Dataset Information

Mitochondrial disease in autism spectrum disorder patients: a cohort analysis.

ABSTRACT:

Background

Previous reports indicate an association between autism spectrum disorders (ASD) and disorders of mitochondrial oxidative phosphorylation. One study suggested that children with both diagnoses are clinically indistinguishable from children with idiopathic autism. There are, however, no detailed analyses of the clinical and laboratory findings in a large cohort of these children. Therefore, we undertook a comprehensive review of patients with ASD and a mitochondrial disorder.

Methodology/principal findings

We reviewed medical records of 25 patients with a primary diagnosis of ASD by DSM-IV-TR criteria, later determined to have enzyme- or mutation-defined mitochondrial electron transport chain (ETC) dysfunction. Twenty-four of 25 patients had one or more major clinical abnormalities uncommon in idiopathic autism. Twenty-one patients had histories of significant non-neurological medical problems. Nineteen patients exhibited constitutional symptoms, especially excessive fatigability. Fifteen patients had abnormal neurological findings. Unusual developmental phenotypes included marked delay in early gross motor milestones (32%) and unusual patterns of regression (40%). Levels of blood lactate, plasma alanine, and serum ALT and/or AST were increased at least once in 76%, 36%, and 52% of patients, respectively. The most common ETC disorders were deficiencies of complex I (64%) and complex III (20%). Two patients had rare mtDNA mutations of likely pathogenicity.

Conclusions/significance

Although all patients' initial diagnosis was idiopathic autism, careful clinical and biochemical assessment identified clinical findings that differentiated them from children with idiopathic autism. These and prior data suggest a disturbance of mitochondrial energy production as an underlying pathophysiological mechanism in a subset of individuals with autism.

SUBMITTER: Weissman JR

PROVIDER: S-EPMC2584230 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Publications

Mitochondrial disease in autism spectrum disorder patients: a cohort analysis.

Weissman Jacqueline R JR Kelley Richard I RI Bauman Margaret L ML Cohen Bruce H BH Murray Katherine F KF Mitchell Rebecca L RL Kern Rebecca L RL Natowicz Marvin R MR

PloS one 20081126 11

<h4>Background</h4>Previous reports indicate an association between autism spectrum disorders (ASD) and disorders of mitochondrial oxidative phosphorylation. One study suggested that children with both diagnoses are clinically indistinguishable from children with idiopathic autism. There are, however, no detailed analyses of the clinical and laboratory findings in a large cohort of these children. Therefore, we undertook a comprehensive review of patients with ASD and a mitochondrial disorder.<h ...[more]

PMID: 19043581

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Project description:Autism spectrum disorder (ASD) is characterized by phenotypic heterogeneity and a complex genetic architecture which includes distinctive epigenetic patterns. We report differential DNA methylation patterns associated with ASD in South African children. An exploratory whole-epigenome methylation screen using the Illumina 450 K MethylationArray identified differentially methylated CpG sites between ASD and controls that mapped to 898 genes (P ≤ 0.05) which were enriched for nine canonical pathways converging on mitochondrial metabolism and protein ubiquitination. Targeted Next Generation Bisulfite Sequencing of 27 genes confirmed differential methylation between ASD and control in our cohort. DNA pyrosequencing of two of these genes, the mitochondrial enzyme Propionyl-CoA Carboxylase subunit Beta (PCCB) and Protocadherin Alpha 12 (PCDHA12), revealed a wide range of methylation levels (9-49% and 0-54%, respectively) in both ASD and controls. Three CpG loci were differentially methylated in PCCB (P ≤ 0.05), while PCDHA12, previously linked to ASD, had two significantly different CpG sites (P ≤ 0.001) between ASD and control. Differentially methylated CpGs were hypomethylated in ASD. Metabolomic analysis of urinary organic acids revealed that three metabolites, 3-hydroxy-3-methylglutaric acid (P = 0.008), 3-methyglutaconic acid (P = 0.018), and ethylmalonic acid (P = 0.043) were significantly elevated in individuals with ASD. These metabolites are directly linked to mitochondrial respiratory chain disorders, with a putative link to PCCB, consistent with impaired mitochondrial function. Our data support an association between DNA methylation and mitochondrial dysfunction in the etiology of ASD. Autism Res 2020, 13: 1079-1093. © 2020 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: Epigenetic changes are chemical modifications of DNA which can change gene function. DNA methylation, a type of epigenetic modification, is linked to autism. We examined DNA methylation in South African children with autism and identified mitochondrial genes associated with autism. Mitochondria are power-suppliers in cells and mitochondrial genes are essential to metabolism and energy production, which are important for brain cells during development. Our findings suggest that some individuals with ASD also have mitochondrial dysfunction.

Dataset Information

Mitochondrial disease in autism spectrum disorder patients: a cohort analysis.

Background

Methodology/principal findings

Conclusions/significance

Publications

Mitochondrial disease in autism spectrum disorder patients: a cohort analysis.

Similar Datasets

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