Elsevier

Mitochondrion

Volume 4, Issues 5–6, September 2004, Pages 665-674
Mitochondrion

The pathophysiology of stroke in mitochondrial disorders

https://doi.org/10.1016/j.mito.2004.07.019Get rights and content

Abstract

Stroke occurs with an increased frequency in patients with mitochondrial disorders and is a characteristic feature of the MELAS phenotype. This article explores the proposed mechanisms by which mitochondrial dysfunction may contribute to both vascular and non-vascular strokes and stroke-like episodes. The clinical features, neuroimaging, and pathologic findings of MELAS are reviewed as evidence for a cytopathologic basis for 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

References (59)

  • R. Annan et al.

    Cardiac involvement in mitochondrial diseases

    Circulation

    (1995)
  • S. Asoh et al.

    Expression of the apoptosis-mediator Fas is enhanced by dysfunctional mitochondria

    J. Biochem.

    (1996)
  • A. Barkovich et al.

    Mitochondrial disorders: analysis of their clinical and imaging characteristics

    Am. J. Neuroradiol.

    (1993)
  • T.E. Bates et al.

    Inhibition of N-acetylaspartate production: implications for 1H MRS studies in vivo

    Neuroreport

    (1996)
  • J. Bogousslavsky et al.

    Ischemic stroke in adults younger than 30 years of age

    Arch. Neurol.

    (1987)
  • B. Chabrol et al.

    Cerebral infarction associated with Kearns–Sayre syndrome

    Neurology

    (1997)
  • J.M. Clark et al.

    MELAS: clinical and pathologic correlations with MRI, xenon/CT, and MR spectroscopy

    Neurology

    (1996)
  • H. Cock et al.

    Mitochondrial DNA mutations and mitochondrial dysfunction in epilepsy

    Epilepsia

    (1999)
  • J. Correale et al.

    Status epilepticus increases CSF levels of neuron-specific enolase and alters the blood–brain barrier

    Neurology

    (1998)
  • S. DeMauro et al.

    Mitochondria in neuromuscular disorders

    Biochem. Biophys. Acta

    (1998)
  • G. de Veber

    Risk factors for childhood stroke: little folks have different strokes!

    Annu. Neurol.

    (2003)
  • L. Durcan et al.

    Distribution of the tRNAleu mtDNA mutation in MELAS brain

    Neurology

    (1992)
  • B. Feddersen et al.

    Aggressive confusional state as a clinical manifestation of status epilepticus in MELAS

    Neurology

    (2003)
  • V. Ganesan et al.

    Investigation of risk factors in children with arterial ischemic stroke

    Annu. Neurol.

    (2003)
  • T. Gropen et al.

    Cerebral hyperemia in MELAS

    Stroke

    (1994)
  • M.G. Hanna et al.

    MELAS: a new disease associated with mitochondrial DNA mutation and evidence for further genetic heterogeneity

    J. Neurol. Neurosurg. Psychiatry

    (1998)
  • M. Iigaya et al.

    Clinical significance of PLEDs in acute stage of cardioembolic stroke

    Clin. Encephalogr.

    (1999)
  • T. Iizuka et al.

    Neuronal hyperexcitability in stroke-like episodes of MELAS syndrome

    Neurology

    (2002)
  • T. Iizuka et al.

    Response to sumatriptan in headache of MELAS syndrome

    Neurology

    (2003)
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