title: A novel mitochondrial DNA mutation in COX1 leads to strokes, seizures, and lactic acidosis.
abstract: Cytochrome c oxidase (COX) is the terminal enzyme of the respiratory chain, with subunits originating both from the mitochondrial and nuclear genome. An eleven-year-old female presented initially with a seizure followed two months later with tonic-clonic seizures, weakness and aphasia. MRI of the cerebral hemispheres showed multiple infarcts. Previous history suggested gross and fine motor control deficits with learning difficulties. A muscle biopsy showed a specific decrease of COX staining in all fibres and pleomorphic mitochondria. Respiratory chain studies confirmed an isolated complex IV defect in muscle, whilst fibroblasts showed an initial COX activity below normal which rapidly came up to the normal range on culture. Sequencing of mtDNA revealed an heteroplasmic m.7023G>A mutation in the COX1 gene, with levels of 96% in muscle, 70% in blood and 50% in the initial skin fibroblast culture dropping to 10% in later passages. The mutation was present in a critical region of the COX1 gene, the V374M change being close to the two histidine residues His376 and His378 co-ordinating with the heme a and a (3), and His367 which co-ordinates a magnesium ion. This case highlights that a MELAS-like syndrome can occur with isolated COX deficiency.
authors: Divison of Neurology, Hospital for Sick Children and the University of Toronto, Toronto, Canada.
authors: E W Y
authors: EW
authors: Tam
authors: A
authors: A
authors: Feigenbaum
authors: J B L
authors: JB
authors: Addis
authors: S
authors: S
authors: Blaser
authors: N
authors: N
authors: Mackay
authors: M
authors: M
authors: Al-Dosary
authors: R W
authors: RW
authors: Taylor
authors: C
authors: C
authors: Ackerley
authors: J M
authors: JM
authors: Cameron
authors: B H
authors: BH
authors: Robinson
mesh_terms: D000140:Acidosis, Lactic / Q000175:diagnosis / Q000235:genetics*; D000483:Alleles; D002544:Cerebral Infarction / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000235:genetics*; D004830:Epilepsy, Tonic-Clonic / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D006639:Histidine / Q000235:genetics; D006801:Humans; D007859:Learning Disabilities / Q000175:diagnosis / Q000235:genetics*; D017241:MELAS Syndrome / Q000175:diagnosis / Q000235:genetics*; D008274:Magnesium / Q000378:metabolism; D011596:Psychomotor Disorders / Q000175:diagnosis / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D004272:DNA, Mitochondrial; D006639:Histidine; D003576:Electron Transport Complex IV; D008274:Magnesium