Journal of Inherited Metabolic Disease

, Volume 19, Issue 4, pp 553–572 | Cite as

Neuropathology and pathogenesis of mitochondrial diseases

  • G. K. Brown
  • M. V. Squier


The majority of patients with mitochondrial disease have significant neuropathology, with the most common features being spongiform degeneration, neuronal loss and gliosis. Although there is considerable overlap between different mitochondrial diseases, the nature and distribution of the lesions is sufficiently distinctive in some cases to suggest a specific diagnosis. On the other hand, a number of different defects in cerebral energy metabolism are associated with common patterns of neuropathology (e.g. Leigh syndrome), suggesting that there is a limited range of responses to this type of metabolic disturbance.

There are many descriptions of neuropathological changes in patients with mitochondrial disease, but there has been remarkably little investigation of the underlying pathogenic mechanisms. Comparisons with other conditions of cerebral energy deprivation such as ischaemia/hypoxia and hypoglycaemia suggest a possible role for excitotoxicity initiated by excitatory amino acid neurotransmitters. An additional contributing factor may be peroxynitrite, which is formed from nitric oxide and the oxygen free radicals which accumulate with defects of the mitochondrial electron transport chain.

Mitochondrial diseases are often characterized by episodes of neurological dysfunction precipitated by intercurrent illness. Depending on the severity of the metabolic abnormality, each of these episodes carries a risk of further neuronal death and the result is usually progressive accumulation of irreversible damage. The balance between reversible functional impairment and neuronal death during episodes of metabolic imbalance is determined by the effectiveness of various protective mechanisms which may act to limit the damage. These include protective metabolic shielding of neurons by astrocytes and suppression of electrical activity (and hence energy demands) by activation of ATP-gated ion channels. In addition, recent evidence suggests that lactic acid, the biochemical abnormality common to these conditions, may not be toxic at moderately high concentrations but may in fact be protective by reducing the sensitivity of neurons to excitotoxic mechanisms. Abnormal brain function is a major manifestation of the majority of disorders of mitochondrial energy metabolism. The neurological features of these diseases are extremely diverse and are associated with a correspondingly wide range of pathological changes. Defects have been defined in enzymes of the mitochondrial matrix and in components of the electron transport chain in the inner mitochondrial membrane and, as these all involve the central common pathways of energy generation in the cell, it is not surprising that there is considerable overlap in structural and functional abnormalities in the different conditions. However, there are some patterns of neuropathology which are characteristic for specific biochemical defects and these may be helpful for diagnosis, in addition to providing detailed information concerning the biological contribution of individual reactions.

Although pathological lesions in the brain are a major feature of mitochondrial disease, there are many enzyme defects involving individual pathways of substrate oxidation in the mitochondria in which there may be remarkably little permanent structural damage to the brain. This is in spite of repeated episodes of metabolic decompensation during which neurological symptoms are prominent. In these cases, the neurological features are related to the intermittent accumulation of toxic intermediates (e.g. methylmalonic acid in methylmalonic aciduria) or reduced supply of metabolizable substrate (e.g. glucose in the fatty acidβ-oxidation defects). If unrecognized or untreated, these conditions may result in permanent structural damage, but this is seldom as extensive as that found in association with defects in the final common pathways of energy metabolism.


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Copyright information

© SSIEM and Kluwer Academic Publishers 1996

Authors and Affiliations

  • G. K. Brown
    • 2
  • M. V. Squier
    • 1
  1. 1.Department of NeuropathologyRadcliffe InfirmaryOxfordUK
  2. 2.Genetics Laboratory, Department of BiochemistryUniversity of OxfordOxfordUK

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