What is the relationship between mitochondrial disease and severe autism?

The Link Between Mitochondrial Disease and Severe Autism

Emerging evidence suggests a significant link between mitochondrial dysfunction and autism spectrum disorders (ASD), particularly in cases with autistic behaviors and speech regression following febrile illness or immunization with subsequent encephalopathy. 1, 2

Clinical Indicators of Mitochondrial Disease in ASD

• Constitutional symptoms, hypotonia, repeated regressions after age 3, and multiple organ dysfunctions are key clinical indicators suggesting mitochondrial disease in patients with ASD 1, 2
• High lactate levels, reported in approximately 20% of children with ASD, may indicate involvement of mitochondria in energy metabolism and brain development 3
• Clinical presentations that should raise suspicion include:
  • Neurodegeneration or developmental regression atypical for autism 1
  • Worsening neurological symptoms, lethargy, and poor physical endurance 1
  • Seizures, which may be associated with both mitochondrial dysfunction and ASD 1
  • Physiologic abnormalities such as acidosis 1
  • Multisystem involvement, particularly cardiac, hepatic, or renal manifestations 1

Prevalence and Significance

• Population-based studies have confirmed that approximately 4% of children with ASD can be diagnosed with definite mitochondrial disease 3
• However, biomarker research suggests that abnormalities of mitochondrial function could affect a much higher percentage of children with ASD, potentially up to 80% 3
• Mitochondrial disorders in ASD are considered "low incidence yet high impact" according to the American College of Medical Genetics and the Society for Inherited Metabolic Disorders 1

Types of Mitochondrial Dysfunction in ASD

• Recent research has identified a novel type of mitochondrial dysfunction in which electron transport chain activity is significantly increased, potentially associated with environmental exposures and neurodevelopmental regression 3
• Mitochondrial disturbances can include:
  • Depletion or decreased quantity of mitochondrial DNA 4
  • Mutations of mitochondrial DNA producing defects in biochemical reactions 4
  • Abnormal function in various tissues including immune cells, buccal cells, fibroblasts, muscle, gastrointestinal tissue, and brain 5

Diagnostic Approach

• A careful medical history for true developmental regression, worsening neurological symptoms, lethargy, poor physical endurance, or seizures is critical 1
• Metabolic screening should be considered in patients with ASD who show signs of metabolic disorders, including:
  • Complete blood count 1
  • Serum metabolic profile 1
  • Serum amino acid analysis 1
• For suspected mitochondrial dysfunction, appropriate mitochondrial testing should be considered 6
• Neuroimaging with magnetic resonance imaging (MRI) may be helpful in patients with ASD and neurological symptoms 1, 6

Treatment Implications

• Several treatments targeting mitochondria have shown evidence for potential benefit in children with ASD, including:
  • L-Carnitine supplementation 3
  • Ketogenic diet 3
• For patients with folate metabolism issues (which can affect mitochondrial function), leucovorin therapy may be considered after appropriate testing 6
• When using medications like aripiprazole in ASD patients with mitochondrial dysfunction, special monitoring is required due to the risk of exacerbating metabolic issues 2

Genetic Considerations

• Multiple genetic abnormalities are associated with mitochondrial dysfunction in ASD, including:
  • Chromosomal abnormalities 5
  • Mitochondrial DNA mutations and large-scale deletions 5
  • Mutations in both mitochondrial and non-mitochondrial nuclear genes 5
• Genetic testing should be considered, particularly for folate metabolism pathway variants which may guide treatment 6

Cautions and Controversies

• Finding biochemical or structural mitochondrial abnormalities in an autistic child does not necessarily imply a primary mitochondrial disorder but can also be secondary to technical inaccuracies or another genetic disorder 7
• Clinicians should be careful in diagnosing a mitochondrial disorder in an autistic child because it has important implications for accurate genetic counseling, prognosis, and therapy 7
• The exact etiology of mitochondrial dysfunction and how to define it in ASD remains unclear, though preliminary evidence suggests mitochondria may be a fruitful target for treatment and prevention 5