Association Between Mitochondrial Dysfunction and Autism

Environmental Exposures Implicated

Mitochondria are described by the Centers for Disease Control and Prevention (CDC) as “tiny parts of almost every cell in the body.” The CDC goes on to explain that mitochondria are the powerplants of cells, turning sugar and oxygen stored inside the body into energy, which cells need to function properly.

But what happens when this power-making process inside of cells is interrupted? Disturbances to this process can lead to mitochondria disease. The United Mitochondria Disease Foundation describes mitochondria disease as a condition where mitochondria failure happens, leading to less energy being generated within cells. When this occurs, cell injury and even cell death can follow. If this process is repeated throughout the body, whole organ systems can fail.

Neurological research from the past decade has produced several studies investigating a possible relationship between autism and malfunctioning mitochondria. A 2010 UC Davis MIND Institute study, a 2016 British study, as well as other research, have consistently found mitochondrial disorders commonly linked to autism. At the conclusion of such studies, a call for more research is typically made by the authors.

Last month, a new addition to mitochondria and autism research was released by Dr. Richard Frye of the Barrow Neurological Institute in Arizona. His review titled, Mitochondrial Dysfunction in Autism Spectrum Disorder: Unique Abnormalities and Target Treatments and published in Seminars in Pediatric Neurology examines earlier evidence that implicates mitochondria in development of autism spectrum disorder (ASD). Unlike previous research, Frye’s study goes further by exploring treatments for individuals who are affected by these mitochondrial irregularities.

The author begins the study by recognizing how challenging it is to understand the underlying biology of autism, due to the disorder’s interaction of many different biological systems, unlike other conditions which typically involve abnormalities to a single system or biological mechanism. Further, Frye notes that due to findings in previous research showing just a minority of children with ASD demonstrate a clear genetics-only etiology, he speculates that the cause of autism is most likely driven by genetic-environmental interactions. Surprisingly, the study reports, mitochondria are very susceptible to damage due to environmental factors. The author speculates that mitochondria could potentially play the role as a key facilitator between environmental-genetic interactions.

The research goes on to distinguish between classical mitochondrial disease which affects only 5% of children with ASD and abnormal mitochondrial function which affects many more children with ASD, anywhere from 30%-80%. Since individuals with autism and classic mitochondrial disease are susceptible to neurodevelopmental regression (NDR), Frye theorizes that NDR, common in individuals with ASD, could be a hallmark of mitochondrial dysfunction as well.

Clinical symptoms of mitochondrial dysfunction in children with autism are included in this research, which many parents will recognize. These symptoms include developmental delay, sudden loss of skills, seizures, ataxia, muscle weakness, peripheral neuropathy, fatigue, gastrointestinal symptoms, endocrine abnormalities, failure to thrive and gross motor delay.

However, Frye doesn’t stop at identifying mitochondrial dysfunction symptoms. He is interested in treatments, which play a large role in this paper. The author advocates using cofactor supplementation since this approach is generally well tolerated and avoids significant adverse effects. The foundation of this approach is the use of L-Carnitine, Coenzyme Q10, along with B vitamins. Frye additionally encourages the use of the ketogenic diet (KD) for children with mitochondrial dysfunction and autism due to its important and long recognized role for treating drug-resistant epilepsy. For children who suffer with both autism and seizures, a trial of the KD would be especially warranted.

Towards the end of his paper, Frye encourages others to think outside of the box when it comes to treating children with ASD who exhibit mitochondrial disorder symptoms. He states,“For children with ASD it is important to realize that it is less likely to find the genetic explanation and withholding treatment for those where a disorder of mitochondrial function just because a gene abnormality cannot be found may deprive a child with a severe neurodevelopmental disability treatment that may be life changing. This is especially true for treatments which are safe and have a low incidence of any adverse effects. For course it is important to recommend all treatments based on the precise overall clinical picture and to ensure that response to treatment is monitored, preferably with standardized validated tools, in order to determine if the specific treatment is useful for a particular child. In this way, a personalized medicine is important to adopt in such patients.”

The conclusion of this innovative paper asserts, “There appears to be clear evidence that the mitochondrial is involved in the pathophysiology of ASD in many cases, although the reason for the abnormalities in mitochondrial function are not certain. ASD appears to be associated with novel types of mitochondrial abnormalities which are just beginning to be understood and the genetic mechanism which drive these abnormalities are still very unclear. Criteria for defining mitochondrial dysfunction which does not rise to the level of mitochondrial disease has not been developed and requires careful consideration of symptoms and biochemical tests. However, mitochondria may be an important and robust treatment target for ASD as several treatments that target the mitochondria appear to be effective in children with ASD in preliminary studies.”

Resources

Cecilia Giulivi, Yi-Fan Zhang, Alicja Omanska-Kluskek. Mitochondria Dysfunction in Autism. JAMA. December 1, 2010.

Maheen F Siddiqui, Clare Elwell, Mark Johnson. Mitochondrial Dysfunction in Autism Spectrum Disorders. Autism Open Access. July 26, 2016.

Suzanne Goh, Zhengchao Dong, Yudong Zhang, Salvatore DiMauro, Bradley Peterson. Mitochondrial Dysfunction as a Neurobiological Subtype of Autism Spectrum Disorder: Evidence from Brain Imaging. JAMA Psychiatry. June 2014.

Richard Frye. Mitochondrial Dysfunction in Autism Spectrum Disorder: Unique Abnormalities and Targeted Treatments. Seminars in Pediatric Neurology. June 23, 2020.

Tammimies K, Marshall CR, Walker S, et al. Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children with Autism Spectrum Disorder. JAMA. September 2015.

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