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

被引:69
作者
Jaksch, M
Horvath, R
Horn, N
Auer, DP
Macmillan, C
Peters, J
Gerbitz, KD
Kraegeloh-Mann, I
Muntau, A
Karcagi, V
Kalmanchey, R
Lochmuller, H
Shoubridge, EA
Freisinger, P
机构
[1] Metab Dis Ctr Munich Schwabing, D-80804 Munich, Germany
[2] Inst Clin Chem Mol Diagnost & Mitochondrial Genet, Munich, Germany
[3] Univ Munich, Childrens Hosp, D-8000 Munich, Germany
[4] Tech Univ Munich, D-8000 Munich, Germany
[5] Univ Munich, Genzentrum, Munich, Germany
[6] Univ Munich, Friedrich Baur Inst, Munich, Germany
[7] John F Kennedy Inst, DK-2600 Glostrup, Denmark
[8] Univ Illinois, Dept Pediat, Chicago, IL 60680 USA
[9] Univ Illinois, Dept Neurol, Chicago, IL 60680 USA
[10] Univ Tubingen, Childrens Hosp, Dept Neuropediat, D-7400 Tubingen, Germany
[11] Natl Inst Publ Hlth, Budapest, Hungary
[12] Semmelweis Univ, Dept Pediat, H-1085 Budapest, Hungary
[13] McGill Univ, Montreal Neurol Inst, Montreal, PQ H3A 2T5, Canada
[14] McGill Univ, Dept Human Genet, Montreal, PQ H3A 2T5, Canada
关键词
D O I
10.1212/WNL.57.8.1440
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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.
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页码:1440 / 1446
页数:7
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