance of autistic children.

2014 showed a nice up-tick in research in the area. With results as reported in the article below, and the explosion in autistic incidence, there isn’t nearly enough research into this area. This article’s title refers to PTSD but includes very important facts for parents of autistics. ‘Brain zapping’: Experimental PTSD / Austism treatment has changed their lives

Magnetic Therapy for Autism – Autistic Spectrum Disorder Repetitive Transcranial Magnetic Stimulation (rTMS) / PEMF Bibliography

To read the original source, use Pubmed and search for Title of the citation

Transcranial Magnetic Stimulation in Conditions Other than Major Depressive Disorder.
Becker JE, Shultz EKB, Maley CT.
Child Adolesc Psychiatr Clin N Am. 2019 Jan;28(1):45-52. doi: 10.1016/j.chc.2018.08.001. Epub 2018 Sep 20. Review.
PMID: 30389075
Transcranial Magnetic and Direct Current Stimulation in Children.
Hameed MQ, Dhamne SC, Gersner R, Kaye HL, Oberman LM, Pascual-Leone A, Rotenberg A.
Curr Neurol Neurosci Rep. 2017 Feb;17(2):11. doi: 10.1007/s11910-017-0719-0. Review.
PMID: 28229395
Transcranial magnetic stimulation in autism spectrum disorder: Challenges, promise, and roadmap for future research.
Oberman LM, Enticott PG, Casanova MF, Rotenberg A, Pascual-Leone A, McCracken JT; TMS in ASD Consensus Group.
Autism Res. 2016 Feb;9(2):184-203. doi: 10.1002/aur.1567. Epub 2015 Nov 4. Review.
PMID: 26536383
Heart Rate Variability and Skin Conductance During Repetitive TMS Course in Children with Autism.
Wang Y, Hensley MK, Tasman A, Sears L, Casanova MF, Sokhadze EM.
Appl Psychophysiol Biofeedback. 2016 Mar;41(1):47-60. doi: 10.1007/s10484-015-9311-z.
PMID: 26341093
Appl Psychophysiol Biofeedback. 2014 Dec;39(3-4):237-57. doi: 10.1007/s10484-014-9264-7.
Neuromodulation integrating rTMS and neurofeedback for the treatment of autism spectrum disorder: an exploratory study.
Sokhadze EM1, El-Baz AS, Tasman A, Sears LL, Wang Y, Lamina EV, Casanova MF.
Brain Stimul. 2014 Mar-Apr;7(2):206-11. doi: 10.1016/j.brs.2013.10.004. Epub 2013 Oct 27.
A double-blind, randomized trial of deep repetitive transcranial magnetic stimulation (rTMS) for autism spectrum disorder.
Enticott PG1, Fitzgibbon BM2, Kennedy HA2, Arnold SL2, Elliot D2, Peachey A2, Zangen A3, Fitzgerald PB2.
Front Hum Neurosci. 2014 Oct 21;8:851. doi: 10.3389/fnhum.2014.00851. eCollection 2014.
Effects of weekly low-frequency rTMS on autonomic measures in children with autism spectrum disorder.
Casanova MF1, Hensley MK2, Sokhadze EM1, El-Baz AS1, Wang Y3, Li X4, Sears L5.
Front Hum Neurosci. 2014 Aug 13;8:627. doi: 10.3389/fnhum.2014.00627. eCollection 2014.
Modulation of corticospinal excitability by transcranial magnetic stimulation in children and adolescents with autism spectrum disorder.
Oberman LM1, Pascual-Leone A2, Rotenberg A3.
Front Syst Neurosci. 2014 Aug 6;8:134. doi: 10.3389/fnsys.2014.00134. eCollection 2014.
rTMS neuromodulation improves electrocortical functional measures of information processing and behavioral responses in autism.
Sokhadze EM1, El-Baz AS2, Sears LL3, Opris I4, Casanova MF1.
Prefrontal neuromodulation using rTMS improves error monitoring and correction function in autism.
Sokhadze EM, Baruth JM, Sears L, Sokhadze GE, El-Baz AS, Casanova MF.
Appl Psychophysiol Biofeedback. 2012 Jun;37(2):91-102. doi: 10.1007/s10484-012-9182-5.
Repetitive transcranial magnetic stimulation (rTMS) improves movement-related cortical potentials in autism spectrum disorders.
Enticott PG, Rinehart NJ, Tonge BJ, Bradshaw JL, Fitzgerald PB.
Brain Stimul. 2012 Jan;5(1):30-7. doi: 10.1016/j.brs.2011.02.001. Epub 2011 Mar 3.
Int Rev Psychiatry. 2011 Oct;23(5):445-53.
Applications of transcranial magnetic stimulation (TMS) in child and adolescent psychiatry.
Croarkin PE, Wall CA, Lee J.
Mayo Clinic, Rochester , Minnesota , USA.
Transcranial magnetic stimulation (TMS) is emerging as a new treatment and neurophysiological research tool for psychiatric disorders. Recent publications suggest that this modality will also serve as a treatment and research tool in child and adolescent psychiatry. Current reports on therapeutic trials of repetitive transcranial magnetic stimulation (rTMS) in adolescents have primarily focused on depression. However, other pilot work involves the treatment of attention-deficit/hyperactivity disorder (ADHD), autism and schizophrenia. Neurophysiological studies typically utilize single and paired-pulse TMS paradigms which index cortical excitability and inhibition. Initial studies have focused on ADHD, autism, and depression. General knowledge regarding TMS among child and adolescent psychiatrists is lacking. The aim of this review is to provide an overview of TMS in the context of child and adolescent psychiatry, discuss recent therapeutic and neurophysiological studies, and examine relevant ethical considerations.
PMID: 22200134 [PubMed – in process]
Brain Stimul. 2011 Mar 3.
Repetitive transcranial magnetic stimulation (rTMS) improves movement-related cortical potentials in autism spectrum disorders.
Enticott PG, Rinehart NJ, Tonge BJ, Bradshaw JL, Fitzgerald PB.
Monash Alfred Psychiatry Research Centre, School of Psychology and Psychiatry, Monash University and The Alfred, The Alfred, Melbourne, Victoria, Australia; Centre for Developmental Psychiatry and Psychology, School of Psychology and Psychiatry, Monash University, Clayton, Victoria, Australia.
Motor impairments are common in autism spectrum disorders (ASD). Electrophysiologic studies reveal abnormalities in the preparation of movement; repetitive transcranial magnetic stimulation (rTMS) to key motor cortical sites may therefore be a useful technique for improving motor function in ASD.
To examine whether rTMS can improve electrophysiologic and behavioral indices of motor activity.
Eleven participants with ASD completed three sessions in which they were administered one of three rTMS conditions (left M1, supplementary motor area [SMA], sham) at 1 Hz for 15 minutes. Movement-related cortical potentials (MRCPs) were assessed before and after rTMS.
rTMS to the SMA was associated with a gradient increase to the early component of MRCPs, whereas rTMS to left M1 produced a stronger gradient in the late component.
rTMS appears to improve movement-related electrophysiologic activity in ASD, perhaps through an influence on cortical inhibitory processes.
PMID: 22037133
J ECT. 2011 Mar;27(1):41-3.
Deep repetitive transcranial magnetic stimulation associated with improved social functioning in a young woman with an autism spectrum disorder.
Enticott PG, Kennedy HA, Zangen A, Fitzgerald PB.
Monash Alfred Psychiatry Research Centre, School of Psychology and Psychiatry, Monash University and The Alfred, Melbourne, Victoria, Australia.
There are currently no biomedical treatments targeting the core symptoms of autism spectrum disorders (ASDs). Considering evidence for cortical dysfunction in ASD, repetitive transcranial magnetic stimulation (rTMS) has been discussed as a potential therapeutic technique.
We describe the application of a new type of rTMS, deep rTMS, to the bilateral medial prefrontal cortex in a young woman with a high-functioning ASD. High-frequency rTMS was applied for 15 minutes each consecutive weekday for an 11-day period (9 treatments in total). Self-reported assessments were conducted before the first rTMS session, immediately after the last rTMS session, and 1-month after the last rTMS session.
Self-reported assessments revealed a number of improvements after deep rTMS. These were primarily in the domain of social relating and interpersonal understanding and were corroborated by family members.
Deep rTMS in ASD may serve to remediate aspects of cortical dysfunction (as standard rTMS seems to do in depression and schizophrenia) and provides a potential new avenue for the development of a biomedical treatment of impaired social relating in ASD.
PMID: 20966773
J Neurother. 2010 Jul 1;14(3):179-194.
Low-Frequency Repetitive Transcranial Magnetic Stimulation (rTMS) Modulates Evoked-Gamma Frequency Oscillations in Autism Spectrum Disorder (ASD).
Baruth JM, Casanova MF, El-Baz A, Horrell T, Mathai G, Sears L, Sokhadze E.
Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY, USA.
It has been reported that individuals with Autism Spectrum Disorder (ASD) have abnormal reactions to the sensory environment and visuo-perceptual abnormalities. Electrophysiological research has provided evidence that gamma band activity (30-80 Hz) is a physiological indicator of the co-activation of cortical cells engaged in processing visual stimuli and integrating different features of a stimulus. A number of studies have found augmented and indiscriminative gamma band power at early stages of visual processing in ASD; this may be related to decreased inhibitory processing and an increase in the ratio of cortical excitation to inhibition. Low frequency or ‘slow’ (≤1HZ) repetitive transcranial magnetic stimulation (rTMS) has been shown to increase inhibition of stimulated cortex by the activation of inhibitory circuits.
We wanted to test the hypothesis of gamma band abnormalities at early stages of visual processing in ASD by investigating relative evoked (i.e. ~ 100 ms) gamma power in 25 subjects with ASD and 20 age-matched controls using Kanizsa illusory figures. Additionally, we wanted to assess the effects of 12 sessions of bilateral ‘slow’ rTMS to the dorsolateral prefrontal cortex (DLPFC) on evoked gamma activity using a randomized controlled design.
In individuals with ASD evoked gamma activity was not discriminative of stimulus type, whereas in controls early gamma power differences between target and non-target stimuli were highly significant. Following rTMS individuals with ASD showed significant improvement in discriminatory gamma activity between relevant and irrelevant visual stimuli. We also found significant improvement in the responses on behavioral questionnaires (i.e., irritability, repetitive behavior) as a result of rTMS.
We proposed that ‘slow’ rTMS may have increased cortical inhibitory tone which improved discriminatory gamma activity at early stages of visual processing. rTMS has the potential to become an important therapeutic tool in ASD treatment and has shown significant benefits in treating core symptoms of ASD with few, if any side effects.
PMID: 21116441
Appl Psychophysiol Biofeedback. 2010 Jun;35(2):147-61.
Low-frequency repetitive transcranial magnetic stimulation (rTMS) affects event-related potential measures of novelty processing in autism.
Sokhadze E, Baruth J, Tasman A, Mansoor M, Ramaswamy R, Sears L, Mathai G, El-Baz A, Casanova MF.
Department of Psychiatry and Behavioral Science, University of Louisville School of Medicine, Louisville, KY, 40292, USA.
In our previous study on individuals with autism spectrum disorder (ASD) (Sokhadze et al., Appl Psychophysiol Biofeedback 34:37-51, 2009a) we reported abnormalities in the attention-orienting frontal event-related potentials (ERP) and the sustained-attention centro-parietal ERPs in a visual oddball experiment. These results suggest that individuals with autism over-process information needed for the successful differentiation of target and novel stimuli. In the present study we examine the effects of low-frequency, repetitive Transcranial Magnetic Stimulation (rTMS) on novelty processing as well as behavior and social functioning in 13 individuals with ASD. Our hypothesis was that low-frequency rTMS application to dorsolateral prefrontal cortex (DLFPC) would result in an alteration of the cortical excitatory/inhibitory balance through the activation of inhibitory GABAergic double bouquet interneurons. We expected to find post-TMS differences in amplitude and latency of early and late ERP components. The results of our current study validate the use of low-frequency rTMS as a modulatory tool that altered the disrupted ratio of cortical excitation to inhibition in autism. After rTMS the parieto-occipital P50 amplitude decreased to novel distracters but not to targets; also the amplitude and latency to targets increased for the frontal P50 while decreasing to non-target stimuli. Low-frequency rTMS minimized early cortical responses to irrelevant stimuli and increased responses to relevant stimuli. Improved selectivity in early cortical responses lead to better stimulus differentiation at later-stage responses as was made evident by our P3b and P3a component findings. These results indicate a significant change in early, middle-latency and late ERP components at the frontal, centro-parietal, and parieto-occipital regions of interest in response to target and distracter stimuli as a result of rTMS treatment. Overall, our preliminary results show that rTMS may prove to be an important research tool or treatment modality in addressing the stimulus hypersensitivity characteristic of autism spectrum disorders.
PMID: 19941058
J Autism Dev Disord. 2009 Apr;39(4):619-34. Epub 2008 Nov 22.
Effects of low frequency repetitive transcranial magnetic stimulation (rTMS) on gamma frequency oscillations and event-related potentials during processing of illusory figures in autism.
Sokhadze EM, El-Baz A, Baruth J, Mathai G, Sears L, Casanova MF.
Cognitive Neuroscience Laboratory, Department of Psychiatry and Behavioral Science, University of Louisville School of Medicine, Louisville, KY 40292, USA.
Previous studies by our group suggest that the neuropathology of autism is characterized by a disturbance of cortical modularity. In this model a decrease in the peripheral neuropil space of affected minicolumns provides for an inhibitory deficit and a readjustment in their signal to noise bias during information processing. In this study we proposed using low frequency transcranial magnetic stimulation (rTMS) as a way increasing the surround inhibition of minicolumns in autism. Thirteen patients (ADOS and ADI-R diagnosed) and equal number of controls participated in the study. Repetitive TMS was delivered at 0.5 Hz, 2 times per week for 3 weeks. Outcome measures based on event-related potentials (ERP), induced gamma activity, and behavioral measures showed significant post-TMS improvement. The results suggest that rTMS offers a potential therapeutic intervention for autism.
PMID: 19030976

Autism and Mitochondrial Dysfunction:

The jury still undecided in regard to prevalence of  “mitochondrial dysfunction” in Autism Spectrum Discorders (ASD). However it appears to us, based on autistic users’ response to EarthPulse™, that there is direct correlation with mitochondrial dysfunction. It is widely accepted that oxidative stress is DEFINITELY a factor in ASD. Now call  me stupid, but wouldn’t oxidative stress cause detrimental effects on the mitochondria? Learn more how PEMF therapy helps mitochondria perform better on anti-aging machine page.

J Autism Dev Disord. 2012 Jan;42(1):105-15.
Proton magnetic resonance spectroscopy and MRI reveal no evidence for brain mitochondrial dysfunction in children with autism spectrum disorder.
Corrigan NM, Shaw DW, Richards TL, Estes AM, Friedman SD, Petropoulos H, Artru AA, Dager SR.
Department of Radiology, University of Washington, Seattle, WA, USA.
Brain mitochondrial dysfunction has been proposed as an etiologic factor in autism spectrum disorder (ASD). Proton magnetic resonance spectroscopic imaging ((1)HMRS) and MRI were used to assess for evidence of brain mitochondrial dysfunction in longitudinal samples of children with ASD or developmental delay (DD), and cross-sectionally in typically developing (TD) children at 3-4, 6-7 and 9-10 years-of-age. A total of 239 studies from 130 unique participants (54ASD, 22DD, 54TD) were acquired. (1)HMRS and MRI revealed no evidence for brain mitochondrial dysfunction in the children with ASD. Findings do not support a substantive role for brain mitochondrial abnormalities in the etiology or symptom expression of ASD, nor the widespread use of hyperbaric oxygen treatment that has been advocated on the basis of this proposed relationship.
PMID: 21404085 [PubMed – in process]
Seizure. 2012 Jan;21(1):17-20. Epub 2011 Sep 8.
Dravet syndrome: Patients with co-morbid SCN1A gene mutations and mitochondrial electron transport chain defects.
Craig AK, de Menezes MS, Saneto RP.
Division of Pediatric Neurology, Seattle Children’s Hospital/University of Washington, 4800 Sand Point Way NE, Seattle, WA 98105, United States.
To review our cohort of patients with Dravet syndrome and determine if patients with SCN1A mutations can also express mitochondrial disease due to electron transport chain dysfunction.
A retrospective chart review was used to describe clinical manifestations and retrieve biochemical testing, neuroimaging, gene sequencing, and electroencephalographic results of patients expressing both mitochondrial disease and Dravet syndrome.
Two children were found to have pathological mutations in the SCN1A gene and defects in mitochondrial electron transport chain complex activity. Both developed early febrile and medically intractable afebrile seizures with resulting neurocognitive decline. In the first patient, a muscle biopsy demonstrated complex IV dysfunction and in the second patient, complex III dysfunction. Patient 1 had more difficult to control seizures, and had features consistent with severe autism. Patient 2, who had earlier control and less severe seizures, did not have features of autism. Patient 1 had SCN1A missense mutation, c. 3734 G>A and patient 2 had a mutation, c. 3733 C>T, which produces a truncation mutation.
Our two patients underscore the need to rule out possible co-morbid mitochondrial disease and Dravet syndrome. The treatment of seizures for each is different, with valproic acid being first line treatment in Dravet syndrome and contraindicated in many mitochondrial diseases, due to possible induction of liver failure and death. Failure to pursue complete diagnostic evaluation might influence medication choice, possible seizure control, and developmental outcomes.
PMID: 21906962
Mol Psychiatry. 2011 Dec 6. doi: 10.1038/mp.2011.165. [Epub ahead of print]
A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures.
Rossignol DA, Frye RE.
International Child Development Resource Center, Melbourne, FL, USA.
Recent studies have implicated physiological and metabolic abnormalities in autism spectrum disorders (ASD) and other psychiatric disorders, particularly immune dysregulation or inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures (‘four major areas’). The aim of this study was to determine trends in the literature on these topics with respect to ASD. A comprehensive literature search from 1971 to 2010 was performed in these four major areas in ASD with three objectives. First, publications were divided by several criteria, including whether or not they implicated an association between the physiological abnormality and ASD. A large percentage of publications implicated an association between ASD and immune dysregulation/inflammation (416 out of 437 publications, 95%), oxidative stress (all 115), mitochondrial dysfunction (145 of 153, 95%) and toxicant exposures (170 of 190, 89%). Second, the strength of evidence for publications in each area was computed using a validated scale. The strongest evidence was for immune dysregulation/inflammation and oxidative stress, followed by toxicant exposures and mitochondrial dysfunction. In all areas, at least 45% of the publications were rated as providing strong evidence for an association between the physiological abnormalities and ASD. Third, the time trends in the four major areas were compared with trends in neuroimaging, neuropathology, theory of mind and genetics (‘four comparison areas’). The number of publications per 5-year block in all eight areas was calculated in order to identify significant changes in trends. Prior to 1986, only 12 publications were identified in the four major areas and 51 in the four comparison areas (42 for genetics). For each 5-year period, the total number of publications in the eight combined areas increased progressively. Most publications (552 of 895, 62%) in the four major areas were published in the last 5 years (2006-2010). Evaluation of trends between the four major areas and the four comparison areas demonstrated that the largest relative growth was in immune dysregulation/inflammation, oxidative stress, toxicant exposures, genetics and neuroimaging. Research on mitochondrial dysfunction started growing in the last 5 years. Theory of mind and neuropathology research has declined in recent years. Although most publications implicated an association between the four major areas and ASD, publication bias may have led to an overestimation of this association. Further research into these physiological areas may provide insight into general or subset-specific processes that could contribute to the development of ASD and other psychiatric disorders.Molecular Psychiatry advance online publication, 6 December 2011; doi:10.1038/mp.2011.165.
PMID: 22143005
Biol Trace Elem Res. 2011 Nov 30. [Epub ahead of print]
Increased Markers of Oxidative Stress in Autistic Children of the Sultanate of Oman.
Essa MM, Guillemin GJ, Waly MI, Al-Sharbati MM, Al-Farsi YM, Hakkim FL, Ali A, Al-Shafaee MS.
Department of Food Science and Nutrition, College of Agriculture and Marine Sciences, Sultan Qaboos University, PO No. 34, Al-Khoud, Muscat, Postal Code 123, Sultanate of Oman,
Autism spectrum disorder (ASD) is a neurodevelopmental disorder of early childhood, and an enumeration about its etiology and consequences is still limited. Oxidative stress-induced mechanisms are believed to be the major cause for ASD. In this study 19 autistic and 19 age-matched normal Omani children were recruited to analyze their degree of redox status and a prewritten consent was obtained. Blood was withdrawn from subjects in heparin-coated tube, and plasma was separated. Plasma oxidative stress indicators such as nitric oxide (NO), malondialdehyde (MDA), protein carbonyl, and lactate to pyruvate ratio were quantified using commercially available kits. A significant elevation was observed in the levels of NO, MDA, protein carbonyl, and lactate to pyruvate ratio in the plasma of Omani autistic children as compared to their age-matched controls. These oxidative stress markers are strongly associated with major cellular injury and manifest severe mitochondrial dysfunction in autistic pathology. Our results also suggest that oxidative stress might be involved in the pathogenesis of ASD, and these parameters could be considered as diagnostic markers to ensure the prevalence of ASD in Omani children. However, the oxidative stress-induced molecular mechanisms in ASD should be studied in detail.
PMID: 22127832
Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):E1070-9. Epub 2011 Oct 24.
Regulable neural progenitor-specific Tsc1 loss yields giant cells with organellar dysfunction in a model of tuberous sclerosis complex.
Goto J, Talos DM, Klein P, Qin W, Chekaluk YI, Anderl S, Malinowska IA, Di Nardo A, Bronson RT, Chan JA, Vinters HV, Kernie SG, Jensen FE, Sahin M, Kwiatkowski DJ.
Translational Medicine Division, Department of Medicine, Brigham and Women’s Hospital, Boston, USA.
Tuberous sclerosis complex (TSC) is a multiorgan genetic disease in which brain involvement causes epilepsy, intellectual disability, and autism. The hallmark pathological finding in TSC is the cerebral cortical tuber and its unique constituent, giant cells. However, an animal model that replicates giant cells has not yet been described. Here, we report that mosaic induction of Tsc1 loss in neural progenitor cells in Tsc1(cc) Nestin-rtTA(+) TetOp-cre(+) embryos by doxycycline leads to multiple neurological symptoms, including severe epilepsy and premature death. Strikingly, Tsc1-null neural progenitor cells develop into highly enlarged giant cells with enlarged vacuoles. We found that the vacuolated giant cells had multiple signs of organelle dysfunction, including markedly increased mitochondria, aberrant lysosomes, and elevated cellular stress. We found similar vacuolated giant cells in human tuber specimens. Postnatal rapamycin treatment completely reversed these phenotypes and rescued the mutants from epilepsy and premature death, despite prenatal onset of Tsc1 loss and mTOR complex 1 activation in the developing brain. This TSC brain model provides insights into the pathogenesis and organelle dysfunction of giant cells, as well as epilepsy control in patients with TSC.
PMID: 22025691
PMCID: PMC3214999
 J Neurodev Disord. 2011 Sep;3(3):211-24. Epub 2011 May 27.
FMR1 premutation and full mutation molecular mechanisms related to autism.
Hagerman R, Au J, Hagerman P.
Department of Pediatrics, University of California, Davis, School of Medicine, Sacramento, CA, USA,
Fragile X syndrome (FXS) is caused by an expanded CGG repeat (>200 repeats) in the 5′ un-translated portion of the fragile X mental retardation 1 gene (FMR1) leading to a deficiency or absence of the FMR1 protein (FMRP). FMRP is an RNA-binding protein that regulates the translation of a number of other genes that are important for synaptic development and plasticity. Furthermore, many of these genes, when mutated, have been linked to autism in the general population, which may explain the high comorbidity that exists between FXS and autism spectrum disorders (ASD). Additionally, premutation repeat expansions (55 to 200 CGG repeats) may also give rise to ASD through a different molecular mechanism that involves a direct toxic effect of FMR1 mRNA. It is believed that RNA toxicity underlies much of the premutation-related involvement, including developmental concerns like autism, as well as neurodegenerative issues with aging such as the fragile X-associated tremor ataxia syndrome (FXTAS). RNA toxicity can also lead to mitochondrial dysfunction, which is common in older premutation carriers both with and without FXTAS. Many of the problems with cellular dysregulation in both premutation and full mutation neurons also parallel the cellular abnormalities that have been documented in idiopathic autism. Research regarding dysregulation of neurotransmitter systems caused by the lack of FMRP in FXS, including metabotropic glutamate receptor 1/5 (mGluR1/5) pathway and GABA pathways, has led to new targeted treatments for FXS. Preliminary evidence suggests that these new targeted treatments will also be beneficial in non-fragile X forms of autism.
PMID: 21617890
J Autism Dev Disord. 2011 Aug 19.
Further Commentary on Mitochondrial Dysfunction in Autism Spectrum Disorder: Assessment and Treatment Considerations.
Dager SR, Corrigan NM, Estes A, Shaw DW.
Department of Radiology, University of Washington, 1100 NE 45th St. Suite 555, Seattle, WA, 98105, USA,
The authors respond to a recent letter (Rossignol and Frye 2011) critical of their paper, “Proton magnetic resonance spectroscopy and MRI reveal no evidence for brain mitochondrial dysfunction in children with autism spectrum disorder” (Corrigan et al. 2011). Further considerations regarding the assessment of mitochondrial dysfunction in autism spectrum disorder, and related treatment considerations, are discussed.
PMID: 21853372
Mol Neurobiol. 2011 Aug;44(1):83-92. Epub 2011 Jun 21.
The mitochondrial aspartate/glutamate carrier AGC1 and calcium homeostasis: physiological links and abnormalities in autism.
Napolioni V, Persico AM, Porcelli V, Palmieri L.
Laboratory of Molecular Psychiatry & Neurogenetics, University Campus Bio-Medico, Via Alvaro del Portillo 21, 00128 Rome, Italy.
Autism spectrum disorder (ASD) is a severe, complex neurodevelopmental disorder characterized by impairments in reciprocal social interaction and communication, and restricted and stereotyped patterns of interests and behaviors. Recent evidence has unveiled an important role for calcium (Ca(2+)) signaling in the pathogenesis of ASD. Post-mortem studies of autistic brains have pointed toward abnormalities in mitochondrial function as possible downstream consequences of altered Ca(2+) signaling, abnormal synapse formation, and dysreactive immunity. SLC25A12, an ASD susceptibility gene, encodes the Ca(2+)-regulated mitochondrial aspartate-glutamate carrier, isoform 1 (AGC1). AGC1 is an important component of the malate/aspartate shuttle, a crucial system supporting oxidative phosphorylation and adenosine triphosphate (ATP) production. Here, we review the physiological roles of AGC1, its links to calcium homeostasis, and its involvement in autism pathogenesis.
PMID: 21691713
Med Sci Monit. 2011 Jun;17(6):PI15-23.
A prospective double-blind, randomized clinical trial of levocarnitine to treat autism spectrum disorders.
Geier DA, Kern JK, Davis G, King PG, Adams JB, Young JL, Geier MR.
The Institute of Chronic Illnesses, Inc., Silver Spring, MD, USA.
L-carnitine was proposed as a potential treatment for patients diagnosed with an autism spectrum disorder to improve mitochondrial dysfunction, but no prior randomized controlled trials have been conducted.
Thirty subjects diagnosed with an ASD were randomly assigned to receive a standardized regimen (50 mg L-carnitine/kg bodyweight/day) of liquid L-carnitine (n=19) or placebo (n=11) for 3-months. Measures included changes in professionally completed Childhood Autism Rating Scale (CARS), hand muscle testing, and modified clinical global impression (CGI) forms; parent completed Autism Treatment Evaluation Checklist (ATEC), treatment adherence measurement (TAM), frequency and intensity of side effect rating (FISER)/global rating of side effect burden (GRSEB)/patient report of incidence of side effects (PRISE) forms; and lab testing.
Significant improvements were observed in CARS (-2.03, 95% CI=-3.7 to -0.31), CGI (-0.69, 95% CI=-1.1 to -0.06), and ATEC scores. Significant correlations between changes in serum free-carnitine levels and positive clinical changes were observed for hand muscle strength (R2=0.23, P=0.046), cognitive scores (R2=0.27, P=0.019), and CARS scores (R2=0.20, P=0.047). Study subjects were protocol-compliant (average adherence was >85%) and generally well-tolerated the L-carnitine therapy given.
L-carnitine therapy (50 mg/kilogram-bodyweight/day) administered for 3-months significantly improved several clinical measurements of ASD severity, but subsequent studies are recommended.
PMID: 21629200
J Autism Dev Disord. 2011 May 10. [Epub ahead of print]
Substantial Problems with Measuring Brain Mitochondrial Dysfunction in Autism Spectrum Disorder Using Magnetic Resonance Spectroscopy.
Rossignol DA, Frye RE.
International Child Development Resource Center, 3800 West Eau Gallie Blvd, Melbourne, FL, 32934, USA,
PMID: 21556966
Int J Dev Neurosci. 2011 May;29(3):283-94. Epub 2010 Sep 15.
Three phases of DiGeorge/22q11 deletion syndrome pathogenesis during brain development: patterning, proliferation, and mitochondrial functions of 22q11 genes.
Meechan DW, Maynard TM, Tucker ES, LaMantia AS.
Department of Pharmacology and Physiology and GW Institute for Neuroscience, The George Washington University School of Medicine and Health Sciences
DiGeorge, or 22q11 deletion syndrome (22q11DS), the most common survivable human genetic deletion disorder, is caused by deletion of a minimum of 32 contiguous genes on human chromosome 22, and presumably results from diminished dosage of one, some, or all of these genes–particularly during development. Nevertheless, the normal functions of 22q11 genes in the embryo or neonate, and their contribution to developmental pathogenesis that must underlie 22q11DS are not well understood. Our data suggests that a substantial number of 22q11 genes act specifically and in concert to mediate early morphogenetic interactions and subsequent cellular differentiation at phenotypically compromised sites–the limbs, heart, face and forebrain. When dosage of a broad set of these genes is diminished, early morphogenesis is altered, and initial 22q11DS phenotypes are established. Thereafter, functionally similar subsets of 22q11 genes–especially those that influence the cell cycle or mitochondrial function–remain expressed, particularly in the developing cerebral cortex, to regulate neurogenesis and synaptic development. When dosage of these genes is diminished, numbers, placement and connectivity of neurons and circuits essential for normal behavior may be disrupted. Such disruptions likely contribute to vulnerability for schizophrenia, autism, or attention deficit/hyperactivity disorder seen in most 22q11DS patients.
PMID: 20833244
Pediatr Res. 2011 May;69(5 Pt 2):41R-7R.
Mitochondrial dysfunction can connect the diverse medical symptoms associated with autism spectrum disorders.
Frye RE, Rossignol DA.
Department of Pediatrics, The Children’s Learning Institute, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
Autism spectrum disorder (ASD) is a devastating neurodevelopmental disorder. Over the past decade, evidence has emerged that some children with ASD suffer from undiagnosed comorbid medical conditions. One of the medical disorders that has been consistently associated with ASD is mitochondrial dysfunction. Individuals with mitochondrial disorders without concomitant ASD manifest dysfunction in multiple high-energy organ systems, such as the central nervous, muscular, and gastrointestinal (GI) systems. Interestingly, these are the identical organ systems affected in a significant number of children with ASD. This finding increases the possibility that mitochondrial dysfunction may be one of the keys that explains the many diverse symptoms observed in some children with ASD. This article will review the importance of mitochondria in human health and disease, the evidence for mitochondrial dysfunction in ASD, the potential role of mitochondrial dysfunction in the comorbid medical conditions associated with ASD, and how mitochondrial dysfunction can bridge the gap for understanding how these seemingly disparate medical conditions are related. We also review the limitations of this evidence and other possible explanations for these findings. This new understanding of ASD should provide researchers a pathway for understanding the etiopathogenesis of ASD and clinicians the potential to develop medical therapies.
PMID: 21289536 PMCID: PMC3179978
Toxicol Environ Chem. 2011 May;93(5-6):1251-1273. Epub 2011 May 20.
The plausibility of a role for mercury in the etiology of autism: a cellular perspective.
Garrecht M, Austin DW.
Swinburne Autism Bio-Research Initiative, Faculty of Life and Social Sciences, Swinburne University of Technology, Hawthorn, Victoria 3122, Australia.
Autism is defined by a behavioral set of stereotypic and repetitious behavioral patterns in combination with social and communication deficits. There is emerging evidence supporting the hypothesis that autism may result from a combination of genetic susceptibility and exposure to environmental toxins at critical moments in development. Mercury (Hg) is recognized as a ubiquitous environmental neurotoxin and there is mounting evidence linking it to neurodevelopmental disorders, including autism. Of course, the evidence is not derived from experimental trials with humans but rather from methods focusing on biomarkers of Hg damage, measurements of Hg exposure, epidemiological data, and animal studies. For ethical reasons, controlled Hg exposure in humans will never be conducted. Therefore, to properly evaluate the Hg-autism etiological hypothesis, it is essential to first establish the biological plausibility of the hypothesis. This review examines the plausibility of Hg as the primary etiological agent driving the cellular mechanisms by which Hg-induced neurotoxicity may result in the physiological attributes of autism. Key areas of focus include: (1) route and cellular mechanisms of Hg exposure in autism; (2) current research and examples of possible genetic variables that are linked to both Hg sensitivity and autism; (3) the role Hg may play as an environmental toxin fueling the oxidative stress found in autism; (4) role of mitochondrial dysfunction; and (5) possible role of Hg in abnormal neuroexcitory and excitotoxity that may play a role in the immune dysregulation found in autism. Future research directions that would assist in addressing the gaps in our knowledge are proposed.
PMID: 22163375
Lipids Health Dis. 2011 Apr 21;10:62.
Plasma fatty acids as diagnostic markers in autistic patients from Saudi Arabia.
El-Ansary AK, Bacha AG, Al-Ayahdi LY.
Biochemistry Department, Science College, King Saud University, P,O Box 22452, Zip Code 11495, Riyadh, Saudi Arabia.
Autism is a family of developmental disorders of unknown origin. The disorder is characterized by behavioral, developmental, neuropathological and sensory abnormalities, and is usually diagnosed between the ages of 2 and 10 with peak prevalence rates observed in children aged 5-8 years. Recently, there has been heightened interest in the role of plasma free fatty acids (FA) in the pathology of neurological disorders. The aim of this study is to compare plasma fatty acid profiles of Saudi autistic patients with those of age-matching control subjects in an attempt to clarify the role of FA in the etiology of autism.
26 autistic patients together with 26-age-matching controls were enrolled in the present study. Methyl esters of FA were extracted with hexane, and the fatty acid composition of the extract was analyzed on a gas chromatography.
The obtained data proved that fatty acids are altered in the plasma of autistic patients, specifically showing an increase in most of the saturated fatty acids except for propionic acid, and a decrease in most of polyunsaturated fatty acids. The altered fatty acid profile was discussed in relation to oxidative stress, mitochondrial dysfunction and the high lead (Pb) concentration previously reported in Saudi autistic patients. Statistical analysis of the obtained data shows that most of the measured fatty acids were significantly different in autistic patients compared to age -matching controls.
Receiver Operating Characteristic (ROC) curve analysis shows satisfactory values of area under the curve (AUC) which could reflect the high degree of specificity and sensitivity of the altered fatty acids as biomarkers in autistic patients from Saudi Arabia.
PMID: 21510882
BMC Med Genet. 2011 Apr 6;12:50.
Reassessing the role of mitochondrial DNA mutations in autism spectrum disorder.
Álvarez-Iglesias V, Mosquera-Miguel A, Cuscó I, Carracedo Á, Pérez-Jurado LA, Salas A.
Unidade de Xenética, Instituto de Medicina Legal and Departamento de Anatomía Patolóxica e Ciencias Forenses, Facultade de Medicina, Universidade de Santiago de Compostela, Galicia, Spain.
There is increasing evidence that impairment of mitochondrial energy metabolism plays an important role in the pathophysiology of autism spectrum disorders (ASD; OMIM number: 209850). A significant proportion of ASD cases display biochemical alterations suggestive of mitochondrial dysfunction and several studies have reported that mutations in the mitochondrial DNA (mtDNA) molecule could be involved in the disease phenotype.
We analysed a cohort of 148 patients with idiopathic ASD for a number of mutations proposed in the literature as pathogenic in ASD. We also carried out a case control association study for the most common European haplogroups (hgs) and their diagnostic single nucleotide polymorphisms (SNPs) by comparing cases with 753 healthy and ethnically matched controls.
We did not find statistical support for an association between mtDNA mutations or polymorphisms and ASD.
Our results are compatible with the idea that mtDNA mutations are not a relevant cause of ASD and the frequent observation of concomitant mitochondrial dysfunction and ASD could be due to nuclear factors influencing mitochondrion functions or to a more complex interplay between the nucleus and the mitochondrion/mtDNA.
PMID: 21470425
Acta Psychiatr Scand. 2011 Feb;123(2):95. doi: 10.1111/j.1600-0447.2010.01654.x.
Suggestive evidence on the genetic link between mitochondria dysfunction and autism.
Villafuerte S.
Comment on
Acta Psychiatr Scand. 2011 Feb;123(2):118-24.
PMID: 21198452
Mol Psychiatry. 2011 Jan 25. [Epub ahead of print]
Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis.
Rossignol DA, Frye RE.
International Child Development Resource Center, Melbourne, FL, USA.
A comprehensive literature search was performed to collate evidence of mitochondrial dysfunction in autism spectrum disorders (ASDs) with two primary objectives. First, features of mitochondrial dysfunction in the general population of children with ASD were identified. Second, characteristics of mitochondrial dysfunction in children with ASD and concomitant mitochondrial disease (MD) were compared with published literature of two general populations: ASD children without MD, and non-ASD children with MD. The prevalence of MD in the general population of ASD was 5.0% (95% confidence interval 3.2, 6.9%), much higher than found in the general population (∼0.01%). The prevalence of abnormal biomarker values of mitochondrial dysfunction was high in ASD, much higher than the prevalence of MD. Variances and mean values of many mitochondrial biomarkers (lactate, pyruvate, carnitine and ubiquinone) were significantly different between ASD and controls. Some markers correlated with ASD severity. Neuroimaging, in vitro and post-mortem brain studies were consistent with an elevated prevalence of mitochondrial dysfunction in ASD. Taken together, these findings suggest children with ASD have a spectrum of mitochondrial dysfunction of differing severity. Eighteen publications representing a total of 112 children with ASD and MD (ASD/MD) were identified. 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. The prevalence of many of these abnormalities was similar to the general population of children with MD, suggesting that ASD/MD represents a distinct subgroup of children with MD. Most ASD/MD cases (79%) were not associated with genetic abnormalities, raising the possibility of secondary mitochondrial dysfunction. Treatment studies for ASD/MD were limited, although improvements were noted in some studies with carnitine, co-enzyme Q10 and B-vitamins. Many studies suffered from limitations, including small sample sizes, referral or publication biases, and variability in protocols for selecting children for MD workup, collecting mitochondrial biomarkers and defining MD. Overall, this evidence supports the notion that mitochondrial dysfunction is associated with ASD. Additional studies are needed to further define the role of mitochondrial dysfunction in ASD.
Molecular Psychiatry advance online publication, 25 January 2011; doi:10.1038/mp.2010.136.
PMID: 21263444
JAMA. 2010 Dec 1;304(21):2389-96.
Mitochondrial dysfunction in autism.
Giulivi C, Zhang YF, Omanska-Klusek A, Ross-Inta C, Wong S, Hertz-Picciotto I, Tassone F, Pessah IN.
University of California, School of Veterinary Medicine, Department of Molecular Biosciences, One Shields Avenue, 1120 Haring Hall, Davis, CA 95616, USA.
Impaired mitochondrial function may influence processes highly dependent on energy, such as neurodevelopment, and contribute to autism. No studies have evaluated mitochondrial dysfunction and mitochondrial DNA (mtDNA) abnormalities in a well-defined population of children with autism.
To evaluate mitochondrial defects in children with autism.
Observational study using data collected from patients aged 2 to 5 years who were a subset of children participating in the Childhood Autism Risk From Genes and Environment study in California, which is a population-based, case-control investigation with confirmed autism cases and age-matched, genetically unrelated, typically developing controls, that was launched in 2003 and is still ongoing. Mitochondrial dysfunction and mtDNA abnormalities were evaluated in lymphocytes from 10 children with autism and 10 controls.
Oxidative phosphorylation capacity, mtDNA copy number and deletions, mitochondrial rate of hydrogen peroxide production, and plasma lactate and pyruvate.
The reduced nicotinamide adenine dinucleotide (NADH) oxidase activity (normalized to citrate synthase activity) in lymphocytic mitochondria from children with autism was significantly lower compared with controls (mean, 4.4 [95% confidence interval {CI}, 2.8-6.0] vs 12 [95% CI, 8-16], respectively; P = .001). The majority of children with autism (6 of 10) had complex I activity below control range values. Higher plasma pyruvate levels were found in children with autism compared with controls (0.23 mM [95% CI, 0.15-0.31 mM] vs 0.08 mM [95% CI, 0.04-0.12 mM], respectively; P = .02). Eight of 10 cases had higher pyruvate levels but only 2 cases had higher lactate levels compared with controls. These results were consistent with the lower pyruvate dehydrogenase activity observed in children with autism compared with controls (1.0 [95% CI, 0.6-1.4] nmol × [min × mg protein](-1) vs 2.3 [95% CI, 1.7-2.9] nmol × [min × mg protein](-1), respectively; P = .01). Children with autism had higher mitochondrial rates of hydrogen peroxide production compared with controls (0.34 [95% CI, 0.26-0.42] nmol × [min × mg of protein](-1) vs 0.16 [95% CI, 0.12-0.20] nmol × [min × mg protein](-1) by complex III; P = .02). Mitochondrial DNA overreplication was found in 5 cases (mean ratio of mtDNA to nuclear DNA: 239 [95% CI, 217-239] vs 179 [95% CI, 165-193] in controls; P = 10(-4)). Deletions at the segment of cytochrome b were observed in 2 cases (ratio of cytochrome b to ND1: 0.80 [95% CI, 0.68-0.92] vs 0.99 [95% CI, 0.93-1.05] for controls; P = .01).
In this exploratory study, children with autism were more likely to have mitochondrial dysfunction, mtDNA overreplication, and mtDNA deletions than typically developing children.
PMID: 21119085
J Child Neurol. 2010 Oct;25(10):1232-5. Epub 2010 Feb 22.
5q14.3 deletion manifesting as mitochondrial disease and autism: case report.
Ezugha H, Goldenthal M, Valencia I, Anderson CE, Legido A, Marks H.
Sections of Neurology, St Christopher’s Hospital for Children, Drexel University College of Medicine, Philadelphia, PA, USA.
Mitochondrial disorders are usually associated with defects of 1 or more of the 5 complexes (I to V) of the electron transport chain, or respiratory chain. Complex I and IV are the 2 most frequent abnormalities of the electron transport chain in humans. The authors report the case of a 12-year-old boy with dysmorphic facies, mental retardation, autism, epilepsy, and leg weakness. Buccal swab electron transport chain analysis revealed severe decrease in complex IV and mild reduction in complex I activity levels. Chromosomal microarray studies, using array-based comparative genomic hybridization, revealed a 1-Mb deletion in the 5q14.3 region. This case illustrates that this deletion can be associated with complex I and IV deficits, hence manifesting as a mitochondrial disease. It could be hypothesized that genes that either encode or regulate the expression and/or assembly of complex IV or I subunits are located within the deleted region of 5q14.3.
Comment in
J Child Neurol. 2011 May;26(5):659-60; author reply 660-1.
PMID: 20179003
Mol Autism. 2010 Sep 21;1(1):12.
Fragile X and autism: Intertwined at the molecular level leading to targeted treatments.
Hagerman R, Hoem G, Hagerman P.
Department of Pediatrics, University of California, Davis, School of Medicine, Sacramento, California, USA.
Fragile X syndrome (FXS) is caused by an expanded CGG repeat (> 200 repeats) in the 5′ untranslated portion of the fragile mental retardation 1 gene (FMR1), leading to deficiency or absence of the FMR1 protein (FMRP). FMRP is an RNA carrier protein that controls the translation of several other genes that regulate synaptic development and plasticity. Autism occurs in approximately 30% of FXS cases, and pervasive developmental disorder, not otherwise specified (PDD-NOS) occurs in an additional 30% of cases. Premutation repeat expansions (55 to 200 CGG repeats) may also give rise to autism spectrum disorders (ASD), including both autism and PDD-NOS, through a different molecular mechanism that involves a direct toxic effect of the expanded CGG repeat FMR1 mRNA. RNA toxicity can also lead to aging effects including tremor, ataxia and cognitive decline, termed fragile X-associated tremor ataxia syndrome (FXTAS), in premutation carriers in late life. In studies of mice bearing premutation expansions, there is evidence of early postnatal neuronal cell toxicity, presenting as reduced cell longevity, decreased dendritic arborization and altered synaptic morphology. There is also evidence of mitochondrial dysfunction in premutation carriers. Many of the problems with cellular dysregulation in both premutation and full mutation neurons also parallel the cellular abnormalities that have been documented in autism without fragile X mutations. Research regarding dysregulation of neurotransmitter systems in FXS, including the metabotropic glutamate receptor (mGluR)1/5 pathway and γ aminobutyric acid (GABA)A pathways, have led to new targeted treatments for FXS. Preliminary evidence suggests that these new targeted treatments will also be beneficial in non-fragile X forms of autism.
PMID: 20858229
Invest Clin. 2010 Sep;51(3):423-31.
Autism associated to a deficiency of complexes III and IV of the mitochondrial respiratory chain.
Guevara-Campos J, González-Guevara L, Briones P, López-Gallardo E, Bulán N, Ruiz-Pesini E, Ramnarine D, Montoya J.
Felipe Guevara Rojas Hospital, Pediatrics Service, University of Oriente, El Tigre-Anzoátegui, Venezuela.
Autism is the prototype of generalized developmental disorders or what today are called autism spectrum disorders. In most cases it is impossible to detect a specific etiology. It is estimated that a causative diagnosis may be shown in approximately 10-37% of the cases, including, congenital rubella, tuberous sclerosis, chromosome abnormalities such as fragile X syndrome and 22q13.3 deletion syndrome, Angelman, Williams, Smith-Magenis, Sotos, Cornelia de Lange, Möbius, Joubert and Goldenhar syndromes, Ito’s hypomelanosis, as well as certain cerebral malformations and several inherited metabolic disorders. The case of a 3-year old girl is described, who was considered as autistic according to the criteria established by the DSM-IV manual for psychiatric disorders. She showed a delay in psychomotor development since she was 18 months old; she pronounces very few words (10), points to some objects, does not look up and it is hard to establish eye contact with her. She has paradoxical deafness and therefore, does not respond when called or when she is given orders, she is beginning to walk. She has not convulsions. Laboratory tests showed an anion gap of 31.6 mEq/L, lactate: 2.55: mmol/L, pyruvate: 0.06 mmol/L, and elevated lactate to/pyruvate ratio: 42.5. Under optical microscopy a muscular biopsy showed a reduction of the diameter of muscular fibers. The study of energy metabolism showed a partial deficiency of complexes III and IV of the respiratory chain, which allowed us to conclude that this was a mitochondrial dysfunction with an autistic clinical spectrum.
PMID: 21302592
Neurotherapeutics. 2010 Jul;7(3):232-40.
Improving the prediction of response to therapy in autism.
Bent S, Hendren RL.
Department of Psychiatry, University of California, San Francisco, San Francisco, California 94121, USA.
Autism is a heterogeneous disorder involving complex mechanisms and systems occurring at diverse times. Because an individual child with autism may have only a subset of all possible abnormalities at a specific time, it may be challenging to identify beneficial effects of an intervention in double-blind, randomized, controlled trials, which compare the mean responses to treatments. Beneficial effects in a small subset of children may be obscured by the lack of effect in the majority. We review the evidence for several potential model systems of biochemical abnormalities that may contribute to the etiology of autism, we describe potential biomarkers or treatment targets for each of these abnormalities, and we provide illustrative treatment trials using this methodology. Potential model systems include immune over and under reactivity, inflammation, oxidative stress, free fatty acid metabolism, mitochondrial dysfunction, and excitotoxicity. Including potential biomarkers and targeted treatments in clinical trials for autism provides a potential method for limiting the heterogeneity of enrolled subjects, which may improve the power of studies to identify beneficial effects of treatments while also improving the understanding of the disease.
PMID: 20643375
Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):1130-7. Epub 2010 May 9.
Mitochondrial dysfunction in autism spectrum disorders: cause or effect?
Palmieri L, Persico AM.
Laboratory of Biochemistry and Molecular Biology, Department of Pharmaco-Biology, University of Bari, Via Orabona 4, 70125, Bari, Italy.
Autism Spectrum Disorders encompass severe developmental disorders characterized by variable degrees of impairment in language, communication and social skills, as well as by repetitive and stereotypic patterns of behaviour. Substantial percentages of autistic patients display peripheral markers of mitochondrial energy metabolism dysfunction, such as (a) elevated lactate, pyruvate, and alanine levels in blood, urine and/or cerebrospinal fluid, (b) serum carnitine deficiency, and/or (c) enhanced oxidative stress. These biochemical abnormalities are accompanied by highly heterogeneous clinical presentations, which generally (but by no means always) encompass neurological and systemic symptoms relatively unusual in idiopathic autistic disorder. In some patients, these abnormalities have been successfully explained by the presence of specific mutations or rearrangements in their mitochondrial or nuclear DNA. However, in the majority of cases, abnormal energy metabolism cannot be immediately linked to specific genetic or genomic defects. Recent evidence from post-mortem studies of autistic brains points toward abnormalities in mitochondrial function as possible downstream consequences of dysreactive immunity and altered calcium (Ca(2+)) signalling.
PMID: 20441769
Dev Disabil Res Rev. 2010 Jun;16(2):144-53.
Autism and mitochondrial disease.
Haas RH.
Department of Neurosciences, UCSD Mitochondrial and Metabolic Disease Center, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Autism spectrum disorder (ASD) as defined by the revised Diagnostic and Statistical Manual of Mental Disorders: DSM IVTR criteria (American Psychiatric Association [2000] Washington, DC: American Psychiatric Publishing) as impairment before the age of 3 in language development and socialization with the development of repetitive behaviors, appears to be increased in incidence and prevalence. Similarly, mitochondrial disorders are increasingly recognized. Although overlap between these disorders is to be expected, accumulating clinical, genetic, and biochemical evidence suggests that mitochondrial dysfunction in ASD is more commonly seen than expected. Some patients with ASD phenotypes clearly have genetic-based primary mitochondrial disease. This review will examine the data linking autism and mitochondria.
PMID: 20818729
Eur Child Adolesc Psychiatry. 2010 May;19(5):441-8. Epub 2009 Nov 6.
Expression analyses of the mitochondrial complex I 75-kDa subunit in early onset schizophrenia and autism spectrum disorder: increased levels as a potential biomarker for early onset schizophrenia.
Taurines R, Thome J, Duvigneau JC, Forbes-Robertson S, Yang L, Klampfl K, Romanos J, Müller S, Gerlach M, Mehler-Wex C.
Department of Child and Adolescent Psychiatry and Psychotherapy, University of Würzburg, Würzburg, Germany.
Searching for a peripheral biological marker for schizophrenia, we previously reported on elevated mitochondrial complex I 75-kDa subunit mRNA-blood concentrations in early onset schizophrenia (EOS). The aim of this study was to further evaluate the utility of this gene as a potential marker for schizophrenia. Both-schizophrenia and autism-are suggested to be neuronal maldevelopmental disorders with reports of mitochondrial dysfunction and increased oxidative stress. Therefore we have investigated the expression levels of mitochondrial complex I 75-kDa subunit mRNA in whole blood of children with autistic spectrum disorder (ASD) and a group of adolescent acute first-episode EOS patients in comparison to matched controls. We have found that compared to the respective controls only the group of EOS patients-and not the ASD group-showed a significantly altered expression of the complex I 75-kDa subunit mRNA. Although further studies are necessary to test for the specificity of this marker, our findings point to the potential use of the mitochondrial complex I as a biomarker for schizophrenia.
PMID: 19894076
Altern Med Rev. 2010 Apr;15(1):15-32.
Biomarker-guided interventions of clinically relevant conditions associated with autism spectrum disorders and attention deficit hyperactivity disorder.
Bradstreet JJ, Smith S, Baral M, Rossignol DA.
International Child Development Resource Center, Melbourne, FL 32934, USA.
Autism spectrum disorders (ASD) and attention-deficit hyperactivity disorder (ADHD) are common and complex neurodevelopmental conditions. Diagnostic criteria for these conditions have traditionally relied solely on behavioral criteria without consideration for potential biomedical underpinnings. Newer evidence, however, reveals that ASDs are associated with: oxidative stress; decreased methylation capacity; limited production of glutathione; mitochondrial dysfunction; intestinal dysbiosis; increased toxic metal burden; immune dysregulation, characterized by a unique inflammatory bowel disease and immune activation of neuroglial cells; and ongoing brain hypoperfusion. Many of these same problems are common features in children with ADHD. These medical conditions, whether co-morbidities or etiopathogenic, would be expected to have synergistically negative effects on the development, cognition, focus, and attention of affected children. It is likely these biological abnormalities contribute significantly to the behavioral symptoms intrinsic in these diagnoses. However, treatment for these underlying medical disorders is clinically justified, even if no clear immediate behavioral improvements are observed. This article reviews the medical literature and discusses the authors clinical experience using various biomarkers for measuring oxidative stress, methylation capacity and transsulfuration, immune function, gastrointestinal problems, and toxic metal burden. These biomarkers provide useful guides for selection, efficacy, and sufficiency of biomedical interventions. The use of these biomarkers is of great importance in young children with ADHD or individuals of any age with ASD, because typically they cannot adequately communicate regarding their symptoms.
Comment in
Altern Med Rev. 2010 Sep;15(3):187.
PMID: 20359266
Curr Opin Neurol. 2010 Apr;23(2):103-10.
Contributions of the environment and environmentally vulnerable physiology to autism spectrum disorders.
Herbert MR.
TRANSCEND Research Program, Pediatric Neurology, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
This review presents a rationale and evidence for contributions of environmental influences and environmentally vulnerable physiology to autism spectrum disorders (ASDs).
Recent studies suggest a substantial increase in ASD prevalence above earlier Centers for Disease Control figures of one in 150, only partly explicable by data artifacts, underscoring the possibility of environmental contributors to increased prevalence. Some gene variants in ASD confer altered vulnerability to environmental stressors and exposures. De-novo mutations and advanced parental age as a risk factor for ASD also suggest a role for environment. Systemic and central nervous system pathophysiology, including oxidative stress, neuroinflammation, and mitochondrial dysfunction can be consistent with a role for environmental influence (e.g. from air pollution, organophosphates, heavy metals) in ASD, and some of the underlying biochemical disturbances (such as abnormalities in glutathione, a critical antioxidant and detoxifier) can be reversed by targeted nutritional interventions. Dietary factors and food contaminants may contribute risk. Improvement and loss of diagnosis in some with ASD suggest brain circuitry amenable to environmental modulation.
Prevalence, genetic, exposure, and pathophysiological evidence all suggest a role for environmental factors in the inception and lifelong modulation of ASD. This supports the need for seeking targets for early and ongoing medical prevention and treatment of ASD.
PMID: 20087183
J Child Neurol. 2010 Apr;25(4):429-34. Epub 2009 Sep 22.
Fever plus mitochondrial disease could be risk factors for autistic regression.
Shoffner J, Hyams L, Langley GN, Cossette S, Mylacraine L, Dale J, Ollis L, Kuoch S, Bennett K, Aliberti A, Hyland K.
Medical Neurogenetics, LLC, Atlanta, Georgia 30338, USA.
Autistic spectrum disorders encompass etiologically heterogeneous persons, with many genetic causes. A subgroup of these individuals has mitochondrial disease. Because a variety of metabolic disorders, including mitochondrial disease show regression with fever, a retrospective chart review was performed and identified 28 patients who met diagnostic criteria for autistic spectrum disorders and mitochondrial disease. Autistic regression occurred in 60.7% (17 of 28), a statistically significant increase over the general autistic spectrum disorder population (P < .0001). Of the 17 individuals with autistic regression, 70.6% (12 of 17) regressed with fever and 29.4% (5 of 17) regressed without identifiable linkage to fever or vaccinations. None showed regression with vaccination unless a febrile response was present. Although the study is small, a subgroup of patients with mitochondrial disease may be at risk of autistic regression with fever. Although recommended vaccinations schedules are appropriate in mitochondrial disease, fever management appears important for decreasing regression risk.
PMID: 19773461
Prostaglandins Leukot Essent Fatty Acids. 2009 Oct;81(4):253-64. Epub 2009 Jul 15.
Novel plasma phospholipid biomarkers of autism: mitochondrial dysfunction as a putative causative mechanism.
Pastural E, Ritchie S, Lu Y, Jin W, Kavianpour A, Khine Su-Myat K, Heath D, Wood PL, Fisk M, Goodenowe DB.
Phenomenome Discoveries Inc., 204-407 Downey Road, Saskatoon, Saskatchewan, Canada S7N 4L8.
Autism is a neurological disorder that manifests as noticeable behavioral and developmental abnormalities predominantly in males between the ages of 2 and 10. Although the genetics, biochemistry and neuropathology of this disease have been extensively studied, underlying causal factors to this disease have remained elusive. Using a longitudinal trial design in which three plasma samples were collected from 15 autistic and 12 non-autistic age-matched controls over the course of 1 year, universal and unambiguous alterations in lipid metabolism were observed. Biomarkers of fatty acid elongation and desaturation (poly-unsaturated long chain fatty acids (PUFA) and/or saturated very long chain fatty acids (VLCFA)-containing ethanolamine phospholipids) were statistically elevated in all autistic subjects. In all 8 of the affected/non-affected sibling pairs, the affected sibling had higher levels of these biomarkers than the unaffected sibling. Exposure of neurons, astrocytes and hepatocytes in vitro to elevated extracellular glutamate levels resulted in lipid biomarker changes indistinguishable from those observed in autistic subjects. Glutamate stress also resulted in in vitro decreased levels of reduced glutathione (GSH), methionine and cysteine, in a similar way to the decreases we observed in autism plasma. Impaired mitochondrial fatty acid oxidation, elevated plasma VLCFAs, and glutamate toxicity as putative causal factors in the biochemistry, neuropathology, and gender bias in autism are discussed.
PMID: 19608392
World J Pediatr. 2009 Aug;5(3):169-76. Epub 2009 Aug 20.
Syndromic autism: causes and pathogenetic pathways.
Benvenuto A, Moavero R, Alessandrelli R, Manzi B, Curatolo P.
Department of Neuroscience, Pediatric Neurology Unit, Tor Vergata University, Italy.
Autism is a severe neurodevelopmental disorder known to have many different etiologies. In the last few years, significant progresses have been made in comprehending the causes of autism and their multiple impacts on the developing brain. This article aims to review the current understanding of the etiologies and the multiple pathogenetic pathways that are likely to lead to the autistic phenotype.
The PubMed database was searched with the keywords “autism” and “chromosomal abnormalities”, “metabolic diseases”, “susceptibility loci”.
Genetic syndromes, defined mutations, and metabolic diseases account for less than 20% of autistic patients. Alterations of the neocortical excitatory/inhibitory balance and perturbations of interneurons’ development represent the most probable pathogenetic mechanisms underlying the autistic phenotype in fragile X syndrome and tuberous sclerosis complex. Chromosomal abnormalities and potential candidate genes are strongly implicated in the disruption of neural connections, brain growth and synaptic/dendritic morphology. Metabolic and mitochondrial defects may have toxic effects on the brain cells, causing neuronal loss and altered modulation of neurotransmission systems.
A wide variety of cytogenetic abnormalities have been recently described, particularly in the low functioning individuals with dysmorphic features. Routine metabolic screening studies should be performed in the presence of autistic regression or suggestive clinical findings. As etiologies of autism are progressively discovered, the number of individuals with idiopathic autism will progressively shrink. Studies of genetic and environmentally modulated epigenetic factors are beginning to provide some clues to clarify the complexities of autism pathogenesis. The role of the neuropediatrician will be to understand the neurological basis of autism, and to identify more homogenous subgroups with specific biologic markers.
PMID: 19693459
J Neurosci. 2009 May 6;29(18):5926-37.
Tuberous sclerosis complex activity is required to control neuronal stress responses in an mTOR-dependent manner.
Di Nardo A, Kramvis I, Cho N, Sadowski A, Meikle L, Kwiatkowski DJ, Sahin M.
The F. M. Kirby Neurobiology Center, Department of Neurology, Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.
Tuberous sclerosis complex (TSC) is a neurogenetic disorder caused by loss-of-function mutations in either the TSC1 or TSC2 genes and frequently results in prominent CNS manifestations, including epilepsy, mental retardation, and autism spectrum disorder. The TSC1/TSC2 protein complex plays a major role in controlling the Ser/Thr kinase mammalian target of rapamycin (mTOR), which is a master regulator of protein synthesis and cell growth. In this study, we show that endoplasmic reticulum (ER) stress regulates TSC1/TSC2 complex to limit mTOR activity. In addition, Tsc2-deficient rat hippocampal neurons and brain lysates from a Tsc1-deficient mouse model demonstrate both elevated ER and oxidative stress. In Tsc2-deficient neurons, the expression of stress markers such as CHOP and HO-1 is increased, and this increase is completely reversed by the mTOR inhibitor rapamycin both in vitro and in vivo. Neurons lacking a functional TSC1/TSC2 complex have increased vulnerability to ER stress-induced cell death via the activation of the mitochondrial death pathway. Importantly, knockdown of CHOP reduces oxidative stress and apoptosis in Tsc2-deficient neurons. These observations indicate that ER stress modulates mTOR activity through the TSC protein complex and that ER stress is elevated in cells lacking this complex. They also suggest that some of the neuronal dysfunction and neurocognitive deficits seen in TSC patients may be attributable to ER and oxidative stress and therefore potentially responsive to agents moderating these pathways.
PMID: 19420259
Curr Neurol Neurosci Rep. 2009 Mar;9(2):129-36.
Neurometabolic disorders and dysfunction in autism spectrum disorders.
Zecavati N, Spence SJ.
Pediatrics and Developmental Neuropsychiatry Branch, National Institute of Mental Health, 10 Center Drive, Bethesda, MD 20892, USA.
The cause of autism remains largely unknown because it is likely multifactorial, arising from the interaction of biologic, genetic, and environmental factors. The specific role of metabolic abnormalities also is largely unknown, but current research may provide insight into the pathophysiologic underpinnings of autism, at least in some patients. We review a number of known neurometabolic disorders identified as having an autistic phenotype. We also discuss the possible involvement of mitochondrial disorders and dysfunction as well as a theory regarding an increased vulnerability to oxidative stress, by which various environmental toxins produce metabolic alterations that impair normal cellular function. Finally, we review various strategies for metabolic work-up and treatment. Accurate diagnosis of neurometabolic disorders and a broader understanding of underlying metabolic disturbance even in the absence of known disease have important implications both for individual patients and for research into the etiology of autism.
PMID: 19268036
Altern Ther Health Med. 2008 Nov-Dec;14(6):54-7.
The history of vaccinations in the light of the autism epidemic.
Cave SF.
Cypress Integrative Medicine, Baton Rouge, Louisiana, USA.
Autism has been characterized as a behavioral disorder since it was first described by Leo Kanner in 1943. The number of autistic children has increased over the last decade. The incidence of autism was 1 in 10000 before the 1970s and has steadily increased to 1 in 150 in 2008 with a male:female predominance of 4:1. The cause of this epidemic has remained unknown, but several hypotheses have been studied. Many of these suggest an environmental trigger, such as the ethyl mercury contained in the preservative thimerosal, which has been used in vaccines since 1931. Other possible triggers associated with vaccinations are chemical toxins and live viruses. James has published studies suggesting a genetic predisposition in the families of autistic children, exposing them to a deficiency in glutathione and an inability to detoxify heavy metals. Vargas has shown autism to encompass ongoing inflammation in the brains of autistic children. The Hannah Poling vaccine decision was a landmark case. Poling’s family was awarded funds for ongoing medical care of an autistic child who was found to have mitochondrial dysfunction exacerbated by vaccines that left her with autistic behavior and seizures. Several studies have emerged supporting the fact that a significant number of autistic children do have mitochondrial dysfunction. The impact that the Poling case will have on the ability of parents of autistic children to gain access to funds to enable them to properly care for their children remains to be seen.
PMID: 19043939
Am J Med Genet B Neuropsychiatr Genet. 2008 Apr 5;147(3):408-10.
Autism-related routines and rituals associated with a mitochondrial aspartate/glutamate carrier SLC25A12 polymorphism.
Silverman JM, Buxbaum JD, Ramoz N, Schmeidler J, Reichenberg A, Hollander E, Angelo G, Smith CJ, Kryzak LA.
Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029, USA
Evidence for a genetic association between autism and two single nucleotide polymorphisms (SNPs), rs2056202 and rs2292813, in the mitochondrial aspartate/glutamate carrier (SLC25A12) gene led us to ask whether any of the four previously identified familial traits in autism spectrum disorders (ASD) varied by these SNPs. In 355 ASD cases from 170 sibships we examined levels of the four traits in these SNPs using ANCOVA models. The primary models selected unrelated affected cases and used age and sex as covariates. An ancillary set of models used all affected siblings and included “sibship” as a random effects independent variable. We found significantly lower levels of routines and rituals associated with the presence of the less frequent A allele in rs2056206. No other significant differences were observed. The rs2056202 polymorphism may be associated with levels of routines and rituals in autism and related disorders.
PMID: 17894412
Folia Neuropathol. 2008;46(1):81-91.
Clinical, biochemical, neuropathological and molecular findings of the first Polish case of adenylosuccinase deficiency.
Mierzewska H, Schmidt-Sidor B, Lewandowska E, Grajkowska W, Kuśmierska K, Jurkiewicz E, Stepień T, Rafałowska J.
Department of Metabolic Diseases, The Children’s Memorial Health Institute, Polish Academy of Sciences, Warsaw, Poland.
Adenylosuccinase (ADSL) deficiency is an autosomal recessive disorder affecting mainly the nervous system. The disease causes psychomotor retardation, frequently with autistic features and epilepsy. ADSL deficiency may be diagnosed by detection of two abnormal metabolites in body fluids–succinyladenosine (S-Ado) and succinylaminoimidazole carboxamide riboside (SAICAr). It is assumed that the former metabolite is neurotoxic. We present clinical, biochemical and neuropathological findings of a child affected by a severe form of ADSL deficiency. She had progressive neurological symptoms that started immediately after birth and died at 2.5 months of age. Macroscopically the brain showed signs of moderate atrophy. Histological examination of all grey matter structures showed widespread damage of neurons accompanied by microspongiosis of neuropile. Cerebral white matter showed lack of myelination in the centrum semiovale and diffuse spongiosis of neuropile. Myelination appropriate for the age was visible in posterior limb of internal capsule, in striatum, thalamus and in brain stem structures but diffuse destruction of myelin sheets was seen with severe marked astroglial reaction with signs of destruction of the cells and their processes. Ultrastructural examination showed enormous destruction of all cellular elements, but astonishingly mitochondria were relatively spared. The neuropathological changes can be considered as the neurotoxic result of metabolic disturbances connected with adenylosuccinase deficiency.
PMID: 18368630
Med Hypotheses. 2008;70(5):967-74. Epub 2007 Nov 5.
The association between tick-borne infections, Lyme borreliosis and autism spectrum disorders.
Bransfield RC, Wulfman JS, Harvey WT, Usman AI.
Department of Psychiatry, Riverview Medical Center, 225 State Route 35, Red Bank, NJ, United States.
Chronic infectious diseases, including tick-borne infections such as Borrelia burgdorferi may have direct effects, promote other infections and create a weakened, sensitized and immunologically vulnerable state during fetal development and infancy leading to increased vulnerability for developing autism spectrum disorders. A dysfunctional synergism with other predisposing and contributing factors may contribute to autism spectrum disorders by provoking innate and adaptive immune reactions to cause and perpetuate effects in susceptible individuals that result in inflammation, molecular mimicry, kynurenine pathway changes, increased quinolinic acid and decreased serotonin, oxidative stress, mitochondrial dysfunction and excitotoxicity that impair the development of the amygdala and other neural structures and neural networks resulting in a partial Klüver-Bucy Syndrome and other deficits resulting in autism spectrum disorders and/or exacerbating autism spectrum disorders from other causes throughout life. Support for this hypothesis includes multiple cases of mothers with Lyme disease and children with autism spectrum disorders; fetal neurological abnormalities associated with tick-borne diseases; similarities between tick-borne diseases and autism spectrum disorder regarding symptoms, pathophysiology, immune reactivity, temporal lobe pathology, and brain imaging data; positive reactivity in several studies with autistic spectrum disorder patients for Borrelia burgdorferi (22%, 26% and 20-30%) and 58% for mycoplasma; similar geographic distribution and improvement in autistic symptoms from antibiotic treatment. It is imperative to research these and all possible causes of autism spectrum disorders in order to prevent every preventable case and treat every treatable case until this disease has been eliminated from humanity.
PMID: 17980971
PLoS One. 2008;3(11):e3815. Epub 2008 Nov 26.
Mitochondrial disease in autism spectrum disorder patients: a cohort analysis.
Weissman JR, Kelley RI, Bauman ML, Cohen BH, Murray KF, Mitchell RL, Kern RL, Natowicz MR.
Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, Ohio, United States of America.
Previous reports indicate an association between autism spectrum disorders (ASD) and disorders of mitochondrial oxidative phosphorylation. One study suggested that children with both diagnoses are clinically indistinguishable from children with idiopathic autism. There are, however, no detailed analyses of the clinical and laboratory findings in a large cohort of these children. Therefore, we undertook a comprehensive review of patients with ASD and a mitochondrial disorder.
We reviewed medical records of 25 patients with a primary diagnosis of ASD by DSM-IV-TR criteria, later determined to have enzyme- or mutation-defined mitochondrial electron transport chain (ETC) dysfunction. Twenty-four of 25 patients had one or more major clinical abnormalities uncommon in idiopathic autism. Twenty-one patients had histories of significant non-neurological medical problems. Nineteen patients exhibited constitutional symptoms, especially excessive fatigability. Fifteen patients had abnormal neurological findings. Unusual developmental phenotypes included marked delay in early gross motor milestones (32%) and unusual patterns of regression (40%). Levels of blood lactate, plasma alanine, and serum ALT and/or AST were increased at least once in 76%, 36%, and 52% of patients, respectively. The most common ETC disorders were deficiencies of complex I (64%) and complex III (20%). Two patients had rare mtDNA mutations of likely pathogenicity.
Although all patients’ initial diagnosis was idiopathic autism, careful clinical and biochemical assessment identified clinical findings that differentiated them from children with idiopathic autism. These and prior data suggest a disturbance of mitochondrial energy production as an underlying pathophysiological mechanism in a subset of individuals with autism.
PMID: 19043581
Rev Neurol. 2008;46 Suppl 1:S79-85.
[Autism, epilepsy and mitochondrial disease: points of contact].
[Article in Spanish]
García-Peñas JJ.
Sección de Neurología Pediátrica, Hospital Infantil Universitario Niño Jesús, Madrid, España.
Autism is a neurodevelopmental disorder with unknown etiology, although several different specific organic conditions have been found to be associated with autism in about 10 to 37% of cases. Autism with regression has been reported in one third of autistic children with previously normal development. Epilepsy is quite common in autism spectrum disorders. The rate of comorbidity varies between 20-30% of cases, depending upon the age and type of disorder. Major risk factors for epilepsy in autistic children are mental retardation and additional neurological disorders, as well as some specific associated medical conditions like chromosomal abnormalities, phakomatosis and inherited metabolic disorders.
To review the possible linkage between autism, epilepsy and mitochondrial dysfunction.
The hypothesis of a disturbed bioenergetic metabolism underlying autism has been suggested by the detection of high lactate levels in some patients. Although the mechanism of hyperlactacidemia remains unknown, a likely possibility involves mitochondrial oxidative phosphorylation dysfunction in neuronal cells. Reduced levels of respiratory mitochondrial enzymes, ultraestructural mitochondrial abnormalities and a broad range of mitochondrial DNA mutations suggest a linkage between autism, epilepsy and mitochondrial disorders.
Though mitochondrial disorders are a rare cause of autism in children, we must keep in mind this etiology in autistic patients with epilepsy and associated signs of neurologic and/or systemic dysfunction. Finding biochemical or structural mitochondrial abnormalities in an autistic child does not necessarily imply a primary mitochondrial disorder but can also be secondary to technical inaccuracies or another genetic disorder.
PMID: 18302129
Dev Med Child Neurol. 2007 Oct;49(10):726-33.
Epidemiology of autism spectrum disorder in Portugal: prevalence, clinical characterization, and medical conditions.
Oliveira G, Ataíde A, Marques C, Miguel TS, Coutinho AM, Mota-Vieira L, Gonçalves E, Lopes NM, Rodrigues V, Carmona da Mota H, Vicente AM.
Centro de Desenvolvimento da Criança, Hospital Pediátrico de Coimbra, Coimbra, Portugal.
The objective of this study was to estimate the prevalence of autistic spectrum disorder (ASD) and identify its clinical characterization, and medical conditions in a paediatric population in Portugal. A school survey was conducted in elementary schools, targeting 332,808 school-aged children in the mainland and 10,910 in the Azores islands. Referred children were directly assessed using the Diagnostic and Statistical Manual of Mental Disorders (4th edn), the Autism Diagnostic Interview-Revised, and the Childhood Autism Rating Scale. Clinical history and a laboratory investigation was performed. In parallel, a systematic multi-source search of children known to have autism was carried out in a restricted region. The global prevalence of ASD per 10,000 was 9.2 in mainland, and 15.6 in the Azores, with intriguing regional differences. A diversity of associated medical conditions was documented in 20%, with an unexpectedly high rate of mitochondrial respiratory chain disorders.
PMID: 17880640
J Child Neurol. 2007 Sep;22(9):1121-3.
Autistic disorder in 2 children with mitochondrial disorders.
Tsao CY, Mendell JR.
Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA.
Autistic disorder is a heterogeneous disorder. The majority of the cases are idiopathic, and only a small number of the autistic children have associated secondary diagnosis. This article reports 2 children with mitochondrial disorders associated with autistic disorder fulfilling the diagnostic criteria of the American Psychiatric Association Manual of Psychiatric Diseases, 4th edition, and briefly reviews the literature on autistic disorder associated with mitochondrial disorders.
PMID: 17890412
Semin Pediatr Neurol. 2007 Mar;14(1):26-33.
Trinucleotide repeat disorders.
Lutz RE.
University of Nebraska Medical Center, Munroe-Meyer Institute for Genetics and Rehabilitation, Omaha, NE 68198-5430, USA.
DNA trinucleotide repeat expansion diseases represent an interesting group of disorders that include a common cause of mental retardation and autism as well as neurodegenerative and other diseases. Many of these disorders have expression in the pediatric age group. The varied molecular mechanisms of these disorders make them model diseases for the study of mitochondrial dysfunction induced apoptosis, abnormal axonal transport induced apoptosis and disrupted transcription of neighboring genes. Clinical variation in the pathogenesis, severity, onset and inheritance of these disorders make them models for clinical study and research.
PMID: 17331881
Med Hypotheses. 2007;68(6):1208-27. Epub 2006 Dec 4.
Hyperbaric oxygen therapy might improve certain pathophysiological findings in autism.
Rossignol DA.
University of Virginia, Department of Family Medicine, P.O. Box 800729, Charlottesville, VA 22908, USA.
Autism is a neurodevelopmental disorder currently affecting as many as 1 out of 166 children in the United States. Numerous studies of autistic individuals have revealed evidence of cerebral hypoperfusion, neuroinflammation and gastrointestinal inflammation, immune dysregulation, oxidative stress, relative mitochondrial dysfunction, neurotransmitter abnormalities, impaired detoxification of toxins, dysbiosis, and impaired production of porphyrins. Many of these findings have been correlated with core autistic symptoms. For example, cerebral hypoperfusion in autistic children has been correlated with repetitive, self-stimulatory and stereotypical behaviors, and impairments in communication, sensory perception, and social interaction. Hyperbaric oxygen therapy (HBOT) might be able to improve each of these problems in autistic individuals. Specifically, HBOT has been used with clinical success in several cerebral hypoperfusion conditions and can compensate for decreased blood flow by increasing the oxygen content of plasma and body tissues. HBOT has been reported to possess strong anti-inflammatory properties and has been shown to improve immune function. There is evidence that oxidative stress can be reduced with HBOT through the upregulation of antioxidant enzymes. HBOT can also increase the function and production of mitochondria and improve neurotransmitter abnormalities. In addition, HBOT upregulates enzymes that can help with detoxification problems specifically found in autistic children. Dysbiosis is common in autistic children and HBOT can improve this. Impaired production of porphyrins in autistic children might affect the production of heme, and HBOT might help overcome the effects of this problem. Finally, HBOT has been shown to mobilize stem cells from the bone marrow to the systemic circulation. Recent studies in humans have shown that stem cells can enter the brain and form new neurons, astrocytes, and microglia. It is expected that amelioration of these underlying pathophysiological problems through the use of HBOT will lead to improvements in autistic symptoms. Several studies on the use of HBOT in autistic children are currently underway and early results are promising.
PMID: 17141962
J Autism Dev Disord. 2006 Nov;36(8):1137-40.
Brief report: High frequency of biochemical markers for mitochondrial dysfunction in autism: no association with the mitochondrial aspartate/glutamate carrier SLC25A12 gene.
Correia C, Coutinho AM, Diogo L, Grazina M, Marques C, Miguel T, Ataíde A, Almeida J, Borges L, Oliveira C, Oliveira G, Vicente AM.
Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2781 Oeiras, Portugal.
In the present study we confirm the previously reported high frequency of biochemical markers of mitochondrial dysfunction, namely hyperlactacidemia and increased lactate/pyruvate ratio, in a significant fraction of 210 autistic patients. We further examine the involvement of the mitochondrial aspartate/glutamate carrier gene (SLC25A12) in mitochondrial dysfunction associated with autism. We found no evidence of association of the SLC25A12 gene with lactate and lactate/pyruvate distributions or with autism in 241 nuclear families with one affected individual. We conclude that while mitochondrial dysfunction may be one of the most common medical conditions associated with autism, variation at the SLC25A12 gene does not explain the high frequency of mitochondrial dysfunction markers and is not associated with autism in this sample of autistic patients.
PMID: 17151801
Pathophysiology. 2006 Aug;13(3):171-81. Epub 2006 Jun 12.
Oxidative stress in autism.
Chauhan A, Chauhan V.
NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA.
Autism is a severe developmental disorder with poorly understood etiology. Oxidative stress in autism has been studied at the membrane level and also by measuring products of lipid peroxidation, detoxifying agents (such as glutathione), and antioxidants involved in the defense system against reactive oxygen species (ROS). Lipid peroxidation markers are elevated in autism, indicating that oxidative stress is increased in this disease. Levels of major antioxidant serum proteins, namely transferrin (iron-binding protein) and ceruloplasmin (copper-binding protein), are decreased in children with autism. There is a positive correlation between reduced levels of these proteins and loss of previously acquired language skills in children with autism. The alterations in ceruloplasmin and transferrin levels may lead to abnormal iron and copper metabolism in autism. The membrane phospholipids, the prime target of ROS, are also altered in autism. The levels of phosphatidylethanolamine (PE) are decreased, and phosphatidylserine (PS) levels are increased in the erythrocyte membrane of children with autism as compared to their unaffected siblings. Several studies have suggested alterations in the activities of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, and catalase in autism. Additionally, altered glutathione levels and homocysteine/methionine metabolism, increased inflammation, excitotoxicity, as well as mitochondrial and immune dysfunction have been suggested in autism. Furthermore, environmental and genetic factors may increase vulnerability to oxidative stress in autism. Taken together, these studies suggest increased oxidative stress in autism that may contribute to the development of this disease. A mechanism linking oxidative stress with membrane lipid abnormalities, inflammation, aberrant immune response, impaired energy metabolism and excitotoxicity, leading to clinical symptoms and pathogenesis of autism is proposed.
PMID: 16766163
Pediatrics. 2006 Jul;118(1):309-21.
Pediatric autonomic disorders.
Axelrod FB, Chelimsky GG, Weese-Mayer DE.
Dysautonomia Treatment and Evaluation Center, Department of Pediatrics and Neurology, New York University School of Medicine, 530 First Ave, Suite 9Q, New York, New York 10016, USA.
The scope of pediatric autonomic disorders is not well recognized. The goal of this review is to increase awareness of the expanding spectrum of pediatric autonomic disorders by providing an overview of the autonomic nervous system, including the roles of its various components and its pervasive influence, as well as its intimate relationship with sensory function. To illustrate further the breadth and complexities of autonomic dysfunction, some pediatric disorders are described, concentrating on those that present at birth or appear in early childhood.
PMID: 16818580 Free full text
J Child Neurol. 2006 Feb;21(2):170-2.
Developmental regression and mitochondrial dysfunction in a child with autism.
Poling JS, Frye RE, Shoffner J, Zimmerman AW.
Department of Neurology and Neurosurgery, Johns Hopkins Hospital, Baltimore, MD, USA.
Autistic spectrum disorders can be associated with mitochondrial dysfunction. We present a singleton case of developmental regression and oxidative phosphorylation disorder in a 19-month-old girl. Subtle abnormalities in the serum creatine kinase level, aspartate aminotransferase, and serum bicarbonate led us to perform a muscle biopsy, which showed type I myofiber atrophy, increased lipid content, and reduced cytochrome c oxidase activity. There were marked reductions in enzymatic activities for complex I and III. Complex IV (cytochrome c oxidase) activity was near the 5% confidence level. To determine the frequency of routine laboratory abnormalities in similar patients, we performed a retrospective study including 159 patients with autism (Diagnostic and Statistical Manual of Mental Disorders-IV and Childhood Autism Rating Scale) not previously diagnosed with metabolic disorders and 94 age-matched controls with other neurologic disorders. Aspartate aminotransferase was elevated in 38% of patients with autism compared with 15% of controls (P <.0001). The serum creatine kinase level also was abnormally elevated in 22 (47%) of 47 patients with autism. These data suggest that further metabolic evaluation is indicated in autistic patients and that defects of oxidative phosphorylation might be prevalent.
Comment in
J Child Neurol. 2008 Sep;23(9):1090-1; author reply 1089-90.
PMID: 16566887
Dev Med Child Neurol. 2005 Mar;47(3):185-9.
Mitochondrial dysfunction in autism spectrum disorders: a population-based study.
Oliveira G, Diogo L, Grazina M, Garcia P, Ataíde A, Marques C, Miguel T, Borges L, Vicente AM, Oliveira CR.
Outpatient Clinic of Autism, Centro de Desenvolvimento da Criança, Hospital Pediátrico de Coimbra, 3000-076 Coimbra, Portugal.
A minority of cases of autism has been associated with several different organic conditions, including bioenergetic metabolism deficiency. In a population-based study, we screened associated medical conditions in a group of 120 children with autism (current age range 11y 5mo to 14y 4mo, mean age 12y 11mo [SD 9.6mo], male:female ratio 2.9:1). Children were diagnosed using Diagnostic and Statistical Manual of Mental Disorders criteria, the Autism Diagnostic Interview–Revised, and the Childhood Autism Rating Scale; 76% were diagnosed with typical autism and 24% with atypical autism. Cognitive functional level was assessed with the Griffiths scale and the Wechsler Intelligence Scale for Children and was in the normal range in 17%. Epilepsy was present in 19 patients. Plasma lactate levels were measured in 69 patients, and in 14 we found hyperlactacidemia. Five of 11 patients studied were classified with definite mitochondrial respiratory chain disorder, suggesting that this might be one of the most common disorders associated with autism (5 of 69; 7.2%) and warranting further investigation.
Comment in
Dev Med Child Neurol. 2005 Mar;47(3):148.
PMID: 15739723
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.
Department of Pediatrics, College of Medicine, University of California, Irvine, CA, USA.
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.
PMID: 15679182
J Pediatr. 2004 Jan;144(1):81-5.
Mitochondrial DNA abnormalities and autistic spectrum disorders.
Pons R, Andreu AL, Checcarelli N, Vilà MR, Engelstad K, Sue CM, Shungu D, Haggerty R, de Vivo DC, DiMauro S.
Departments of Neurology, Pediatrics, and Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
To further characterize mtDNA defects associated with autistic features, especially the A3243G mtDNA mutation and mtDNA depletion.Study design Five patients with autistic spectrum disorders and family histories of mitochondrial DNA diseases were studied. We performed mtDNA analysis in all patients and magnetic resonance spectroscopy in three.
Three patients manifested isolated autistic spectrum features and two had additional neurologic symptoms. Two patients harbored the A3243G mutation. In two others, the A3243G mutation was not found in accessible tissues but was present in tissues from their mothers. The fifth patient had 72% mtDNA depletion in skeletal muscle.
Autistic spectrum disorders with or without additional neurologic features can be early presentations of the A3243G mtDNA mutation and can be a prominent clinical manifestation of mtDNA depletion. Mitochondrial dysfunction should be considered in patients who have autistic features and associated neurologic findings or who have evidence of maternal inheritance.
PMID: 14722523
Med Hypotheses. 2004;62(6):970-5.
Is autism a disorder of fatty acid metabolism? Possible dysfunction of mitochondrial beta-oxidation by long chain acyl-CoA dehydrogenase.
Clark-Taylor T, Clark-Taylor BE.
Long chain acyl-CoA dehydrogenase (LCAD) has recently been shown to be the mitochondrial enzyme responsible for the beta-oxidation of branched chain and unsaturated fatty acids [Biochim. Biophys. Acta 1393 (1998) 35; Biochim. Biophys. Acta 1485 (2000) 121]. Whilst disorders of short, medium and very long chain acyl dehydrogenases are known, there is no known disorder of LCAD deficiency in humans. Experimental LCAD deficiency in mice shows an acyl-carnitine profile with prominent elevations of unsaturated fatty acid metabolites C14:1 and C14:2 [Hum. Mol. Genet. 10 (2001) 2069]. A child with autism whose acyl-carnitine profile also shows these abnormalities is presented, and it is hypothesized that the child may have LCAD deficiency. Additional metabolic abnormalities seen in this patient include alterations of TCA energy production, ammonia detoxification, reduced synthesis of omega-3 DHA, and abnormal cholesterol metabolism. These metabolic changes are also seen as secondary abnormalities in dysfunction of fatty acid beta-oxidation, and have also been reported in autism. It is hypothesized that LCAD deficiency may be a cause of autism. Similarities between metabolic disturbances in autism, and those of disorders of fatty acid beta-oxidation are discussed.
PMID: 15142659
Int J Neurosci. 2003 Nov;113(11):1537-59.
A hypothalamic digoxin-mediated model for autism.
Kurup RK, Kurup PA.
Department of Neurology, Medical College Hospital, Trivandrum, Kerala, India.
The isoprenoid pathway and its metabolites–digoxin, dolichol, and ubiquinone–were assessed in autism. The isoprenoid pathway and digoxin status was also studied for comparison in individuals of differing hemispheric dominance to determine the role of cerebral dominance in the genesis of autism. There was an upregulation of the isoprenoid pathway as evidenced by elevated HMG CoA reductase activity in autism. Digoxin, an endogenous Na+-K+ ATPase inhibitor secreted by the hypothalamus, was found to be elevated and RBC membrane Na+-K+ ATPase activity was found to be reduced in autism. Membrane Na+-K+ ATPase inhibition can result in increased intracellular Ca2+ and reduced magnesium levels. Hypothalamic digoxin can modulate conscious and subliminal perception and its dysfunction may lead to autism. Digoxin can also preferentially upregulate tryptophan transport over tyrosine resulting in increased levels of depolarizing tryptophan catabolites–serotonin, quinolinic acid (NMDA agonist), strychnine (blocks glycinergic inhibitory transmission), and nicotine (promotes dopamine release) and decreased levels of hyperpolarizing tyrosine catabolites–dopamine, noradrenaline, and morphine–contributing to membrane Na+-K+ ATPase inhibition. Increased nicotine levels can produce increased dopaminergic transmission in the presence of low dopamine levels. NMDA excitotoxicity could result from hypomagnesemia induced by membrane Na+-K+ ATPase inhibition and quinolinic acid, an NMDA agonist acting on the NMDA receptor. Hypomagnesemia and increased dolichol level can affect glycoconjugate metabolism and membranogenesis leading on to disordered synaptic connectivity in the limbic allocortex and defective presentation of viral antigens and neuronal antigens contributing to autoimmunity and viral persistence important in the pathogenesis. Membrane Na+-K+ ATPase inhibition can produce immune activation, a component of autoimmunity. Mitochondrial dysfunction consequent to altered calcium/magnesium ratios and reduced ubiquinone levels can result in increased free radical generation and reduced free radical scavenging and defective apoptosis leading to abnormal synaptogenesis. Autism can thus be considered a syndrome of hypothalamic digoxin hypersecretion consequent to an upregulated isoprenoid pathway. The biochemical patterns including hyperdigoxinemia observed in autism correlated with those obtained in right hemispheric chemical dominance. Right hemispheric chemical dominance is a predisposing factor for autism.
PMID: 14585753
Ann Neurol. 2003 Jun;53(6):801-4.
Mitochondrial dysfunction in autistic patients with 15q inverted duplication.
Filipek PA, Juranek J, Smith M, Mays LZ, Ramos ER, Bocian M, Masser-Frye D, Laulhere TM, Modahl C, Spence MA, Gargus JJ.
Department of Pediatrics, College of Medicine, University of California, Irvine, CA, USA.
Two autistic children with a chromosome 15q11-q13 inverted duplication are presented. Both had uneventful perinatal courses, normal electroencephalogram and magnetic resonance imaging scans, moderate motor delay, lethargy, severe hypotonia, and modest lactic acidosis. Both had muscle mitochondrial enzyme assays that showed a pronounced mitochondrial hyperproliferation and a partial respiratory chain block most parsimoniously placed at the level of complex III, suggesting candidate gene loci for autism within the critical region may affect pathways influencing mitochondrial function.
PMID: 12783428
Am J Med Genet. 2002 Aug 15;111(3):238-42.
Infantile hypotonia as a presentation of Rett syndrome.
Heilstedt HA, Shahbazian MD, Lee B.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
Rett syndrome (RTT) is classically defined by meeting certain clinical diagnostic criteria. It affects mostly females, and one possible pathogenic mechanism was considered to involve mitochondrial function. This was based on the finding of ultrastructural alterations in the mitochondria and decreased respiratory chain enzyme activity. However, the principal etiology of RTT has since been found to be mutations in the MECP2 gene, which is located on the X chromosome. Molecular analysis has allowed the phenotype of MECP2 mutations to be broadened beyond RTT to include girls who have mild mental retardation, autism, and an Angelman syndrome phenotype, as well as males with severe encephalopathy. We present a girl with a previously described mutation in the MECP2 gene whose phenotype is of atypical RTT. She presented with hypotonia and developmental delay in infancy without a clear period of normal development. As part of her evaluation for hypotonia, a muscle biopsy and respiratory chain enzyme analysis showed a slight decrease in respiratory chain enzyme activity consistent with previous reports. This report supports broadening the phenotype of patients who should be considered for MECP2 mutation analysis to include cases of developmental delay and hypotonia without evidence of an initial period of normal development. Furthermore, it supports the hypothesis of an underlying secondary defect in energy metabolism contributing to the pathogenesis of RTT.
PMID: 12210319
J Child Neurol. 2002 Jun;17(6):435-9.
Mitochondrial dysfunction in patients with hypotonia, epilepsy, autism, and developmental delay: HEADD syndrome.
Fillano JJ, Goldenthal MJ, Rhodes CH, Marín-García J.
Department of Pediatrics, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.
A group of 12 children clinically presenting with hypotonia, intractable epilepsy, autism, and developmental delay, who did not fall into previously described categories of mitochondrial encephalomyopathy, were evaluated for mitochondrial respiratory enzyme activity levels, mitochondrial DNA, and mitochondrial structural abnormalities. Reduced levels in specific respiratory activities were found solely in enzymes with subunits encoded by mitochondrial DNA in seven of eight biopsied skeletal muscle specimens evaluated. Five cases exhibited increased levels of large-scale mitochondrial DNA deletions, whereas pathogenic point mutations previously described in association with mitochondrial encephalomyopathies were not found. Mitochondrial structural abnormalities were present in three of four patients examined. Our findings suggest that mitochondrial dysfunction, including extensive abnormalities in specific enzyme activities, mitochondrial structure, and mitochondrial DNA integrity, may be present in children with a clinical constellation including hypotonia, epileptic seizures, autism, and developmental delay. The acronym HEADD is presented here to facilitate pursuit of mitochondrial defects in patients with this clinical constellation after other causes have been excluded.
PMID: 12174964
J Child Neurol. 2000 Jun;15(6):357-61.
Autism associated with the mitochondrial DNA G8363A transfer RNA(Lys) mutation.
Graf WD, Marin-Garcia J, Gao HG, Pizzo S, Naviaux RK, Markusic D, Barshop BA, Courchesne E, Haas RH.
Department of Pediatrics, University of Washington, Seattle, USA.
We report a family with a heterogeneous group of neurologic disorders associated with the mitochondrial DNA G8363A transfer ribonucleic acid (RNA)Lys mutation. The phenotype of one child in the family was consistent with autism. During his second year of life, he lost previously acquired language skills and developed marked hyperactivity with toe-walking, abnormal reciprocal social interaction, stereotyped mannerisms, restricted interests, self-injurious behavior, and seizures. Brain magnetic resonance imaging (MRI) and repeated serum lactate studies were normal. His older sister developed signs of Leigh syndrome with progressive ataxia, myoclonus, seizures, and cognitive regression. Her laboratory studies revealed increased MRI T2-weighted signal in the putamen and posterior medulla, elevated lactate in serum and cerebrospinal fluid, and absence of cytochrome c oxidase staining in muscle histochemistry. Molecular analysis in her revealed the G8363A mutation of the mitochondrial transfer RNA(Lys) gene in blood (82% mutant mitochondrial DNA) and muscle (86%). The proportions of mutant mitochondrial DNA from her brother with autism were lower (blood 60%, muscle 61%). It is likely that the origin of his autism phenotype is the pathogenic G8363A mitochondrial DNA mutation. This observation suggests that certain mitochondrial point mutations could be the basis for autism in some individuals.
PMID: 10868777
Med Hypotheses. 1998 Jun;50(6):497-500.
Autism: a mitochondrial disorder?
Lombard J.
Westchester Square Medical Center, New York, NY 10461, USA.
Autism is a developmental disorder characterized by disturbance in language, perception and socialization. A variety of biochemical, anatomical and neuroradiographical studies imply a disturbance of brain energy metabolism in autistic patients. The underlying etiology of a disturbed bioenergetic metabolism in autism is unknown. A likely etiological possibility may involve mitochondrial dysfunction with concomitant defects in neuronal oxidative phosphorylation within the central nervous system. This hypothesis is supported by a frequent association of lactic acidosis and carnitine deficiency in autistic patients. Mitochondria are vulnerable to a wide array of endogenous and exogenous factors which appear to be linked by excessive nitric oxide production. Strategies to augment mitochondrial function, either by decreasing production of endogenous toxic metabolites, reducing nitric oxide production, or stimulating mitochondrial enzyme activity may be beneficial in the treatment of autism.
PMID: 9710323
Semin Nucl Med. 1993 Jul;23(3):255-64.
Brain single-photon emission computed tomography for behavior disorders in children.
O’Tuama LA, Treves ST.
Department of Radiology, Children’s Hospital Boston, MA.
Single-photon emission computed tomography (SPECT) of the brain has been used to define functional abnormalities in two groups of childhood behavior disorders: (1) a “primary” category in which there is exclusive or predominant presentation with cognitive and/or behavioral dysfunction and (2) encephalopathies, often defined etiologically at the biochemical or molecular level, in which clinical expression includes, but is not confined to, neural dysfunction. Radiopharmaceuticals available for such studies are manifold, but those used to date have been predominantly perfusion agents, eg, Xenon-133 (133Xe) and technetium-99m (99mTc) hexamethylpropylene amine oxime, and studies with [99mTc]bicisate are eagerly awaited. Xenon-133 studies require that the patient be in the field of view of the detector while the tracer is administered. This renders it difficult for a subject to perform cognitive and other exercises while being imaged, because the environment is quite foreign. On the other hand, the 99mTc-labeled perfusion agents permit a scintigraphic “snapshot” of regional cerebral blood flow during a behavioral event without having to have the patient under the imaging instrument. Thus, one can separate the administration of the radiotracer, which can be done under more controlled and physiological conditions, from the actual imaging. In addition, greater spatial resolution is achieved with the technetium-based agents. Currently, multidetector or dedicated annular crystal-type cameras are the preferred brain SPECT devices, and they are essential to applications such as cortical “activation mapping” or tomographic detection of receptor systems. Close attention to technical detail and standardization of the child’s behavioral environment during the investigation are critical to a successful study. The relative advantages and disadvantages of qualitative versus semiquantitative analysis of imaging date are reviewed. Among primary behavioral disorders, 133Xe SPECT studies in attention deficit disorder-hyperactivity (ADHD) have suggested a pattern of hypoperfusion of striatal and periventricular structures with sensorimotor cortical hyperperfusion. This pattern is consistent with some neurophysiological models of the disorder. In cerebral palsy, perfusional abnormalities have paralleled clinical deficits and may offer information to help predict outcome. The important field of childhood affective disorders (schizophrenia, juvenile autism, depression, etc) remains largely unstudied with SPECT. Finally, representative examples of the use of SPECT to study perfusion in encephalopathies with behavioral expression (phenylketonuria, MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) syndrome, Wilson’s disease, etc) are given.
PMID: 8378798
Brain Dev. 1992 May;14 Suppl:S89-98.
The neuropathology of the Rett syndrome.
Armstrong DD.
Department of Pathology, Baylor College of Medicine, Houston.
The neuropathology of the Rett syndrome is summarized utilizing a format of clinical pathological correlations, describing the pathology at specific anatomic sites which could correlate with the well defined clinical signs and symptoms in the Rett syndrome; decreased head and body size, autism, gait dysfunction, spasticity, movement and breathing disorder. Published reports of altered morphology in the cerebral cortex, basal ganglia, substantia nigra, cerebellum, spinal cord, muscle, nerve, pituitary gland and somatic organs are supplemented by the author’s observations. These include studies of dendritic morphology employing Scholl analysis of Golgi preparation, and quantitation of cerebellar Purkinje cells. The possible pathoetiology of the Rett syndrome is considered, particularly, in relation to the ultrastructural demonstration of altered mitochondria and accumulations of lipidic bodies in several tissues.

This concludes our Austism / Autistic Spectrum Disorder & Repetitive Transcranial Magnetic Stimulation (rTMS) / Pulsed Electromagnetic Field Therapy Research Bibliography