Abstract
BackgroundPrevious 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 FindingsWe 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/SignificanceAlthough 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.
Highlights
Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by impaired social interaction and communication, as well as isolated interests and repetitive or stereotyped behaviors [1]
The cohort of 25 patients reported here comprises the largest group of individuals with co-occurrence of autism spectrum disorders (ASD) and defective oxidative phosphorylation reported to date
While previous case reports implicated an association of ASD and mitochondrial dysfunction, it could be argued that this was a chance occurrence in those individuals
Summary
Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by impaired social interaction and communication, as well as isolated interests and repetitive or stereotyped behaviors [1]. ASDs pose a significant burden to affected individuals, their families and society. Oliveira and colleagues published a population-based survey of school-age children with ASD. They found that 7% of those who were fully tested met criteria for definite mitochondrial respiratory chain disorders and were clinically indistinguishable from other children with ASD [15]. To better describe the clinical spectrum of children with ‘mitochondrial autism’, we undertook a chart review of the biochemical, genetic, and histopathological findings in 25 patients with ASD who had unequivocal evidence of a disorder of oxidative phosphorylation. Previous reports indicate an association between autism spectrum disorders (ASD) and disorders of mitochondrial oxidative phosphorylation. We undertook a comprehensive review of patients with ASD and a mitochondrial disorder
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