Abstract
Autism Spectrum Disorder (ASD) is characterized by persistent deficits in social communication and restricted-repetitive patterns of behavior, interests, or activities. ASD is generally associated with chronic inflammatory states, which are linked to immune system dysfunction and/or hyperactivation. The latter might be considered as one of the factors damaging neuronal cells. Several cell types trigger and sustain such neuroinflammation. In this study, we traced different markers of immune system activation on both cellular (immune cell phenotypes) and mediatory levels (production of cytokines) alongside adverse hematology and biochemistry screening in a group of autistic children. In addition, we analyzed the main metabolic pathways potentially involved in ASD development: energy (citric acid cycle components), porphyrin, and neurotransmitter metabolism. Several ASD etiological factors, like heavy metal intoxication, and risk factors—genetic polymorphisms of the relevant neurotransmitters and vitamin D receptors—were also analyzed. Finally, broad linear regression analysis allowed us to elucidate the possible scenario that led to the development of chronic inflammation in ASD patients. Obtained data showed elevated levels of urinary cis-aconitate, isocitrate, alfa-ketoglutarate, and HMG. There were no changes in levels of metabolites of monoamine neurotransmitters, however, the liver-specific tryptophan kinurenine pathway metabolites showed increased levels of quinolinate (QUIN) and picolinate, whereas the level of kynurenate remained unchanged. Abovementioned data demonstrate the infringement in energy metabolism. We found elevated levels of lead in red blood cells, as well as altered porphyrin metabolism, which support the etiological role of heavy metal intoxication in ASD. Lead intoxication, the effect of which is intensified by a mutation of the VDR-Taq and MAO-A, leads to quinolinic acid increase, resulting in energy metabolism depletion and mitochondrial dysfunction. Moreover, our data backing the CD4+CD3+ T-cell dependence of mitochondrial dysfunction development in ASD patients reported in our previous study leads us to the conclusion that redox-immune cross-talk is considered a main functional cell damaging factor in ASD patients.
Highlights
Autism and its related neurodevelopmental disorder (Autism Spectrum Disorder-ASD) are clinically heterogeneous pathologies, which are caused by a number of factors
We found elevated levels of lead in red blood cells, as well as altered porphyrin metabolism, which support the etiological role of heavy metal intoxication in ASD
We demonstrated that persistent inflammation shown in ASD patients may lead to depletion of the respiratory burst capability in neutrophils, and accumulation of damage and pathological change resulting in disability and disease [13]
Summary
Autism and its related neurodevelopmental disorder (Autism Spectrum Disorder-ASD) are clinically heterogeneous pathologies, which are caused by a number of factors. Such heterogeneity makes it difficult to single out individual causal elements of this disease(s). Clinical signs of ASD are frequently present at 3 years of age and recent prospective studies in toddlers indicate that abnormalities in social, communicative, and play behavior, which may represent early indicators of autism, can be detected as early as at 14 months of age [3]. Abnormalities in language development, delayed mental development, and epilepsy are frequent problems in the clinical profiles of patients with autism, and some patients may exhibit features of clinical regression, in which neurodevelopmental milestones are lost and/or other clinical signs are worsened [4]. Cases of ASD are clinically heterogeneous and can be associated in up to 10% of patients with well-described neurological and genetic disorders, such as tuberous sclerosis, fragile X, Rett’s and Down syndromes, in most patients the causes are still unknown [5, 6]
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