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Mitochondrial disease in autism spectrum disorder patients: a cohort analysis
Jacqueline R Weissman1, Richard I Kelley, Margaret L Bauman
1Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, Ohio, United States of America.
Insights
Children with autism spectrum disorder (ASD) and mitochondrial disorders often present with distinct clinical and biochemical differences compared to idiopathic autism. These findings suggest impaired mitochondrial energy production in some autism cases.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Autism spectrum disorders (ASD) have been linked to mitochondrial oxidative phosphorylation disorders.
- Previous research suggested clinical similarity between ASD with mitochondrial disorders and idiopathic autism.
- A comprehensive analysis of this patient group was lacking.
Purpose of the Study:
- To conduct a detailed review of clinical and laboratory findings in patients diagnosed with both ASD and mitochondrial disorders.
- To identify differentiating features between ASD with mitochondrial dysfunction and idiopathic ASD.
Main Methods:
- Retrospective review of medical records for 25 patients with primary ASD diagnosis (DSM-IV-TR) and confirmed mitochondrial electron transport chain (ETC) dysfunction.
- Analysis of clinical abnormalities, medical history, neurological findings, developmental phenotypes, and biochemical markers (lactate, alanine, ALT/AST).
- Identification of specific ETC enzyme deficiencies and genetic mutations.
Main Results:
- 24/25 patients exhibited major clinical abnormalities not typical of idiopathic autism.
- Significant non-neurological medical problems (21/25) and constitutional symptoms like fatigability (19/25) were common.
- Biochemical abnormalities (elevated lactate, alanine, ALT/AST) were present in a majority of patients.
- Complex I (64%) and Complex III (20%) deficiencies were the most frequent ETC disorders.
- Unusual developmental patterns included gross motor delays and regression.
Conclusions:
- Clinical and biochemical assessments revealed distinct features in ASD patients with mitochondrial disorders, differentiating them from idiopathic autism.
- These findings support the hypothesis that mitochondrial energy production disturbances are implicated in a subset of autism cases.
- Early identification of mitochondrial dysfunction may be crucial for understanding autism pathophysiology.
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.
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