Developmental regression and mitochondrial function in children with autism

Abstract

Background: Developmental regression (DR) occurs in about one-third of children with Autism Spectrum Disorder (ASD) yet it is poorly understood. Current evidence suggests that mitochondrial function in not normal in many children with ASD. However, the relationship between mitochondrial function and DR has not been well-studied in ASD. Methods: This cross-sectional study of 32 children, 2 to 8 years old with ASD, with (n = 11) and without (n = 12) DR, and non-ASD controls (n = 9) compared mitochondrial respiration and mtDNA damage and copy number between groups and their relation to standardized measures of ASD severity. Results: Individuals with ASD demonstrated lower ND1, ND4, and CYTB copy number (Ps < 0.01) as compared to controls. Children with ASD and DR had higher maximal oxygen consumption rate (Ps < 0.02), maximal respiratory capacity (P < 0.05), and reserve capacity (P = 0.01) than those with ASD without DR. Coupling Efficiency and Maximal Respiratory Capacity were associated with disruptive behaviors but these relationships were different for those with and without DR. Higher ND1 copy number was associated with better behavior. Conclusions: This study suggests that individuals with ASD and DR may represent a unique metabolic endophenotype with distinct abnormalities in respiratory function that may put their mitochondria in a state of vulnerability. This may allow physiological stress to trigger mitochondrial decompensation as is seen clinically as DR. Since mitochondrial function was found to be related to ASD symptoms, the mitochondria could be a potential target for novel therapeutics. Additionally, identifying those with vulnerable mitochondrial before DR could result in prevention of ASD.

Prenatal air pollution influences neurodevelopment and behavior in autism spectrum disorder by modulating mitochondrial physiology

“…We have suggested that this may represent a model of mitochondrial associated NDR as mitochondrial function is lost with a mild increase in ROS in the AD-A LCL model and NDR is known to be associated with triggers that increase physiological stressor which can increase ROS. In fact, a recent study examining mitochondrial function in PBMCs in children with ASD in a manner similar to the current study found that those with a history of NDR demonstrated elevated respiratory rates, similar to our LCL model, as compared to those without a history of NDR [25].…”

“…In general, separate variables were used for (1) environmental exposure, (2) mitochondrial energy production, (3) mitochondrial oxidative stress control, (4) redox metabolism (both iGSH and iGSSG), (5) cognitive neurodevelopment, (6) behavior and (7) age of NDR in the models for those with NDR. These models did introduce measures of redox metabolism since it is so important in regards to mitochondrial function in ASD [64], especially with respect to NDR [25,26,30,31], and is a prominent physiological abnormality found in ASD [53,65,66]. Since ASD behavior depended on neurodevelopment in the regression models above as well in our previous studies [40,41], a relationship between neurodevelopment and behavior was considered in the models and was found to be significant in every model.…”

Paving the Way toward Personalized Medicine: Current Advances and Challenges in Multi-OMICS Approach in Autism Spectrum Disorder for Biomarkers Discovery and Patient Stratification

“…Mitochondrial dysfunction is linked to ASD. A systematic meta-analysis study showed that the prevalence of mitochondrial diseases in ASD was 4–5%, which is markedly higher than the general population (around 0.01%) [ 126 , 127 ]. Lactate was the first biomarker that was found to be elevated in ASD children’s serum [ 126 , 127 ].…”

“…A systematic meta-analysis study showed that the prevalence of mitochondrial diseases in ASD was 4–5%, which is markedly higher than the general population (around 0.01%) [ 126 , 127 ]. Lactate was the first biomarker that was found to be elevated in ASD children’s serum [ 126 , 127 ]. Other mitochondrial biomarkers that were shown to be elevated in children with ASD are AST, pyruvate, and creatine kinase [ 126 , 128 ].…”

Treatment of Folate Metabolism Abnormalities in Autism Spectrum Disorder

“…Interestingly, abnormal mitochondrial metabolism has been linked to ASD. 70 – 73 Clinical 74 and basic research studies 75 suggest that folate is important in mitochondrial function. In a recent study, our group measured the function of several mitochondrial enzymes in children with ASD who were receiving various supplements that could influence mitochondrial function.…”