Autism and Intellectual Disability Associated with Mitochondrial Disease and Hyperlactacidemia

Abstract

Autism spectrum disorder (ASD) with intellectual disability (ID) is a life-long debilitating condition, which is characterized by cognitive function impairment and other neurological signs. Children with ASD-ID typically attain motor skills with a significant delay. A sub-group of ASD-IDs has been linked to hyperlactacidemia and alterations in mitochondrial respiratory chain activity. The objective of this report is to describe the clinical features of patients with these comorbidities in order to shed light on difficult diagnostic and therapeutic approaches in such patients. We reported the different clinical features of children with ID associated with hyperlactacidemia and deficiencies in mitochondrial respiratory chain complex II–IV activity whose clinical presentations are commonly associated with the classic spectrum of mitochondrial diseases. We concluded that patients with ASD and ID presenting with persistent hyperlactacidemia should be evaluated for mitochondrial disorders. Administration of carnitine, coenzyme Q10, and folic acid is partially beneficial, although more studies are needed to assess the efficacy of this vitamin/cofactor treatment combination.

Genetic Evidence for Elevated Pathogenicity of Mitochondrial DNA Heteroplasmy in Autism Spectrum Disorder

“…We found that mtDNA mutations at non-polymorphic sites as well as nonsynonymous and predicted pathogenic mtDNA mutations that were private to probands significantly increased the risk of ID in ASD (ORs = 1.98–2.75, P = 0.0022–0.039, Table 2), The estimated ORs did not qualitatively change after additional adjustment for ASD severity (proband SRS scores) and whether carrying de novo LGD SNPs or CNVs on nuclear DNA (Table 2). It suggests that mtDNA mutations and the resulting mitochondrial dysfunction may be responsible for intellectual disability in ASD, which is consistent with clinical reports on ASD-ID cases who manifested defects in mitochondrial OXPHOS [45]. …”

“…Some neurological and developmental pathologies of MD [61] are present in ASD patients, including seizure, eating disorders, impaired motor ability and developmental delay [45,62,63]. Among the 33 autistic children detected with predicted pathogenic and/or disease-associated private mtDNA mutations in the current study, whose medical records were also available at SFARI phenotype database, six were reported with febrile or non-febrile seizures and two were diagnosed with epilepsy (S3 Table).…”

Increased homocysteine levels correlate with the communication deficit in children with autism spectrum disorder

“…ASD affects approximately 1% of children and is on the rise (MMWR, 2010). There are significant genetic mechanisms underlying these disorders and research studies have uncovered several metabolic abnormalities associated with ASD (Guevara-Campos et al, 2013, 2015Frye and Rossignol, 2014;West et al, 2014). Several clinical trials with different drugs aimed to reduce oxidative stress in ASD patients have been conducted (Frustaci et al, 2012) and the overall studies led to mixed results.…”

Correction of Fatty Acids Metabolism as Treatment Strategy of Autism

“…Another evidence for fatty acids metabolic disturbances as one potential etiological mechanism in autism is the remarkable increase of adipic and suberic acids, as two dicarboxylic acids produced by the omega (ω)-oxidation pathway, a minor catabolic pathway for medium-chain fatty acids that becomes more important when β-oxidation is impaired [51,61] ( Figure 3). Based on the previously discussed association between impaired FAO and autism [50,56,62,63], it was suggested that altered β-oxidation can increase the activity of ω fatty acid oxidation, thus leading to increased production of adipic and suberic acid [58,61]. There is a strong body of evidence between mitochondrial dysfunction and PUFAs transport and metabolism in autism.…”