Brain, Vol. 123, No. 3, 591-600,
March 2000
© 2000 Oxford University Press
Invited review |
Cytochrome oxidase immunohistochemistry: clues for genetic mechanisms
1 Metabolic Unit, Institute of Child Health, University College, 2 University Department of Clinical Neurosciences, Royal Free Hospital and 3 University Department of Clinical Neurology, Institute of Neurology, London
Correspondence to:
Dr Shamima Rahman, Metabolic Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK E-mail: S.Rahman{at}ich.ucl.ac.uk
Cytochrome c oxidase (COX) is encoded by three mitochondrial and nine nuclear genes. COX deficiency is genetically heterogeneous but current diagnostic methods cannot easily distinguish between mitochondrial and nuclear defects. We hypothesized that there may be differential expression of COX subunits depending on the underlying mutation. COX subunit expression was investigated in five patients with known mtDNA mutations. Severe and selective reduction of mtDNA-encoded COX subunits I and II was consistently observed in all these patients and was restricted to COX-deficient fibres. Immunostaining of nuclear-encoded subunits COX IV and Va was normal, whilst subunit VIc, also nuclear-encoded, was decreased. Twelve of 36 additional patients with histochemically defined COX deficiency also had this pattern of staining, suggesting that they had mtDNA defects. Clinical features in this group were heterogeneous, including infantile encephalopathy, multisystem disease, cardiomyopathy and childhood-onset isolated myopathy. The remaining patients did not have the same pattern of immunostaining. Fourteen had reduced staining of all subunits, whilst 10 had normal staining of all subunits despite reduced enzyme activity. Patients with COX deficiency secondary to mtDNA mutations have a specific pattern of subunit loss, but the majority of children with COX deficiency do not have this pattern of subunit loss and are likely to have nuclear gene defects.
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