The pathophysiology of stroke in mitochondrial disorders
Introduction
Stroke in the context of mitochondrial disorders can be due to traditional vascular mechanisms, from the failure of organ systems outside of the brain, and to non-vascular mechanisms of energy failure within the brain. Stroke-like episodes that occur in association with the clinical syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) may illustrate the pathophysiology of non-vascular acute neurologic dysfunction due to mitochondrial dysfunction. Evidence from the clinical, neuroimaging, and pathology findings in patients with MELAS will be presented.
Section snippets
Epidemiology
Strokes in older adults are almost exclusively vascular events due to identifiable vascular risk factors. Young adults and children have different causes for stroke and only 10–25% are felt to be at risk for recurrent events (Lynch et al., 2002; de Veber, 2003). Direct causes for stroke, identifiable in more than two thirds of children, consist of both predisposing factors, such as prothrombotic disorders, anemia, or cardiac disease, and triggering factors, such as dehydration, trauma, or
Atherothrombotic stroke
Endocrine glands, exocrine glands, and renal cortex are among those tissues with a higher demand for oxidative metabolism, and consequently a lower threshold for symptomatic energy failure with mitochondrial dysfunction. For mitochondrial inheritance, the degree of genetic heteroplasmy within each tissue determines the risk of exceeding this threshold. Traditional risk factors for atherothrombotic stroke, including diabetes mellitus, dyslipidemia, and mild hypertension, are common findings in
Clinical features
The common genetic mutations responsible for MELAS occur in the mitochondrial DNA (mtDNA) encoded transfer RNA for leucine, an A to G point mutation at base pair 3243 in 80–85% of cases and a T to C point mutation at base pair 3271 in another 10% of cases. The A3243G mutation changes the tertiary structure of the tRNALeu(UUR) so that it becomes less stable, interacts poorly with leucyl-tRNA synthetase, and leads to a general reduction in mitochondrial protein synthesis (Chomyn et al., 2000).
Conclusions
In summary, stroke and stroke-like episodes occur as complications of mitochondrial disorders. Traditional risk factors for atherothrombotic or cardioembolic stroke can result from common dysfunction of extracranial organ systems, although strokes of these types are rarely observed. The pathophysiology of the stroke-like episodes of MELAS syndrome is a continuing subject of investigation, although there is ample evidence that it is markedly different from typical vascular stroke. Current
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