Brief Report: High Frequency of Biochemical Markers for Mitochondrial Dysfunction in Autism: No Association with the Mitochondrial Aspartate/Glutamate Carrier SLC25A12 Gene

Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2781 Oeiras, Portugal.
Journal of Autism and Developmental Disorders (Impact Factor: 3.34). 12/2006; 36(8):1137-40. DOI: 10.1007/s10803-006-0138-6
Source: PubMed


In the present study we confirm the previously reported high frequency of biochemical markers of mitochondrial dysfunction, namely hyperlactacidemia and increased lactate/pyruvate ratio, in a significant fraction of 210 autistic patients. We further examine the involvement of the mitochondrial aspartate/glutamate carrier gene (SLC25A12) in mitochondrial dysfunction associated with autism. We found no evidence of association of the SLC25A12 gene with lactate and lactate/pyruvate distributions or with autism in 241 nuclear families with one affected individual. We conclude that while mitochondrial dysfunction may be one of the most common medical conditions associated with autism, variation at the SLC25A12 gene does not explain the high frequency of mitochondrial dysfunction markers and is not associated with autism in this sample of autistic patients.

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    • "Several studies have identified brain metabolism abnormalities in ASC (increased cytochrome c oxidase activity, increased oxidative stress) which might be a result of mitochondrial oxidative dysfunction in neural cells [9,12,13]. SLC25A12 may play a key role in the pathways that are altered in autism and thus can be considered a candidate gene to test in ASC. "
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    ABSTRACT: Autism Spectrum Conditions (ASC) are a group of developmental conditions which affect communication, social interactions and behaviour. Mitochondrial oxidative dysfunction has been suggested as a mechanism of autism based on the results of multiple genetic association and expression studies. SLC25A12 is a gene encoding a calcium-binding carrier protein that localizes to the mitochondria and is involved in the exchange of aspartate for glutamate in the inner membrane of the mitochondria regulating the cytosolic redox state. rs2056202 SNP in this gene has previously been associated with ASC. SNPs rs6716901 and rs3765166 analysed in this study have not been previously explored in association with AS. We genotyped three SNPs (rs2056202, rs3765166, and rs6716901) in SLC25A12 in n = 117 individuals with Asperger syndrome (AS) and n = 426 controls, all of Caucasian ancestry. rs6716901 showed significant association with AS (P = 0.008) after correcting for multiple testing. We did not replicate the previously identified association between rs2056202 and AS in our sample. Similarly, rs3765166 (P = 0.11) showed no significant association with AS. The present study, in combination with previous studies, provides evidence for SLC25A12 as involved in the etiology of AS. Further cellular and molecular studies are required to elucidate the role of this gene in ASC.
    Molecular Autism 03/2014; 5(1):25. DOI:10.1186/2040-2392-5-25 · 5.41 Impact Factor
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    • "Hyperlactacidemia and an increased lactate/pyruvate ratio may result from several inherited metabolic defects of gluconeogenesis, pyruvate oxidation, the Krebs cycle, or the respiratory chain. Mutations in multiple genes may influence the observed changes in lactate and pyruvate levels, with genetic heterogeneity underlying mitochondrial dysfunction associated with autism.94–96 "
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    ABSTRACT: Autism spectrum disorder (ASD) is a pervasive neuro-developmental disorder characterized by impaired social interaction, reduced/absent verbal and non-verbal communication, and repetitive behavior during early childhood. The etiology of this developmental disorder is poorly understood, and no biomarkers have been identified. Identification of novel biochemical markers related to autism would be advantageous for earlier clinical diagnosis and intervention. Studies suggest that oxidative stress-induced mechanisms and reduced antioxidant defense, mitochondrial dysfunction, and impaired energy metabolism (NAD(+), NADH, ATP, pyruvate, and lactate), are major causes of ASD. This review provides renewed insight regarding current autism research related to oxidative stress, mitochondrial dysfunction, and altered tryptophan metabolism in ASD.
    International Journal of Tryptophan Research 07/2013; 6(Suppl 1):15-28. DOI:10.4137/IJTR.S11355
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    • "Although most people with autism have no discernible mutation indicating primary mitochondrial disorder, labwork gives evidence to reduced mitochondrial function, namely elevated plasma lactate, hyperlactacidemia and increased lactate/pyruvate ratio. Rarely have mtDNA changes been found in people with autism with clinical signs of mitochondrial dysfunction [51-53]. In addition, levels of enzymes associated with resolving mitochondrial produced radical production have been found to be lower in people with autism [54]. "
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    ABSTRACT: Autism is the fastest growing developmental disorder in the world today. The prevalence of autism in the US has risen from 1 in 2500 in 1970 to 1 in 88 children today. People with autism present with repetitive movements and with social and communication impairments. These impairments can range from mild to profound. The estimated total lifetime societal cost of caring for one individual with autism is $3.2 million US dollars. With the rapid growth in this disorder and the great expense of caring for those with autism, it is imperative for both individuals and society that techniques be developed to model and understand autism. There is increasing evidence that those individuals diagnosed with autism present with highly diverse set of abnormalities affecting multiple systems of the body. To this date, little to no work has been done using a whole body systems biology approach to model the characteristics of this disorder. Identification and modelling of these systems might lead to new and improved treatment protocols, better diagnosis and treatment of the affected systems, which might lead to improved quality of life by themselves, and, in addition, might also help the core symptoms of autism due to the potential interconnections between the brain and nervous system with all these other systems being modeled. This paper first reviews research which shows that autism impacts many systems in the body, including the metabolic, mitochondrial, immunological, gastrointestinal and the neurological. These systems interact in complex and highly interdependent ways. Many of these disturbances have effects in most of the systems of the body. In particular, clinical evidence exists for increased oxidative stress, inflammation, and immune and mitochondrial dysfunction which can affect almost every cell in the body. Three promising research areas are discussed, hierarchical, subgroup analysis and modeling over time. This paper reviews some of the systems disturbed in autism and suggests several systems biology research areas. Autism poses a rich test bed for systems biology modeling techniques.
    Journal of Clinical Bioinformatics 10/2012; 2(1):17. DOI:10.1186/2043-9113-2-17
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