Abstract
Patients with autism spectrum disorder (ASD) may have an increase in blood acyl-carnitine (AC) concentrations indicating a mitochondrial fatty acid β-oxidation (mtFAO) impairment. However, there are no data on systematic mtFAO analyses in ASD. We analyzed tritiated palmitate oxidation rates in fibroblasts from patients with ASD before and after resveratrol (RSV) treatment, according to methods used for the diagnosis of congenital defects in mtFAO. ASD participants (N = 10, 60%; male; mean age (SD) 7.4 (3.2) years) were divided in two age-equivalent groups based on the presence (N = 5) or absence (N = 5) of elevated blood AC levels. In addition, electron transport chain (ETC) activity in fibroblasts and muscle biopsies and clinical characteristics were compared between the ASD groups. Baseline fibroblast mtFAO was not significantly different in patients in comparison with control values. However, ASD patients with elevated AC exhibited significantly decreased mtFAO rates, muscle ETC complex II activity, and fibroblast ETC Complex II/III activity (p < 0.05), compared with patients without an AC signature. RSV significantly increased the mtFAO activity in all study groups (p = 0.001). The highest mtFAO changes in response to RSV were observed in fibroblasts from patients with more severe symptoms on the Social Responsiveness Scale total (p = 0.001) and Awareness, Cognition, Communication and Motivation subscales (all p < 0.01). These findings suggested recognition of an ASD patient subset characterized by an impaired mtFAO flux associated with abnormal blood AC. The study elucidated that RSV significantly increased fibroblast mtFAO irrespective of plasma AC status, and the highest changes to RSV effects on mtFAO were observed in the more severely affected patients.
Highlights
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by early social communication deficits and repetitive motor behavior, sensory abnormalities, and restricted interests, with a global prevalence of about 1% [1] and, according to the most recent estimates, of about 2% in the United States (US) [2]
We tested the effects of RSV on fibroblasts mitochondrial fatty acid β-oxidation (mtFAO) rates in patients with autism spectrum disorder (ASD) and we evaluated whether the mtFAO response upon RSV treatment was depended on clinical characteristics
We found that patients who had highest mtFAO activity in response to RSV were the most impaired on the Social Responsiveness Scale (SRS)–total
Summary
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by early social communication deficits and repetitive motor behavior, sensory abnormalities, and restricted interests, with a global prevalence of about 1% [1] and, according to the most recent estimates, of about 2% in the United States (US) [2]. ASD biology is complex, including individual genetic contributions interacting with multiple environmental factors. The vast majority of ASD is idiopathic, with a specific cause identified in only 4–20% of patients, including a genetic etiology. Association of ASD behavioral phenotypes to specific genetic subtypes is envisaged; patients with molecularly defined ASD are not clinically identified because clinical and neurobehavioral correlates of a given genetic contribution vary widely [3,4]. Complex biological changes play a role in ASD clinical heterogeneity, hindering the discovery of universal biomarkers for diagnosis and treatments. ASD diagnosis is based on measurements of behavioral symptoms according to the Diagnostic Statistical Manual of Mental Disorders Version 5
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