Metabolic Dysfunction Underlying Autism Spectrum Disorder and Potential Treatment Approaches.

Ning Cheng,Jong M Rho,Susan A Masino

doi:10.3389/fnmol.2017.00034

Abstract

Autism spectrum disorder (ASD) is characterized by deficits in sociability and communication, and increased repetitive and/or restrictive behaviors. While the etio-pathogenesis of ASD is unknown, clinical manifestations are diverse and many possible genetic and environmental factors have been implicated. As such, it has been a great challenge to identify key neurobiological mechanisms and to develop effective treatments. Current therapies focus on co-morbid conditions (such as epileptic seizures and sleep disturbances) and there is no cure for the core symptoms. Recent studies have increasingly implicated mitochondrial dysfunction in ASD. The fact that mitochondria are an integral part of diverse cellular functions and are susceptible to many insults could explain how a wide range of factors can contribute to a consistent behavioral phenotype in ASD. Meanwhile, the high-fat, low-carbohydrate ketogenic diet (KD), used for nearly a century to treat medically intractable epilepsy, has been shown to enhance mitochondrial function through a multiplicity of mechanisms and affect additional molecular targets that may address symptoms and comorbidities of ASD. Here, we review the evidence for the use of metabolism-based therapies such as the KD in the treatment of ASD as well as emerging co-morbid models of epilepsy and autism. Future research directions aimed at validating such therapeutic approaches and identifying additional and novel mechanistic targets are also discussed.

Highlights

Autism spectrum disorder (ASD) is characterized by deficits in sociability and communication, and increased repetitive and/or restrictive behaviors
The fact that mitochondria are an integral part of diverse cellular functions and are susceptible to many insults could explain how a wide range of factors can contribute to a consistent behavioral phenotype in ASD
We review the evidence for the use of metabolism-based therapies such as the ketogenic diet (KD) in the treatment of ASD as well as emerging co-morbid models of epilepsy and autism

Summary

METABOLIC THERAPY FOR ASD

A metabolic therapy in use for decades is the ketogenic diet (KD), a high-fat, low-carbohydrate diet—a remarkably effective nonpharmacological treatment for medically intractable epilepsy (Neal et al, 2008). Two hallmark biochemical features after the KD treatment are increased ketone body production by the liver through fatty acid oxidation and reduced blood glucose levels (Stafstrom and Rho, 2012). More specific metabolic effects, such as increases in specific polyunsaturated fatty acids, might regulate neuronal membrane excitability (Voskuyl and Vreugdenhil, 2001), reduce inflammation (Cullingford, 2008; Jeong et al, 2011), or decrease the production of ROS by mitochondria (Kim do and Rho, 2008). Ketone bodies themselves have been shown to possess neuroprotective properties through improved bioenergetics - raising ATP levels and reducing ROS production through enhancement of NADH oxidation and inhibition of mitochondrial permeability transition (Kim do et al, 2007, 2015); related to this, a KD has been shown to stimulate mitochondrial biogenesis (Bough et al, 2006; Ahola-Erkkila et al, 2010). The KD has been proposed to increase adenosine (a product of extracellular ATP dephosphorylation); ATP and adenosine are purines with pleiotropic neuromodulatory and neuroprotective roles proposed to underlie in part the diet’s

Evidence of mitochondrial dysfunction

Multiple families

Six or multiple families

Findings

MITOCHONDRIAL DYSFUNCTION IN ANIMAL MODELS OF ASD BASED ON ENVIRONMENTAL FACTORS