Mitochondrial dysfunction in autism spectrum disorders: cause or effect? Biochim Biophys Acta

Laboratory of Biochemistry and Molecular Biology, Department of Pharmaco-Biology, University of Bari, Via Orabona 4, 70125, Bari, Italy.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 06/2010; 1797(6-7):1130-7. DOI: 10.1016/j.bbabio.2010.04.018
Source: PubMed


Autism Spectrum Disorders encompass severe developmental disorders characterized by variable degrees of impairment in language, communication and social skills, as well as by repetitive and stereotypic patterns of behaviour. Substantial percentages of autistic patients display peripheral markers of mitochondrial energy metabolism dysfunction, such as (a) elevated lactate, pyruvate, and alanine levels in blood, urine and/or cerebrospinal fluid, (b) serum carnitine deficiency, and/or (c) enhanced oxidative stress. These biochemical abnormalities are accompanied by highly heterogeneous clinical presentations, which generally (but by no means always) encompass neurological and systemic symptoms relatively unusual in idiopathic autistic disorder. In some patients, these abnormalities have been successfully explained by the presence of specific mutations or rearrangements in their mitochondrial or nuclear DNA. However, in the majority of cases, abnormal energy metabolism cannot be immediately linked to specific genetic or genomic defects. Recent evidence from post-mortem studies of autistic brains points toward abnormalities in mitochondrial function as possible downstream consequences of dysreactive immunity and altered calcium (Ca(2+)) signalling.

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    • "Carnitine deficiency appears to be common in the wider populations with ASD, but children with ASD and carnitine deficiency have not been well characterized regarding their ASD and medical symptoms such as epilepsy [94]. Given the lack of carnitine genes found to be directly related to ASD, some authors have hypothesized that carnitine deficiency in ASD may be secondary to mitochondrial disease or dysfunction [25] [95], while others have suggested that carnitine metabolism abnormalities may be related to the overproduction of short-chain fatty acids resulting from imbalances in enteric bacteria [96] [97]. 1.1.4. "
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    ABSTRACT: Autism spectrum disorder (ASD) affects a significant number of individuals in the United States, with the prevalence continuing to grow. A significant proportion of individuals with ASD have comorbid medical conditions such as epilepsy. In fact, treatment-resistant epilepsy appears to have a higher prevalence in children with ASD than in children without ASD, suggesting that current antiepileptic treatments may be suboptimal in controlling seizures in many individuals with ASD. Many individuals with ASD also appear to have underlying metabolic conditions. Metabolic conditions such as mitochondrial disease and dysfunction and abnormalities in cerebral folate metabolism may affect a substantial number of children with ASD, while other metabolic conditions that have been associated with ASD such as disorders of creatine, cholesterol, pyridoxine, biotin, carnitine, γ-aminobutyric acid, purine, pyrimidine, and amino acid metabolism and urea cycle disorders have also been associated with ASD without the prevalence clearly known. Interestingly, all of these metabolic conditions have been associated with epilepsy in children with ASD. The identification and treatment of these disorders could improve the underlying metabolic derangements and potentially improve behavior and seizure frequency and/or severity in these individuals. This paper provides an overview of these metabolic disorders in the context of ASD and discusses their characteristics, diagnostic testing, and treatment with concentration on mitochondrial disorders. To this end, this paper aims to help optimize the diagnosis and treatment of children with ASD and epilepsy. This article is part of a Special Issue entitled "Autism and Epilepsy".
    Full-text · Article · Nov 2014 · Epilepsy & Behavior
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    • "Mitochondrial dysfunction can be a downstream consequence of many proposed factors including dysreactive immunity and altered calcium (Ca2+) signaling (80), increased nitric oxide and peroxynitrite (68), propionyl CoA (81), malnutrition (82), vitamin B6 or iron deficiencies (83), toxic metals (83), elevated nitric acid (84, 85), oxidative stress (86), exposure to environmental toxicants, such as heavy metals (87–89), chemicals (90), polychlorinated biphenyls (PCBs) (91), pesticides (92, 93), persistent organic pollutants (POPs) (94), and radiofrequency radiation (95). Other sources of mitochondrial distress include medications such as valproic acid (VPA), which inhibits oxidative phosphorylation (96) and neuroleptics (97, 98). "
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    ABSTRACT: Autism spectrum disorders (ASDs) are complex, heterogeneous disorders caused by an interaction between genetic vulnerability and environmental factors. In an effort to better target the underlying roots of ASD for diagnosis and treatment, efforts to identify reliable biomarkers in genetics, neuroimaging, gene expression, and measures of the body's metabolism are growing. For this article, we review the published studies of potential biomarkers in autism and conclude that while there is increasing promise of finding biomarkers that can help us target treatment, there are none with enough evidence to support routine clinical use unless medical illness is suspected. Promising biomarkers include those for mitochondrial function, oxidative stress, and immune function. Genetic clusters are also suggesting the potential for useful biomarkers.
    Full-text · Article · Aug 2014 · Frontiers in Psychiatry
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    • "Furthermore, circulating autoantibodies have been detected against GFAP and other proteins involved in neuronal and synaptic functions, including neurotrophic factors and neuronal-axonal filaments [17,18]. Finally, changes in mitochondrial and energy pathways have also been reported [19], although it has been hypothesized that these changes may be secondary to an as yet unidentified disease process [20]. Several independent studies have corroborated that creatine kinase (CK), an enzyme important for energy homeostasis, is one of the most robust chemical changes in autism and this is likely to parallel changes in synaptic remodelling [21]. "
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    ABSTRACT: Background Autism is a neurodevelopmental disorder characterized by impaired language, communication and social skills. Although genetic studies have been carried out in this field, none of the genes identified have led to an explanation of the underlying causes. Here, we have investigated molecular alterations by proteomic profiling of post mortem brain samples from autism patients and controls. The analysis focussed on prefrontal cortex and cerebellum as previous studies have found that these two brain regions are structurally and functionally connected, and they have been implicated in autism. Methods Post mortem prefrontal cortex and cerebellum samples from autism patients and matched controls were analysed using selected reaction monitoring mass spectrometry (SRM-MS). The main objective was to identify significantly altered proteins and biological pathways and to compare these across these two brain regions. Results Targeted SRM-MS resulted in identification of altered levels of proteins related to myelination, synaptic vesicle regulation and energy metabolism. This showed decreased levels of the immature astrocyte marker vimentin in both brain regions, suggesting a decrease in astrocyte precursor cells. Also, decreased levels of proteins associated with myelination and increased synaptic and energy-related proteins were found in the prefrontal cortex, indicative of increased synaptic connectivity. Finally, opposite directional changes were found for myelination and synaptic proteins in the cerebellum. Conclusion These findings suggest altered structural and/or functional connectivity in the prefrontal cortex and cerebellum in autism patients, as shown by opposite effects on proteins involved in myelination and synaptic function. Further investigation of these findings could help to increase our understanding of the mechanisms underlying autism relating to brain connectivity, with the ultimate aim of facilitating novel therapeutic approaches.
    Full-text · Article · Jul 2014 · Molecular Autism
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