January 2014 Teleconference

January 2014 Teleconference
Written By:  Alyssa Davi

January 14th, 2014

January’s teleconference was a literature review of research taking place in Dr. Richard Frye's lab at Arkansas Children’s Hospital Research Institute.  Dr. Frye is a neurologist and over the last few years has published a much-needed body of research on children with autism spectrum disorder. 

Much of his published research has focused on studying mitochondrial function and how it relates to children who have been diagnosed with ASD as well as epidemiological factors that contribute to the formation of an ASD.  In an article written in 2012 by Dr. Frye (and Dr. Daniel Rossignol) titled "Metabolic Disorders and Abnormalities Associated with Autism Spectrum Disorder," he states that children with ASD and mitochondrial disease present with clinical features that may include developmental regression, gross motor delay, fatigability, ataxia and gastrointestinal abnormalities.  In this article (which is available to read on Dr. Rossignol’s website at: www.rossignolmedicalcenter.com) they also write that there is increasing data documenting metabolic abnormalities in children with ASD. 

In another article written by Dr. Frye and Dr. Rossignol titled, "Mitochondrial physiology and autism spectrum disorder," they state that mitochondrial dysfunction and mitochondrial disease (believed to be much rarer than mitochondrial dysfunction) and cerebral folate disorders appear to be the most common associated metabolic disorders in children with ASD, at this time.  Through their research they have found and documented cerebral folate abnormalities, including cerebral folate deficiency, and folate receptor autoantibodies in ASD children.

The table below (taken from that same article) lists the following mitochondrial disorders associated with ASD.    

And they further state that the following metabolic disorders have also been seen in children with ASD:

1.     urea cycle disorders

2.     succinic semialdehyde dehydrogenase deficiency

3.     adenylosuccinate lyase deficiency

4.     phenylketonuria

5.     creatine deficiency syndromes

6.     pyridoxine dependent and responsive seizures

7.     biotinidase deficiency

8.      Smith-Lemli-Opitz syndrome

9.      general cholesterol metabolism disorder

10.    tetrahydrobiopterin metabolism disorder

Yet currently, at this time, there is no “standard of care” for children to be evaluated for any metabolic disorders when they are initially diagnosed with ASD.

In the article titled, "Mitochondrial physiology and autism spectrum disorder," Drs. Frye and Rossignol state that “the mitochondria’s role in producing en­ergy is complex and linked to other metabolic systems.”  As seen in the table below, mitochondrial function is not just ATP production, but it is also a critical aspect of carbohydrate metabolism, calcium buffering, heat production, inflammation and fatty acid oxidation.

Full PDF is available at : http://www.rossignolmedicalcenter.com/articles/

The interconnectedness of mitochondrial function and other metabolic systems can now be more easily understood.

One of the important points discussed in this article is “the mitochondrion is an adaptable organelle which can modify its function depending on the intracellular and extracellular envi­ronment. Specific conditions could be inhibiting the function of the mito­chondria in some children with ASD, causing them to be dysfunctional. If this is the case, changing the intracel­lular and extracellular environment may restore mitochondrial function, at least theoretically. In addition, the mitochondrion is capable of repair and regeneration. In the absence of a genetic defect, it is possible that the function of the mitochondria could be restored by these repair mecha­nisms, and it might be possible in the future to enhance these repair mech­anisms.”  They state that “carnitine, CoQ, B vitamins, vitamin C and vita­min E as well as antioxidants” can help support mitochondrial function.

A 2014 paper Dr. Frye co-authored titled "Oxidative Stress induces Mitochondrial Dysfunction in a Subset of Autism Lymphoblastoid Cell Lines in a Well-Matched Case Control Cohort" examined lymphoblastoid cells in children with ASD and measured the mitochondria’s ability to respond to stress.  What they found was that, “children with AD have an abnormal mitochondrial reserve capacity before and after exposure to increasingly higher concentrations of intracellular reactive oxygen species (ROS).

And they write that recent research suggests that alterations in mitochondrial function in a group of children with ASD disorder are caused by a combination of genetic and environmental factors.    “This study suggests that a significant subgroup of AD children may have alterations in mitochondrial function which could render them more vulnerable to a pro-oxidant microenvironment derived from intrinsic and extrinsic sources of ROS such as immune activation and pro-oxidant environmental toxicants. These findings are consistent with the notion that AD is caused by a combination of genetic and environmental factors.”

“This raises the possibility of acquired mitochondrial dysfunction since mitochondrial damage can result from environmental exposures implicated in ASD such as heavy metals, exhaust fumes, polychlorinated biphenyls or pesticides. Alternatively, mitochondria can be damaged by endogenous stressors associated with ASD such as elevated proinflammatory cytokines resulting from an activated immune system or other conditions associated with oxidative stress. The notion of an acquired mitochondrial disorder is supported by a recent twin study which concluded that the environment contributes a greater percent of the risk of developing autistic disorder (55%) as compared to genetic factors (37%) with these factors contributing about equally for the broader ASD diagnosis.”

“This has raised the idea that children with ASD might have a type of mitochondrial dysfunction that is more prevalent and distinct from classic MD. This study has demonstrated a new type of mitochondrial dysfunction that may be the result of redox abnormalities and chronic oxidative stress and could affect a significant number of children with ASD.”  And further stated, “This study suggests that mitochondrial dysfunction in individuals with ASD may not manifest unless there are simultaneous ongoing physiological stressors.”

Full PDF is available at :http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0085436

 Dr. Frye’s team is currently conducting clinical trials.  For more information about these clinical trials and research taking place at Arkansas Children’s Hospital Research Institute please visit this link at ARKANSAS AUTISM ALLIANCE: www.arkansasautismalliance.org/research

Another way to access this information is through clinicaltrials.gov. Enter NCT02000284 in the search field and it will take you directly to a detailed account of the trial.

Below find a list of published research by Dr. Frye (and Dr. Rossignol) on the topic of mitochondria and ASD:

2013

Mitochondrial physiology and autism spectrum disorder: http://www.oapublishinglondon.com/images/article/pdf/1367537332.pdf

2012

Treatments for mitochondrial dysfunction associated with autism spectrum disorders: Available at http://www.rossignolmedicalcenter.com/articles/

Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis: http://www.nature.com/mp/journal/v17/n3/pdf/mp2010136a.pdf

Metabolic disorders and abnormalities associated with autism spectrum disorder: Available at: http://www.rossignolmedicalcenter.com/articles/

Mitochondrial and metabolic abnormalities in neurodevelopmental disorders: Available at: http://www.rossignolmedicalcenter.com/articles/

A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures:

http://www.nature.com/mp/journal/v17/n4/pdf/mp2011165a.pdf

Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis: http://www.nature.com/mp/journal/v17/n3/pdf/mp2010136a.pdf

Substantial Problems with Measuring Brain Mitochondrial Dysfunction in Autism Spectrum Disorder Using Magnetic Resonance Spectroscopy: http://link.springer.com/article/10.1007%2Fs10803-011-1276-z

2011

Mitochondrial Dysfunction Can Connect the Diverse Medical Symptoms Associated With Autism Spectrum: http://www.nature.com/pr/journal/v69/n5-2/pdf/pr9201192a.pdf