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Mol Psychiatry. 2012 Mar;
17(3):290-314.
Mitochondrial dysfunction in autism
spectrum disorders:
a systematic review and meta-analysis.
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.
Mitochondrial Dysfunction Linked to
Autism
January 31, 2011 — Mitochondrial dysfunction (MD) is more
common in children with autism and autism spectrum disorder
(ASD) than the general population, a comprehensive
systematic review and meta-analysis of relevant research
confirms.
Mitochondrial dysfunction "may play a significant role in
contributing to the symptoms of autism and is generally
underrecognized in these children," Daniel A. Rossignol, MD,
of the International Child Development Resource Center,
Melbourne, Florida, told Medscape Medical News.
Dr. Daniel A. Rossignol
"Testing for mitochondrial dysfunction is available, and
early treatment might lead to better long-term developmental
outcomes," said Dr. Rossignol, who coauthored the review
with Richard E. Frye, MD, PhD, of the University of Texas in
Houston.
The report was published online January 25 in Molecular
Psychiatry.
Commenting on the study Cecilia Giulivi, PhD, professor of
biochemistry and metabolic regulation, at the University of
California, Davis, who was not involved in the analysis,
said, "At this point, it looks like there is a higher
incidence of mitochondrial disease in autism, much higher
than we suspected."
She noted, however, that testing for MD "is not a trivial
task [and] we need more research to come up with a consensus
of diagnostic tests to run. In addition, maybe other
metabolic syndromes should be looked into," Dr. Giulivi
said.
The primary objectives of the analysis were to identify
features of MD in the general population of children with
ASD and compare characteristics of MD in children with ASD
and concomitant significant and severe MD with that of ASD
children without MD and non-ASD children with MD.
They included 68 relevant published articles in a
qualitative synthesis, including 18 studies with a total of
112 children with ASD and MD.
Genetics Not the Culprit
The results showed the prevalence of MD in the general
population of children with ASD is approximately 5% (95%
confidence interval [CI], 3.2% – 6.9%), which is 500% higher
than the general population prevalence of 0.01%. For a
variety of reasons, "this 5% value is most likely an
underestimation," Dr. Rossignol said.
It also appears that one-third or more of children with
autism may have some type of dysfunction in their
mitochondria. On the basis of laboratory testing, the
prevalence of abnormal biomarker values of MD, including
lactate, pyruvate, carnitine, and ubiquinone, was high in
children with ASD, much higher than the prevalence of MD.
Some of these markers correlated with the severity of ASD.
Most of the 112 children with ASD and MD (79%) had no
identifiable genetic abnormality that could account for the
MD.
"The mitochondrial dysfunction and disease reported in
autism are related to a genetic abnormality in only 1 out of
5 children; meaning that a majority of these children have
something else contributing to this dysfunction, which might
include multiple environmental factors, such as toxins,
oxidative stress, inflammation, and decreased levels of
antioxidants," said Dr. Rossignol.
"Clearly, mitochondrial function is a ripe area of research
when investigating the biological mechanism(s) of action of
environmental toxicant exposures and indigenous
abnormalities associated with ASD," the study authors write.
Loss of Social Skills
Children with ASD and MD had some distinct characteristics
compared with the general population of children with ASD.
In 12 studies, "children with autism and mitochondrial
problems were more likely to lose acquired skills compared
to children with autism in general," said Dr. Rossignol.
However, it was not clear whether MD contributed to or
caused the reported regression.
In addition to a higher prevalence of developmental
regression (52%), seizures (41%), motor delay (51%), and
gastrointestinal abnormalities (74%), such as reflux and
constipation, also appear to be significantly more common in
children with ASD and MD relative to children with just ASD.
Currently, "testing for mitochondrial problems in children
with autism is rarely done, and we feel that testing should
be routine, especially in children with regression or loss
of skills," said Dr. Rossignol. "This is important because
early recognition of mitochondrial problems in autism might
lead to better outcomes in children with autism."
Dr. Rossignol and Dr. Frye note in their report that
published studies looking at treatment for ASD and MD are
limited. However, some studies have suggested that treatment
with mitochondrial cofactor supplementation, including
antioxidants, carnitine, coenzyme Q10, and B vitamins, may
improve mitochondrial function and behavior in some children
with ASD.
"A therapeutic trial of mitochondrial cofactors and
antioxidants may be reasonable in children with ASD/MD," the
study authors conclude. Carnitine, they say, may be
particularly helpful in children with ASD because carnitine
deficiency has been implicated in ASD, and some studies have
reported improvements with the use of carnitine in ASD.
The researchers emphasize, however, that systematic studies
documenting the efficacy of this and other potential
treatments for MD in children with ASD are generally
lacking.
.
Children With Autism Have
Mitochondrial Dysfunction, Study Finds
Nov. 30, 2010 — Children with autism are far more likely to
have deficits in their ability to produce cellular energy
than are typically developing children, a new study by
researchers at UC Davis has found. The study, published in
the Journal of the American Medical Association (JAMA),
found that cumulative damage and oxidative stress in
mitochondria, the cell's energy producer, could influence
both the onset and severity of autism, suggesting a strong
link between autism and mitochondrial defects.
After the heart, the brain is the most voracious consumer of
energy in the body. The authors propose that deficiencies in
the ability to fuel brain neurons might lead to some of the
cognitive impairments associated with autism. Mitochondria
are the primary source of energy production in cells and
carry their own set of genetic instructions, mitochondrial
DNA (mtDNA), to carry out aerobic respiration. Dysfunction
in mitochondria already is associated with a number of other
neurological conditions, including Parkinson's disease,
Alzheimer's disease, schizophrenia and bipolar disorder.
"Children with mitochondrial diseases may present exercise
intolerance, seizures and cognitive decline, among other
conditions. Some will manifest disease symptoms and some
will appear as sporadic cases," said Cecilia Giulivi, the
study's lead author and professor in the Department of
Molecular Biosciences in the School of Veterinary Medicine
at UC Davis. "Many of these characteristics are shared by
children with autism."
The researchers stress that these new findings, which may
help physicians provide early diagnoses, do not identify the
cause or the effects of autism, which affects as many as 1
in every 110 children in the United States, according to the
U.S. Centers for Disease Control and Prevention.
While previous studies have revealed hints of a connection
between autism and mitochondrial dysfunction, these reports
have been either anecdotal or involved tissues that might
not be representative of neural metabolism.
"It is remarkable that evidence of mitochondrial dysfunction
and changes in mitochondrial DNA were detected in the blood
of these young children with autism," said Geraldine Dawson,
chief science officer of Autism Speaks, which provided
funding for the study. "One of the challenges has been that
it has been difficult to diagnose mitochondrial dysfunction
because it usually requires a muscle biopsy. If we could
screen for these metabolic problems with a blood test, it
would be a big step forward."
Here is the published Study
JAMA. 2010;
304(21):2389-2396.
Mitochondrial Dysfunction in Autism
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. (PdLA Complex can specifically increase
Complex1 Activity)
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).
(This could be due to increase HIF-1 Levels due to
Hypoxia........per the last email I sent to you from Johns
Hopkins. PDK protein is binding with PDH and preventing the
breakdown of Pyruvate into Acetyl-CoA........thus there are
higher levels of pyruvate.)
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). (Same reason as above)
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). (PdLA complex reverses hydrogen peroxide
production)
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