Mitochondrial Disease in Autism Spectrum Disorder Patients: A Cohort Analysis

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.

Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions

“…69 This association has been recognized in persons with autistic behaviors and loss of speech after a febrile illness or immunization with subsequent encephalopathy. 70 Constitutional symptoms, hypotonia, repeated regressions after the age of 3 years, and multiple organ dysfunctions are clues to consider mitochondrial disease ( Table 3). A review of 25 patients with a known mitochondrial disorder who presented with an initial diagnosis of ASD found that all had an abnormal neurologic examination and/or an elevated plasma lactate concentration.…”

“…A review of 25 patients with a known mitochondrial disorder who presented with an initial diagnosis of ASD found that all had an abnormal neurologic examination and/or an elevated plasma lactate concentration. 70 As with metabolic disorders, testing for mitochondrial disorders in persons with ASDs is recommended only if supporting symptoms or laboratory abnormalities are present.…”

Genetic causes of syndromic and non‐syndromic autism

“…Oliveira et al 75 found that 7 ⁄ 100 of children with ASD, clinically indistinguishable from other children with ASD, exhibited a mitochondrial respiratory chain disorder. 71 Finally, Weissman et al 76 proposed that defective mitochondrial oxidative phosphorylation is an additional pathogenetic basis in a subset of individuals with autism. 76 …”

Improving the Prediction of Response to Therapy in Autism

“…Furthermore, because known mitochondrial disorders are rare in the general population (occurring in 1 in 10,000 children), the increased prevalence in children with ASD suggests that these disorders may be related to disease pathogenesis. In a careful phenotypic and biochemical analysis of 25 children with ASD and known mitochondrial disorders, Weissman et al 33 noted that most children with ASD and mitochondrial dysfunction have findings that are not typical of idiopathic autism. Specifically, children with ASD and mitochondrial dysfunction had a very high prevalence of delayed gross motor development (64%), and 40% had unusual patterns of regressive symptoms.…”

“…Nonetheless, the authors suggest that a broader clinical, biochemical, and genetic spectrum of mitochondrial disorders is likely to exist in ASD. 33 …”