Study finds children with autism have mitochondrial dysfunction
November 30th, 2010 in Medicine & Health / Diseases
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 today 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
for these metabolic problems with a blood test, it would be a big step forward."
For the study, Giulivi and her colleagues recruited 10 autistic children aged 2 to 5,
and 10 age-matched typically developing children from similar backgrounds. The children
were randomly selected from Northern California subjects who previously had participated
in the 1,600-participant Childhood Autism Risk from Genetics and the Environment
(CHARGE) Study and who also consented to return for a subsequent study known as
CHARGE-BACK, conducted by the UC Davis Center for Children's Environmental Health and
Disease Prevention.
The children with autism met stringent diagnostic criteria for autism as defined by
the two most widely used and rigorous assessment tools. Though the total number of
children studied was small, it is generally representative of the much larger CHARGE
cohort, and that increases the significance of the study results, the authors said.
The researchers obtained blood samples from each child and analyzed the metabolic
pathways of mitochondria in immune cells called lymphocytes. Previous studies
sampled mitochondria obtained from muscle, but the mitochondrial dysfunction
sometimes is not expressed in muscle. Muscle cells can generate much of their
energy through anaerobic glycolysis, which does not involve mitochondria. By
contrast, lymphocytes, and to a greater extent brain neurons, rely more heavily
on the aerobic respiration conducted by mitochondria.
The researchers found that mitochondria from children with autism consumed far
less oxygen than mitochondria from the group of control children, a sign of lowered
mitochondrial activity. For example, the oxygen consumption of one critical mitochondrial
enzyme complex, NADH oxidase, in autistic children was only a third of that found in
control children.
"A 66 percent decrease is significant," Giulivi said. "When these levels are lower,
you have less capability to produce ATP (adenosine triphosphate) to pay for cellular work.
Even if this decrease is considered moderate, deficits in mitochondrial energy output do
not have to be dismissed, for they could be exacerbated or evidenced during the perinatal
period but appear subclinical in the adult years."
Reduced mitochondrial enzyme function proved widespread among the autistic children.
Eighty percent had lowered activity in NADH oxidase than did controls, while 60 percent,
40 percent and 30 percent had low activity in succinate oxidase, ATPase and cytochrome c
oxidase, respectively. The researchers went on to isolate the origins of these defects by
assessing the activity of each of the five enzyme complexes involved in mitochondrial
respiration. Complex I was the site of the most common deficiency, found in 60 percent
of autistic subjects, and occurred five out of six times in combination with Complex V.
Other children had problems in Complexes III and IV.
Levels of pyruvate, the raw material mitochondria transform into cellular energy, also
were elevated in the blood plasma of autistic children. This suggests the mitochondria
of children with autism are unable to process pyruvate fast enough to keep up with the
demand for energy, pointing to a novel deficiency at the level of an enzyme named pyruvate
dehydrogenase.
Mitochondria also are the main intracellular source of oxygen free radicals. Free radicals
are very reactive species that can harm cellular structures, including DNA. Cells are able
to repair typical levels of such oxidative damage. Giulivi and her colleagues found that
hydrogen peroxide levels in autistic children were twice as high as in normal children.
As a result, the cells of children with autism were exposed to higher oxidative stress.
Mitochondria often respond to oxidative stress by making extra copies of their own DNA.
The strategy helps ensure that some normal genes are present even if others have been
damaged by oxidation. The researchers found higher mtDNA copy numbers in the lymphocytes
of half of the children with autism. These children carried equally high numbers of mtDNA
sets in their granulocytes, another type of immune cell, demonstrating that these effects
were not limited to a specific cell type. Two of the five children also had deletions in
their mtDNA genes, whereas none of the control children showed deletions.
Taken together, the various abnormalities, defects and levels of malfunction measured in
the mitochondria of autistic children imply that oxidative stress in these organelles
could be influencing autism's onset.
"The various dysfunctions we measured are probably even more extreme in brain cells,
which rely exclusively on mitochondria for energy," said Isaac Pessah, director of the
Center for Children's Environmental Health and Disease Prevention, a UC Davis MIND
Institute researcher and professor of molecular biosciences at the UC Davis School
of Veterinary Medicine.
Giulivi cautions that these findings do not amount to establishing a cause for autism.
"We took a snapshot of the mitochondrial dysfunction when the children were 2-to-5
years old. Whether this happened before they were born or after, this study can't tell
us," she said. "However, the research furthers the understanding of autism on several
fronts and may, if replicated, be used to help physicians diagnose the problem earlier."
"Pediatricians need to be aware of this issue so that they can ask the right questions
to determine whether children with autism have vision or hearing problems or myopathies,"
Giulivi said. Exercise intolerance in the form of muscle cramps during intensive physical
activity is one of the characteristics of mitochondrial myopathies.
The chemical fingerprints of mitochondrial dysfunction also may hold potential as a
diagnostic tool. Giulivi and colleagues are now examining the mitochondrial DNA of
their subjects more closely to pinpoint more precise differences between autistic and
non-autistic children.
"If we find some kind of blood marker that is consistent with and unique to children
with autism, maybe we can change the way we diagnose this difficult-to-assess condition,"
she said.
The study also helps refine the search for autism's origins.
"The real challenge now is to try and understand the role of mitochondrial dysfunction
in children with autism," Pessah said. "For instance, many environmental stressors can
cause mitochondrial damage. Depending on when a child was exposed, maternally or neonatally,
and how severe that exposure was, it might explain the range of the symptoms of autism."
"This important exploratory research addresses in a rigorous way an emerging hypothesis
about potential mitochondrial dysfunction and autism," said Cindy Lawler, program director
at the National Institute of Environmental Health Sciences (NIEHS), which provided funding
for the study. "Additional research in this area could ultimately lead to prevention or
efforts for this serious developmental disorder."
More information: JAMA. 2010;304[21]:2389-2396.
Provided by University of California - Davis
"Study finds children with autism have mitochondrial dysfunction." November 30th, 2010.
http://www.physorg.com/news/2010-11-children-autism-mitochondrial-defects-impacting.html
PERSONAL NOTE: I would like to see a study of children who were vaccinated and have autism compared to children who have autism and not vaccinated. How do we know that vaccinations do not create DNA damage or have a negative impact on mitochondrial function?
November 30th, 2010 in Medicine & Health / Diseases
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 today 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
for these metabolic problems with a blood test, it would be a big step forward."
For the study, Giulivi and her colleagues recruited 10 autistic children aged 2 to 5,
and 10 age-matched typically developing children from similar backgrounds. The children
were randomly selected from Northern California subjects who previously had participated
in the 1,600-participant Childhood Autism Risk from Genetics and the Environment
(CHARGE) Study and who also consented to return for a subsequent study known as
CHARGE-BACK, conducted by the UC Davis Center for Children's Environmental Health and
Disease Prevention.
The children with autism met stringent diagnostic criteria for autism as defined by
the two most widely used and rigorous assessment tools. Though the total number of
children studied was small, it is generally representative of the much larger CHARGE
cohort, and that increases the significance of the study results, the authors said.
The researchers obtained blood samples from each child and analyzed the metabolic
pathways of mitochondria in immune cells called lymphocytes. Previous studies
sampled mitochondria obtained from muscle, but the mitochondrial dysfunction
sometimes is not expressed in muscle. Muscle cells can generate much of their
energy through anaerobic glycolysis, which does not involve mitochondria. By
contrast, lymphocytes, and to a greater extent brain neurons, rely more heavily
on the aerobic respiration conducted by mitochondria.
The researchers found that mitochondria from children with autism consumed far
less oxygen than mitochondria from the group of control children, a sign of lowered
mitochondrial activity. For example, the oxygen consumption of one critical mitochondrial
enzyme complex, NADH oxidase, in autistic children was only a third of that found in
control children.
"A 66 percent decrease is significant," Giulivi said. "When these levels are lower,
you have less capability to produce ATP (adenosine triphosphate) to pay for cellular work.
Even if this decrease is considered moderate, deficits in mitochondrial energy output do
not have to be dismissed, for they could be exacerbated or evidenced during the perinatal
period but appear subclinical in the adult years."
Reduced mitochondrial enzyme function proved widespread among the autistic children.
Eighty percent had lowered activity in NADH oxidase than did controls, while 60 percent,
40 percent and 30 percent had low activity in succinate oxidase, ATPase and cytochrome c
oxidase, respectively. The researchers went on to isolate the origins of these defects by
assessing the activity of each of the five enzyme complexes involved in mitochondrial
respiration. Complex I was the site of the most common deficiency, found in 60 percent
of autistic subjects, and occurred five out of six times in combination with Complex V.
Other children had problems in Complexes III and IV.
Levels of pyruvate, the raw material mitochondria transform into cellular energy, also
were elevated in the blood plasma of autistic children. This suggests the mitochondria
of children with autism are unable to process pyruvate fast enough to keep up with the
demand for energy, pointing to a novel deficiency at the level of an enzyme named pyruvate
dehydrogenase.
Mitochondria also are the main intracellular source of oxygen free radicals. Free radicals
are very reactive species that can harm cellular structures, including DNA. Cells are able
to repair typical levels of such oxidative damage. Giulivi and her colleagues found that
hydrogen peroxide levels in autistic children were twice as high as in normal children.
As a result, the cells of children with autism were exposed to higher oxidative stress.
Mitochondria often respond to oxidative stress by making extra copies of their own DNA.
The strategy helps ensure that some normal genes are present even if others have been
damaged by oxidation. The researchers found higher mtDNA copy numbers in the lymphocytes
of half of the children with autism. These children carried equally high numbers of mtDNA
sets in their granulocytes, another type of immune cell, demonstrating that these effects
were not limited to a specific cell type. Two of the five children also had deletions in
their mtDNA genes, whereas none of the control children showed deletions.
Taken together, the various abnormalities, defects and levels of malfunction measured in
the mitochondria of autistic children imply that oxidative stress in these organelles
could be influencing autism's onset.
"The various dysfunctions we measured are probably even more extreme in brain cells,
which rely exclusively on mitochondria for energy," said Isaac Pessah, director of the
Center for Children's Environmental Health and Disease Prevention, a UC Davis MIND
Institute researcher and professor of molecular biosciences at the UC Davis School
of Veterinary Medicine.
Giulivi cautions that these findings do not amount to establishing a cause for autism.
"We took a snapshot of the mitochondrial dysfunction when the children were 2-to-5
years old. Whether this happened before they were born or after, this study can't tell
us," she said. "However, the research furthers the understanding of autism on several
fronts and may, if replicated, be used to help physicians diagnose the problem earlier."
"Pediatricians need to be aware of this issue so that they can ask the right questions
to determine whether children with autism have vision or hearing problems or myopathies,"
Giulivi said. Exercise intolerance in the form of muscle cramps during intensive physical
activity is one of the characteristics of mitochondrial myopathies.
The chemical fingerprints of mitochondrial dysfunction also may hold potential as a
diagnostic tool. Giulivi and colleagues are now examining the mitochondrial DNA of
their subjects more closely to pinpoint more precise differences between autistic and
non-autistic children.
"If we find some kind of blood marker that is consistent with and unique to children
with autism, maybe we can change the way we diagnose this difficult-to-assess condition,"
she said.
The study also helps refine the search for autism's origins.
"The real challenge now is to try and understand the role of mitochondrial dysfunction
in children with autism," Pessah said. "For instance, many environmental stressors can
cause mitochondrial damage. Depending on when a child was exposed, maternally or neonatally,
and how severe that exposure was, it might explain the range of the symptoms of autism."
"This important exploratory research addresses in a rigorous way an emerging hypothesis
about potential mitochondrial dysfunction and autism," said Cindy Lawler, program director
at the National Institute of Environmental Health Sciences (NIEHS), which provided funding
for the study. "Additional research in this area could ultimately lead to prevention or
efforts for this serious developmental disorder."
More information: JAMA. 2010;304[21]:2389-2396.
Provided by University of California - Davis
"Study finds children with autism have mitochondrial dysfunction." November 30th, 2010.
http://www.physorg.com/news/2010-11-children-autism-mitochondrial-defects-impacting.html
PERSONAL NOTE: I would like to see a study of children who were vaccinated and have autism compared to children who have autism and not vaccinated. How do we know that vaccinations do not create DNA damage or have a negative impact on mitochondrial function?
