autism spectrum
disorders and frequency specific pulsed electromagnetic field
therapy research
Results: 7
1.
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.
Source
Mayo Clinic, Rochester , Minnesota , USA.
Abstract
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]
Related citations
2.
Brain Stimul. 2011 Mar 3. [Epub ahead of print]
Repetitive transcranial magnetic stimulation (rTMS) improves
movement-related cortical potentials in autism spectrum disorders.
Enticott PG, Rinehart NJ, Tonge BJ, Bradshaw JL, Fitzgerald PB.
Source
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.
Abstract
BACKGROUND:
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.
OBJECTIVE:
To examine whether rTMS can improve electrophysiologic and
behavioral indices of motor activity.
METHODS:
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.
RESULTS:
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.
CONCLUSIONS:
rTMS appears to improve movement-related electrophysiologic
activity in ASD, perhaps through an influence on cortical
inhibitory processes.
Copyright © 2011 Elsevier Inc. All rights reserved.
PMID: 22037133 [PubMed - as supplied by publisher]
Related citations
3.
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.
Source
Monash Alfred Psychiatry Research Centre, School of Psychology and
Psychiatry, Monash University and The Alfred, Melbourne, Victoria,
Australia. peter.enticott@monash.edu
Abstract
OBJECTIVES:
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.
METHODS:
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.
RESULTS:
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.
CONCLUSIONS:
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 [PubMed - indexed for MEDLINE]
4.
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.
Source
Department of Anatomical Sciences and Neurobiology, University of
Louisville School of Medicine, Louisville, KY 40202.
Abstract
INTRODUCTION:
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.
METHODS:
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.
RESULTS:
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.
CONCLUSION:
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 [PubMed] PMCID: PMC2992386 Free PMC Article
Related citations
5.
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.
Source
Department of Psychiatry and Behavioral Science, University of
Louisville School of Medicine, Louisville, KY, 40292, USA.
tato.sokhadze@louisville.edu
Abstract
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 [PubMed - indexed for MEDLINE] PMCID: PMC2876218
Free PMC Article
Related citations
6.
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.
Source
Cognitive Neuroscience Laboratory, Department of Psychiatry and
Behavioral Science, University of Louisville School of Medicine,
Louisville, KY 40292, USA. tato.sokhadze@louisville.edu
Abstract
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 [PubMed - indexed for MEDLINE]
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Results: 58
1.
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.
Source
Department of Radiology, University of Washington, Seattle, WA,
USA.
Abstract
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]
Related citations
2.
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.
Source
Division of Pediatric Neurology, Seattle Children's
Hospital/University of Washington, 4800 Sand Point Way NE,
Seattle, WA 98105, United States.
Abstract
PURPOSE:
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.
METHODS:
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.
RESULTS:
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.
CONCLUSION:
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.
Copyright © 2011 British Epilepsy Association. Published by
Elsevier Ltd. All rights reserved.
PMID: 21906962 [PubMed - in process]
Related citations
3.
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.
Source
International Child Development Resource Center, Melbourne, FL,
USA.
Abstract
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 [PubMed - as supplied by publisher]
Related citations
4.
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.
Source
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,
drmdessa@gmail.com.
Abstract
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 [PubMed - as supplied by publisher]
Related citations
5.
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.
Source
Translational Medicine Division, Department of Medicine, Brigham
and Women's Hospital, Boston, MA 02115, USA.
Abstract
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 [PubMed - in process] PMCID: PMC3214999 [Available
on 2012/5/8]
Related citations
Publication Types, Grant Support
6.
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.
Source
Department of Pediatrics, University of California, Davis, School
of Medicine, Sacramento, CA, USA,
Randi.hagerman@ucdmc.ucdavis.edu.
Abstract
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 [PubMed]
Related citations
7.
J Autism Dev Disord. 2011 Aug 19. [Epub ahead of print]
Further Commentary on Mitochondrial Dysfunction in Autism Spectrum
Disorder: Assessment and Treatment Considerations.
Dager SR, Corrigan NM, Estes A, Shaw DW.
Source
Department of Radiology, University of Washington, 1100 NE 45th
St. Suite 555, Seattle, WA, 98105, USA, srd@u.washington.edu.
Abstract
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 [PubMed - as supplied by publisher]
Related citations
8.
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.
Source
Laboratory of Molecular Psychiatry & Neurogenetics, University
Campus Bio-Medico, Via Alvaro del Portillo 21, 00128 Rome, Italy.
Abstract
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 [PubMed - indexed for MEDLINE]
Related citations
Publication Types, MeSH Terms, Substances
9.
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.
Source
The Institute of Chronic Illnesses, Inc., Silver Spring, MD, USA.
mgeier@comcast.net
Abstract
BACKGROUND:
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.
MATERIAL/METHODS:
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.
RESULTS:
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.
CONCLUSIONS:
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 [PubMed - indexed for MEDLINE]
Related citations
Publication Types, MeSH Terms, Substances
10.
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.
Source
International Child Development Resource Center, 3800 West Eau
Gallie Blvd, Melbourne, FL, 32934, USA, rossignolmd@gmail.com.
PMID: 21556966 [PubMed - as supplied by publisher]
Related citations
11.
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.
Source
Department of Pharmacology and Physiology and GW Institute for
Neuroscience, The George Washington University School of Medicine
and Health Sciences, 2300 Eye Street NW, Washington, DC, USA.
Abstract
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.
Copyright © 2010 ISDN. Published by Elsevier Ltd. All rights
reserved.
PMID: 20833244 [PubMed - indexed for MEDLINE]
Related citations
Publication Types, MeSH Terms, Grant Support
12.
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.
Source
Department of Pediatrics, The Children's Learning Institute,
University of Texas Health Science Center at Houston, Houston,
Texas 77030, USA. richard.e.frye@uth.tmc.edu
Abstract
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 [PubMed - indexed for MEDLINE] PMCID: PMC3179978
[Available on 2012/5/1]
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13.
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.
Source
Swinburne Autism Bio-Research Initiative, Faculty of Life and
Social Sciences, Swinburne University of Technology, Hawthorn,
Victoria 3122, Australia.
Abstract
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 [PubMed] PMCID: PMC3173748 Free PMC Article
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14.
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.
Source
Biochemistry Department, Science College, King Saud University,
P,O Box 22452, Zip Code 11495, Riyadh, Saudi Arabia.
elansary@ksu.edu.sa
Abstract
BACKGROUNDS:
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.
METHODS:
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.
RESULTS:
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.
CONCLUSIONS:
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 [PubMed - indexed for MEDLINE] PMCID: PMC3107800
Free PMC Article
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15.
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.
Source
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.
Abstract
BACKGROUND:
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.
METHODS:
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.
RESULTS:
We did not find statistical support for an association between
mtDNA mutations or polymorphisms and ASD.
CONCLUSIONS:
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 [PubMed - indexed for MEDLINE] PMCID: PMC3080282
Free PMC Article
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16.
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 [PubMed - indexed for MEDLINE]
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Publication Types, MeSH Terms, Substances
17.
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.
Source
International Child Development Resource Center, Melbourne, FL,
USA.
Abstract
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 [PubMed - as supplied by publisher]
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18.
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.
Source
University of California, School of Veterinary Medicine,
Department of Molecular Biosciences, One Shields Avenue, 1120
Haring Hall, Davis, CA 95616, USA. cgiulivi@ucdavis.edu
Abstract
CONTEXT:
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.
OBJECTIVE:
To evaluate mitochondrial defects in children with autism.
DESIGN, SETTING, AND PATIENTS:
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.
MAIN OUTCOME MEASURES:
Oxidative phosphorylation capacity, mtDNA copy number and
deletions, mitochondrial rate of hydrogen peroxide production, and
plasma lactate and pyruvate.
RESULTS:
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).
CONCLUSION:
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 [PubMed - indexed for MEDLINE]
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19.
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.
Source
Sections of Neurology, St Christopher's Hospital for Children,
Drexel University College of Medicine, Philadelphia, PA, USA.
Abstract
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 [PubMed - indexed for MEDLINE]
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Publication Types, MeSH Terms
20.
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.
Source
Department of Pediatrics, University of California, Davis, School
of Medicine, Sacramento, California, USA.
randi.hagerman@ucdmc.ucdavis.edu.
Abstract
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 [PubMed] PMCID: PMC2954865 Free PMC Article
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Grant Support
21.
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.
Source
Felipe Guevara Rojas Hospital, Pediatrics Service, University of
Oriente, El Tigre-Anzoátegui, Venezuela.
joguevara90@hotmail.com
Abstract
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 [PubMed - indexed for MEDLINE]
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22.
Neurotherapeutics. 2010 Jul;7(3):232-40.
Improving the prediction of response to therapy in autism.
Bent S, Hendren RL.
Source
Department of Psychiatry, University of California, San Francisco,
San Francisco, California 94121, USA. stephen.bent@ucsf.edu
Abstract
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.
(c) 2010 The American Society for Experimental NeuroTherapeutics,
Inc. Published by Elsevier Inc. All rights reserved.
PMID: 20643375 [PubMed - indexed for MEDLINE]
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23.
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.
Source
Laboratory of Biochemistry and Molecular Biology, Department of
Pharmaco-Biology, University of Bari, Via Orabona 4, 70125, Bari,
Italy. lpalm@farmbiol.uniba.it
Abstract
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.
Copyright © 2010 Elsevier B.V. All rights reserved.
PMID: 20441769 [PubMed - indexed for MEDLINE]
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Publication Types, MeSH Terms, Substances
24.
Dev Disabil Res Rev. 2010 Jun;16(2):144-53.
Autism and mitochondrial disease.
Haas RH.
Source
Department of Neurosciences, UCSD Mitochondrial and Metabolic
Disease Center, University of California-San Diego, 9500 Gilman
Drive, La Jolla, CA 92093, USA. rhaas@ucsd.edu
Abstract
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.
(c) 2010 Wiley-Liss, Inc.
PMID: 20818729 [PubMed - indexed for MEDLINE]
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Publication Types, MeSH Terms, Substances
25.
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.
Source
Department of Child and Adolescent Psychiatry and Psychotherapy,
University of Würzburg, Würzburg, Germany.
Huennerkopf@kjp.uni-wuerzburg.de
Abstract
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 [PubMed - indexed for MEDLINE]
Related citations
MeSH Terms, Substances
26.
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.
Source
International Child Development Resource Center, Melbourne, FL
32934, USA. DrBradstreet@aol.com
Abstract
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 [PubMed - indexed for MEDLINE] Free full text
Related citations
Publication Types, MeSH Terms, Substances
27.
Curr Opin Neurol. 2010 Apr;23(2):103-10.
Contributions of the environment and environmentally vulnerable
physiology to autism spectrum disorders.
Herbert MR.
Source
TRANSCEND Research Program, Pediatric Neurology, Massachusetts
General Hospital, Charlestown, Massachusetts, USA.
mherbert1@partners.org
Abstract
PURPOSE OF REVIEW:
This review presents a rationale and evidence for contributions of
environmental influences and environmentally vulnerable physiology
to autism spectrum disorders (ASDs).
RECENT FINDINGS:
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.
SUMMARY:
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 [PubMed - indexed for MEDLINE]
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Publication Types, MeSH Terms
28.
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.
Source
Medical Neurogenetics, LLC, Atlanta, Georgia 30338, USA.
jshoffner@medicalneurogenetics.com
Abstract
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 [PubMed - indexed for MEDLINE]
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29.
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.
Source
Phenomenome Discoveries Inc., 204-407 Downey Road, Saskatoon,
Saskatchewan, Canada S7N 4L8.
Abstract
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 [PubMed - indexed for MEDLINE]
Related citations
MeSH Terms, Substances
30.
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.
Source
Department of Neuroscience, Pediatric Neurology Unit, Tor Vergata
University, via Montpellier 1, 00133, Rome, RM, Italy.
Abstract
BACKGROUND:
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.
DATA SOURCES:
The PubMed database was searched with the keywords "autism" and
"chromosomal abnormalities", "metabolic diseases", "susceptibility
loci".
RESULTS:
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.
CONCLUSIONS:
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 [PubMed - indexed for MEDLINE]
Related citations
Publication Types, MeSH Terms
31.
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.
Source
The F. M. Kirby Neurobiology Center, Department of Neurology,
Children's Hospital Boston, Harvard Medical School, Boston,
Massachusetts 02115, USA.
Abstract
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 [PubMed - indexed for MEDLINE] PMCID: PMC2691854
Free PMC Article
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32.
Curr Neurol Neurosci Rep. 2009 Mar;9(2):129-36.
Neurometabolic disorders and dysfunction in autism spectrum
disorders.
Zecavati N, Spence SJ.
Source
Pediatrics and Developmental Neuropsychiatry Branch, National
Institute of Mental Health, 10 Center Drive, Bethesda, MD 20892,
USA. spences2@mail.nih.gov
Abstract
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 [PubMed - indexed for MEDLINE]
Related citations
Publication Types, MeSH Terms
33.
Altern Ther Health Med. 2008 Nov-Dec;14(6):54-7.
The history of vaccinations in the light of the autism epidemic.
Cave SF.
Source
Cypress Integrative Medicine, Baton Rouge, Louisiana, USA.
Abstract
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 [PubMed - indexed for MEDLINE]
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34.
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.
Source
Department of Psychiatry, Mount Sinai School of Medicine, New
York, New York 10029, USA. jeremy.silverman@mssm.edu
Abstract
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.
Copyright 2007 Wiley-Liss, Inc.
PMID: 17894412 [PubMed - indexed for MEDLINE]
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35.
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.
Source
Department of Metabolic Diseases, The Children's Memorial Health
Institute, Polish Academy of Sciences, Warsaw, Poland.
h.mierzewska@gmail.com
Abstract
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 [PubMed - indexed for MEDLINE]
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36.
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.
Source
Department of Psychiatry, Riverview Medical Center, 225 State
Route 35, Red Bank, NJ, United States. bransfield@comcast.net
Abstract
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 [PubMed - indexed for MEDLINE]
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Publication Types, MeSH Terms
37.
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.
Source
Cleveland Clinic Lerner College of Medicine, Cleveland Clinic,
Cleveland, Ohio, United States of America.
Abstract
BACKGROUND:
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.
METHODOLOGY/PRINCIPAL FINDINGS:
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.
CONCLUSIONS/SIGNIFICANCE:
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 [PubMed - indexed for MEDLINE] PMCID: PMC2584230
Free PMC Article
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38.
Rev Neurol. 2008;46 Suppl 1:S79-85.
[Autism, epilepsy and mitochondrial disease: points of contact].
[Article in Spanish]
García-Peñas JJ.
Source
Sección de Neurología Pediátrica, Hospital
Infantil Universitario Niño Jesús, Madrid,
España. jgarciape.hnjs@salud.madrid.org
Abstract
INTRODUCTION:
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.
AIM:
To review the possible linkage between autism, epilepsy and
mitochondrial dysfunction.
DEVELOPMENT:
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.
CONCLUSIONS:
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 [PubMed - indexed for MEDLINE] Free full text
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39.
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.
Source
Centro de Desenvolvimento da Criança, Hospital
Pediátrico de Coimbra, Coimbra, Portugal.
guiomar@hpc.chc.min-saude.pt
Abstract
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 [PubMed - indexed for MEDLINE]
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Publication Types, MeSH Terms, Substances
40.
J Child Neurol. 2007 Sep;22(9):1121-3.
Autistic disorder in 2 children with mitochondrial disorders.
Tsao CY, Mendell JR.
Source
Department of Pediatrics, The Ohio State University, Columbus,
Ohio, USA. tsaoc@pediatrics.ohio-state.edu
Abstract
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 [PubMed - indexed for MEDLINE]
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Publication Types, MeSH Terms, Substances
41.
Semin Pediatr Neurol. 2007 Mar;14(1):26-33.
Trinucleotide repeat disorders.
Lutz RE.
Source
University of Nebraska Medical Center, Munroe-Meyer Institute for
Genetics and Rehabilitation, Omaha, NE 68198-5430, USA.
rlutz@unmc.edu
Abstract
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 [PubMed - indexed for MEDLINE]
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Publication Types, MeSH Terms
42.
Med Hypotheses. 2007;68(6):1208-27. Epub 2006 Dec 4.
Hyperbaric oxygen therapy might improve certain pathophysiological
findings in autism.
Rossignol DA.
Source
University of Virginia, Department of Family Medicine, P.O. Box
800729, Charlottesville, VA 22908, USA. dlross7@hotmail.com
Abstract
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 [PubMed - indexed for MEDLINE]
Related citations
MeSH Terms
43.
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.
Source
Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6,
2781 Oeiras, Portugal.
Abstract
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 [PubMed - indexed for MEDLINE]
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Publication Types, MeSH Terms, Substances
44.
Pathophysiology. 2006 Aug;13(3):171-81. Epub 2006 Jun 12.
Oxidative stress in autism.
Chauhan A, Chauhan V.
Source
NYS Institute for Basic Research in Developmental Disabilities,
1050 Forest Hill Road, Staten Island, NY 10314, USA.
Abstract
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 [PubMed]
Related citations
45.
Pediatrics. 2006 Jul;118(1):309-21.
Pediatric autonomic disorders.
Axelrod FB, Chelimsky GG, Weese-Mayer DE.
Source
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.
felicia.axelrod@med.nyu.edu
Abstract
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 [PubMed - indexed for MEDLINE] Free full text
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46.
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.
Source
Department of Neurology and Neurosurgery, Johns Hopkins Hospital,
Baltimore, MD, USA.
Abstract
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 [PubMed - indexed for MEDLINE] PMCID: PMC2536523
Free PMC Article
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47.
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.
Source
Outpatient Clinic of Autism, Centro de Desenvolvimento da
Criança, Hospital Pediátrico de Coimbra, 3000-076
Coimbra, Portugal. guiomar@hpc.chc.min-saude.pt
Abstract
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 [PubMed - indexed for MEDLINE]
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48.
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.
Source
Department of Pediatrics, College of Medicine, University of
California, Irvine, CA, USA. filipek@uci.edu
Abstract
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 [PubMed - indexed for MEDLINE]
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49.
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.
Source
Departments of Neurology, Pediatrics, and Psychiatry, Columbia
University College of Physicians and Surgeons, New York, New York
10032, USA.
Abstract
OBJECTIVES:
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.
RESULTS:
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.
CONCLUSIONS:
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 [PubMed - indexed for MEDLINE]
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50.
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.
Source
tbct@bigpond.net.au
Abstract
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 [PubMed - indexed for MEDLINE]
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51.
Int J Neurosci. 2003 Nov;113(11):1537-59.
A hypothalamic digoxin-mediated model for autism.
Kurup RK, Kurup PA.
Source
Department of Neurology, Medical College Hospital, Trivandrum,
Kerala, India.
Abstract
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 [PubMed - indexed for MEDLINE]
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52.
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.
Source
Department of Pediatrics, College of Medicine, University of
California, Irvine, CA, USA. filipek@uci.edu
Abstract
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 [PubMed - indexed for MEDLINE]
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53.
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.
Source
Department of Molecular and Human Genetics, Baylor College of
Medicine, Houston, Texas, USA. hah@bcm.tmc.edu
Abstract
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.
Copyright 2002 Wiley-Liss, Inc.
PMID: 12210319 [PubMed - indexed for MEDLINE]
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54.
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.
Source
Department of Pediatrics, Dartmouth Hitchcock Medical Center,
Lebanon, NH, USA.
Abstract
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 [PubMed - indexed for MEDLINE]
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MeSH Terms, Substances
55.
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.
Source
Department of Pediatrics, University of Washington, Seattle, USA.
wgraf@chmc.org
Abstract
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 [PubMed - indexed for MEDLINE]
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56.
Med Hypotheses. 1998 Jun;50(6):497-500.
Autism: a mitochondrial disorder?
Lombard J.
Source
Westchester Square Medical Center, New York, NY 10461, USA.
Abstract
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 [PubMed - indexed for MEDLINE]
Related citations
MeSH Terms
57.
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.
Source
Department of Radiology, Children's Hospital Boston, MA.
Abstract
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 [PubMed - indexed for MEDLINE]
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58.
Brain Dev. 1992 May;14 Suppl:S89-98.
The neuropathology of the Rett syndrome.
Armstrong DD.
Source
Department of Pathology, Baylor College of Medicine, Houston.
Abstract
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.