Homozygosity (E140K) in SCO2 causes delayed infantile onset of cardiomyopathy and neuropathy

Objective: To report three unrelated infants with a distinctive phenotype o f Leigh-like syndrome, neurogenic muscular atrophy, and hypertrophic obstru ctive cardiomyopathy. The patients all had a homozygous missense mutation i n SCO2. Background: SCO2 encodes a mitochondrial inner membrane protein, th ought to function as a copper transporter to cytochrome c oxidase (COX), th e terminal enzyme of the respiratory chain. Mutations in SCO2 have been des cribed in patients with severe COX deficiency and early onset fatal infanti le hypertrophic cardioencephalomyopathy. All patients so far reported are c ompound heterozygotes for a missense mutation (E140K) near the predicted Cx xxC metal binding motif; however, recent functional studies of the homologo us mutation in yeast failed to demonstrate an effect on respiration. Method s: Here we present clinical, biochemical, morphologic, functional, MRI, and MRS data in two infants, and a short report in an additional patient, all carrying a homozygous G1541A transition (E140K). Results: The disease onset and symptoms differed significantly from those in compound heterozygotes. MRI and muscle morphology demonstrated an age-dependent progression of dise ase with predominant involvement of white matter, late appearance of basal ganglia lesions, and neurogenic muscular atrophy in addition to the relativ ely late onset of hypertrophic cardiomyopathy. The copper uptake of culture d fibroblasts was significantly increased. Conclusions: The clinical spectr um of SCO2 deficiency includes the delayed development of hypertrophic obst ructive cardiomyopathy and severe neurogenic muscular atrophy. There is inc reased copper uptake in patients' fibroblasts indicating that the G1541A mu tation effects cellular copper metabolism.