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Leigh syndrome


Wednesday 28 May 2003

Definition: Leigh syndrome is a disease of early childhood, characterized by lactic acidemia, arrest of psychomotor development, feeding problems, seizures, extraocular palsies, and weakness with hypotonia. Death usually occurs within 1 to 2 years.

Leigh syndrome is the most frequent, although genetically heterogeneous, mitochondrial disease.

Leigh syndrome is a typical example of how mitochondrial disorders present and how mitochondrial diagnostics is carried out. Leigh syndrome is a progressive, subcortical encephalopathy.

Most cases are inherited in an autosomal-recessive pattern and show decreased activity of complex IV (cytochrome c oxidase) of mitochondrial oxidative phosphorylation.


On histologic examination, there are multifocal, moderately symmetric regions of destruction of brain tissue with a spongiform appearance and proliferation of blood vessels.

The areas that are most commonly affected include the periventricular gray matter of the midbrain, the tegmentum of the pons, and the periventricular regions of the thalamus and hypothalamus.

Clinical synopsis

The first symptoms usually appear before two years of age and consist of optic atrophy, ophtalmoparesis, hypotonia, ataxia, and dystonia.

Neuropathy and myopathy are common and the specific neurological features help to distinguish Leigh syndrome from other brain diseases, such as encephalitis.

The course is fluctuating, with exacerbations often triggered by mild intercurrent illnesses. Most patients die a few years after the onset of symptoms.


Most often, the mutation affects a protein that is required for assembly of this complex of oxidative phosphorylation, rather than a structural component of the complex.

Other cases with comparable clinical and pathologic features have been linked to deficits in other complexes of the respiratory chain as well as mtDNA tRNA mutations.

Interestingly, a point mutation in the mitochondrial gene for ATPase 6 subunit of complex V (T8993G) can cause a maternally inherited form of Leigh syndrome; in this form, heteroplasmy results in mitochondria with this mutation being nearly the only kind present.

When there is a higher degree of heteroplasmy with normal mitochondria, the disease takes on a different clinical and pathologic appearance, as neuropathy, ataxia, and retinitis pigmentosa (NARP).

An extensive genetic heterogeneity has been observed in Leigh syndrome. Mutations have been identified in both nuclear- and mitochondrial-encoded genes involved in energy metabolism, including mitochondrial respiratory chain complexe I, complexe II, complexe III, complexe IV, and complexe V, which are involved in oxidative phosphorylation and the generation of ATP, and components of the pyruvate dehydrogenase complex.

- Mutations in complex I genes

  • mitochondrial-encoded genes
    • MTND2 (MIM.516001)
    • MTND3 (MIM.516002)
    • MTND5 (MIM.516005)
    • MTND6 (MIM.516006)
  • nuclear-encoded genes
    • NDUFV1 (MIM.161015)
    • NDUFS1 (MIM.157655)
    • NDUFS3 (MIM.603846)
    • NDUFS4 (MIM.602694)
    • NDUFS7 (MIM.601825)
    • NDUFS8 (MIM.602141)
    • NDUFA2 (MIM.602137).

- Mutations in complex II genes

  • A mutation has been found in the gene coding for the flavoprotein subunit A of succinate dehydrogenase complex (SDHA) (MIM.600857).

- Mutation in complex III genes

  • BCS1L (MIM.603647), involved in the assembly of complex III.

- Mutations in complex IV genes

  • mitochondrial-encoded MTCO3 (516050)
  • nuclear-encoded COX10 (MIM.602125)
  • COX15 (MIM.603646)
  • SCO2 (MIM.604272)
  • SURF1 (MIM.185620) (16222681) (involved in the assembly of complex IV)

- Mutation in complex V gene

  • mitochondrial-encoded MTATP6 (MIM.516060).

- Mutations in genes encoding mitochondrial tRNA proteins

  • MTTV (MIM.590105)
  • MTTK (MIM.590060)
  • MTTW (MIM.590095)
  • MTTL1 (MIM.590050)

- Mutations in components of the pyruvate dehydrogenase complex

  • DLD (MIM.238331)
  • PDHA1 (MIM.300502) (see X-linked Leigh syndrome, MIM.308930).

- Leigh syndrome with COX deficiency (LSFC) (MIM.220111)

  • The French-Canadian (or Saguenay-Lac Saint Jean) type of Leigh syndrome with COX deficiency (LSFC) (MIM.220111) is caused by mutation in the LRPPRC gene (MIM.607544).

- Deficiency of coenzyme Q10 (MIM.607426) can present as Leigh syndrome.

See also

- mitochondrial diseases
- oxidative phosphorylation diseases