title: Homozygosity (E140K) in SCO2 causes delayed infantile onset of cardiomyopathy and neuropathy.
abstract: OBJECTIVE
  To report three unrelated infants with a distinctive phenotype of Leigh-like syndrome, neurogenic muscular atrophy, and hypertrophic obstructive cardiomyopathy. The patients all had a homozygous missense mutation in SCO2.
  
  
  BACKGROUND
  SCO2 encodes a mitochondrial inner membrane protein, thought to function as a copper transporter to cytochrome c oxidase (COX), the terminal enzyme of the respiratory chain. Mutations in SCO2 have been described in patients with severe COX deficiency and early onset fatal infantile hypertrophic cardioencephalomyopathy. All patients so far reported are compound heterozygotes for a missense mutation (E140K) near the predicted CxxxC metal binding motif; however, recent functional studies of the homologous mutation in yeast failed to demonstrate an effect on respiration.
  
  
  METHODS
  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 disease with predominant involvement of white matter, late appearance of basal ganglia lesions, and neurogenic muscular atrophy in addition to the relatively late onset of hypertrophic cardiomyopathy. The copper uptake of cultured fibroblasts was significantly increased.
  
  
  CONCLUSIONS
  The clinical spectrum of SCO2 deficiency includes the delayed development of hypertrophic obstructive cardiomyopathy and severe neurogenic muscular atrophy. There is increased copper uptake in patients' fibroblasts indicating that the G1541A mutation effects cellular copper metabolism.
authors.affiliation: Metabolic Disease Centre Munich, Germany. Michaela.Jaksch@lrz.uni-muenchen.de
authors.forename: M
authors.initials: M
authors.lastname: Jaksch
authors.forename: R
authors.initials: R
authors.lastname: Horvath
authors.forename: N
authors.initials: N
authors.lastname: Horn
authors.forename: D P
authors.initials: DP
authors.lastname: Auer
authors.forename: C
authors.initials: C
authors.lastname: Macmillan
authors.forename: J
authors.initials: J
authors.lastname: Peters
authors.forename: K D
authors.initials: KD
authors.lastname: Gerbitz
authors.forename: I
authors.initials: I
authors.lastname: Kraegeloh-Mann
authors.forename: A
authors.initials: A
authors.lastname: Muntau
authors.forename: V
authors.initials: V
authors.lastname: Karcagi
authors.forename: R
authors.initials: R
authors.lastname: Kalmanchey
authors.forename: H
authors.initials: H
authors.lastname: Lochmuller
authors.forename: E A
authors.initials: EA
authors.lastname: Shoubridge
authors.forename: P
authors.initials: P
authors.lastname: Freisinger
mesh_terms: D017668:Age of Onset; D001927:Brain Diseases / Q000235:genetics* / Q000473:pathology; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins; D005260:Female; D006720:Homozygote; D006801:Humans; D007223:Infant; D007888:Leigh Disease / Q000235:genetics / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D020125:Mutation, Missense; D009206:Myocardium / Q000473:pathology; D011506:Proteins / Q000235:genetics*; D011522:Protons; D029701:Saccharomyces cerevisiae Proteins
chemical_list: D002352:Carrier Proteins; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D011506:Proteins; D011522:Protons; C498516:SCO2 protein, S cerevisiae; C400285:SCO2 protein, human; D029701:Saccharomyces cerevisiae Proteins