Genetic and clinical evidence of mitochondrial dysfunction in autism spectrum disorder and intellectual disability

Abstract

Clinical conditions commonly associated with mitochondrial disorders (CAMDs) are often present in autism spectrum disorders (ASD) and intellectual disability (ID). Therefore, the mitochondrial dysfunction hypothesis has been proposed as a transversal mechanism that may function in both disorders. Here, we investigated the presence of conditions associated with mitochondrial disorders and mitochondrial DNA (mtDNA) alterations in 122 subjects who presented ASD with ID (ASD group), 115 subjects who presented ID but not ASD (ID group) and 112 healthy controls (HC group). We assessed in the three study groups the presence of the clinical conditions through a questionnaire and the mtDNA content of two mitochondrial genes, MT-ND1 and MT-ND4, by qPCR. The mtDNA sequences of 98 ASD and 95 ID subjects were obtained by mtDNA-targeted next generation sequencing and analysed through the MToolBox pipeline to identify mtDNA mutations. Subjects with ASD and ID showed higher frequencies of constipation, edema, seizures, vision alterations, strabismus and sphincter incontinence than HCs subjects. ASD and ID subjects showed significantly lower mtDNA content than HCs in both MT-ND1 and MT-ND4 genes. In addition, we identified 49 putative pathogenic variants with a heteroplasmy level higher than 60%: 8 missense, 29 rRNA and 12 tRNA variants. A total of 28.6% of ASD and 30.5% of ID subjects carried at least one putative pathogenic mtDNA mutation. The high frequency of CAMDs, the low mtDNA content and the presence of putative pathogenic mtDNA mutations observed in both ASD and ID subjects are evidence of mitochondrial dysfunction in ASD and ID.

The Mitochondrial Dysfunction Hypothesis in Autism Spectrum Disorders: Current Status and Future Perspectives

“…The evidence provided so far describes either variations directly involving the nucleotide sequence of mtDNA [24,25,27] or variations concerning the quantity of the same mutated mitochondria in the cell [23] (for a complete review of the main findings, see Table 2). The most important variations in the nucleotide sequence fall mainly in mitochondrial genes that encode proteins involved in cellular respiration [24,27], a set of metabolic processes occurring in the cells of organisms useful to convert chemical energy from oxygen molecules into adenosine triphosphate. As stated by Park et al [26], because mtDNA encodes 13 essential subunits of the respiratory chain, the integrity of mtDNA and the expression of genes within mtDNA are crucial for maintaining the oxidative phosphorylation system.…”

“…Valiente-Pallejà A. et al, 2018 [27] The lower presence of mtDNA in ASD with respect to HCs correlates with a high frequency of CAMDs.…”

“…These clinical conditions may be grouped under the umbrella term commonly associated with mitochondrial disorders (CAMDs), since impaired mitochondria affect most organ systems, producing a wide spectrum of phenotypes. The purpose of the Valiente-Palleja et al study [27] was to evaluate the presence of CAMDs and mitochondrial DNA (mtDNA) alterations in ASD and patients with an intellectual disability (ID). The authors investigated 122 subjects who presented ID and ASD (ID-ASD group); 115 subjects who presented ID but not ASD (ID group) and 112 healthy controls (HC).…”

Oxidative Stress and Immune System Dysfunction in Autism Spectrum Disorders

“…Indeed, in these individuals, oxygen radicals alter RBC shape and morphology, which therefore differ from those in the healthy controls. In addition, chronic mitochondrial dysfunctions associated with electron transport chain (ETC) complex I and III have been identified in patients with ASD [28,29].…”

Genetics and epigenetics of autism spectrum disorder—current evidence in the field

“…ASD can also occur in some metabolic diseases such as phenylketonuria ( PAH gene) and Smith-Lemli-Opitz syndrome ( DHCR7 gene) (Caglayan 2010 ). Several studies have proposed that another group of ASD related to monogenic disorders is caused by mutations in the mitochondrial DNA (mtDNA) and impairment of mitochondrial energy metabolism (Wang et al 2016 ; Valiente-Pallejà et al 2018 ).…”