Elsevier

Medical Hypotheses

Volume 78, Issue 4, April 2012, Pages 548-552
Medical Hypotheses

Methylglyoxal, advanced glycation end products and autism: Is there a connection?

https://doi.org/10.1016/j.mehy.2012.01.032Get rights and content

Abstract

Autism is a complex and heterogeneous neurodevelopmental disorder of unknown etiology but very likely resulting from both genetic and environmental factors. Recent estimates suggest that it affects 1 in 100–150 individuals in the US. Oxidative stress, inflammation and mitochondrial dysfunction have all been suggested to play key roles in autism and may be linked via alterations in cellular redox homeostasis. The glutathione/glutathione disulfide (GSH/GSSG) redox pair forms the major redox couple in cells and as such plays a critical role in regulating redox-dependent cellular functions. A number of studies have shown that variations in genes involved in GSH metabolism are associated with autism. GSH also modulates the activity of glyoxalase 1 (Glo-1), the rate-limiting enzyme for the removal of reactive dicarbonyls such as methylglyoxal (MG). MG is the major precursor for the formation of advanced glycation end products (AGEs). Both MG and AGEs can induce oxidative stress, inflammation and mitochondrial dysfunction and are implicated in diabetic complications and multiple, age-related neurological diseases. Dietary consumption of AGEs and MG correlates with food intake which has increased 20–30% over the past 20 years. Both MG and AGEs are orally absorbed, leading to increased levels in the blood. Furthermore, in humans, increased MG and AGE levels in maternal blood correlate with increased MG and AGE levels in newborn blood, potentially exposing infants to high oxidative stress and inflammation. It is hypothesized that diet derived MG and AGEs in combination with inborn genetic vulnerabilities that affect the cellular redox status are major contributors to the development of autism and provide a causal link between oxidative stress, inflammation and mitochondrial dysfunction. If future research supports this hypothesis, then by reducing the exposure to these diet-derived factors, it might be possible to decrease the prevalence of at least a subset of autism cases.

Section snippets

Background

Autism is a heterogeneous neurodevelopmental disorder defined by a broad spectrum of atypical social, cognitive and verbal behaviors along with repetitive and sometimes self-injurious actions. Despite affecting an increasing number of children, there are no effective treatments for the disorder [1]. Although the exact causes of autism are unknown, many investigators believe that it is likely the result of a combination of genetic vulnerabilities and environmental insults interacting at a

Hypothesis

Based on these observations, I propose that a combination of inborn genetic vulnerabilities affecting GSH metabolism, Glo-1 and/or mitochondrial function coupled with increased dietary exposure to AGEs and/or the AGE precursor MG could lead to neuropathological changes in the brain and the subsequent behavioral deficits that are characteristic of autism.

This hypothesis ties together a number of the observations that have been made regarding the pathophysiological factors underlying autism and

Predictions

Since both obesity and diabetes [34] are associated with higher exposure to AGEs, this hypothesis predicts that there would be an association between these disorders in mothers and higher rates of autism in their offspring. The limited epidemiological studies on this question suggest that this may be the case. First, on a general level, the prevalence of overweight and obesity [52], [53], [54] as well as diabetes [55], [56], [57] in women of child bearing age in the US, Canada and the UK has

Conflict of interest statement

The author declares that there are no conflicts of interest.

Acknowledgments

This work was supported by a grant from the not-for-profit Fritz B. Burns Foundation. The author would like to thank Drs. David Schubert and Michael Nunn for critical reading of the manuscript.

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