Mitochondrial Dysfunction in Autism Spectrum Disorder

This is a summary of the article published on October 2020 in connection with the journal Seminars in Pediatric Neurology. The entire article can be found here:
https://pubmed.ncbi.nlm.nih.gov/32892956/

SUMMARY

Several lines of evidence implicate mitochondria in the pathophysiology of autism spectrum disorder (ASD). A suspicion of the mitochondrion’s involvement in ASD can be traced back to 1985 when lactic acidosis was noted in a subset of children with ASD. A large population-based study in 2007 confirmed this notion and found that a subset of children with ASD (around 5%) could be diagnosed with a definite mitochondrial disease. Further studies suggested that children with ASD and mitochondrial disease may have certain characteristics such as fatigability, gastrointestinal disorders, unusual types of neurodevelopmental regression, seizures/epilepsy, and motor delay. Further research examining biomarkers of mitochondrial dysfunction and electron transport chain activity suggest that abnormalities of mitochondrial function could affect a much higher number of children with ASD, perhaps up to 80%. Recent research has identified a type of dysfunction of mitochondria in which the activity of the electron transport chain is significantly increased. This novel type of mitochondrial dysfunction may be associated with environmental exposures and neurodevelopmental regression. Several treatments that target mitochondria appear to have evidence for use in children with ASD, including cofactors such as L-Carnitine and the ketogenic diet.

This article also raises another interesting point concerning mitochondrial disease/dysfunction, namely:

It is always important to look for a genetic cause for mitochondrial disease and dysfunction. However, only approximately 25% of children with ASD and classically defined mitochondrial disease have a clear genetic mutation to explain their mitochondrial disease. This means that 75% of children with ASD and mitochondrial disease do not have an identified mutation to explain their classically defined mitochondrial disease. Furthermore, genetic disorders which are associated with ASD but not classically associated with mitochondrial disease, including Down syndrome, Rett syndrome, Phelan-McDermid Syndrome, 15q11-13 duplication and others sometime involved mitochondrial dysfunction and respond to mitochondrial interventions. Thus, in our previous publication, we recommended a trial of mitochondrial-targeted treatments when mitochondrial dysfunction is identified while the search for the genetic causes of the mitochondrial abnormality is ongoing. For children with ASD, it is important to realize that finding a genetic explanation is unlikely and withholding treatment for those where a disorder of mitochondrial function is evident just because a gene abnormality cannot be found to explain the mitochondrial dysfunction may deprive a child with a severe neurodevelopmental disability a treatment that may be life changing.

This article further mentions a unique study that implemented a mitochondrial cocktail:

In the only study of its kind, Legido et al conducted a small (n = 11) open-label cross-over study for children with ASD and mitochondrial ETC abnormalities. Children were treated for 3 months with a mitochondrial cocktail containing L-Carnitine, Coenzyme Q10, and alpha-lipoic acid. The cocktail improved mitochondrial function as well as ASD behavior. Discontinuation of the cocktail resulted in worsening of behavior.

This article concludes with the notion that: the understanding of the involvement of mitochondria in ASD is evolving, the mitochondrion is clearly a novel molecular target which can be helpful in understanding the etiology of ASD and treatments that may improve function of children with ASD.

Dr. Richard Frye is a Child Neurologist with expertise in neurodevelopmental and neurometabolic disorders. He received an MD and PhD in Physiology and Biophysics from Georgetown University. He completed a residency in Pediatrics at the University of Miami, Residency in Child Neurology and Fellowship in Behavioral Neurology and Learning Disabilities at Harvard University/Children’s Hospital Boston and Fellowship in Psychology at Boston University. He also received a Masters in Biomedical Science and Biostatistics from Drexel University. He holds board certifications in Pediatrics, and in Neurology with Special Competence in Child Neurology. Dr. Frye is a national leader in autism research. He has authored over 150 peer-reviewed publications and book chapters, and serves on several editorial boards.

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