21. Johnson M. The beta-adrenoceptor. Am J Resp Crit Care Med 1998;158:S146 –S153. 22. Hayes A, Williams DA. Contractile properties of clenbuterol- treated mdx muscle are enhanced by low-intensity swimming. J Appl Physiol 1997;82:435– 439. 23. Dupont-Versteegden EE. Exercise and clenbuterol as strate- gies to decrease the progression of muscular dystrophy in mdx mice. J Appl Physiol 1996;80:734 –741. 24. Lynch GS, Hinkle RT, Faulkner JA. Year-long clenbuterol treatment of mice increases mass, but not specific force or normalized power, of skeletal muscles. Clin Exp Pharmacol Physiol 1999;26:117–120. Homozygosity (E140K) in SCO2 causes delayed infantile onset of cardiomyopathy and neuropathy M. Jaksch, MD; R. Horvath, MD; N. Horn, PhD; D.P. Auer, MD; C. Macmillan, MD; J. Peters, MD; K.–D. Gerbitz, MD; I. Kraegeloh–Mann, MD; A. Muntau, MD; V. Karcagi, PhD; R. Kalmanchey, MD; H. Lochmuller, MD; E.A. Shoubridge, PhD; and P. Freisinger, MD Article 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 demon- strated 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. NEUROLOGY 2001;57:1440 –1446 Cytochrome c oxidase (COX) deficiency is found in patients with different clinical phenotypes primarily affecting organs with high energy demand such as the brain, skeletal muscle, heart, and kidney. 1 Pedi- gree studies suggest an autosomal recessive inheri- tance in most cases; however, mutations in nuclear genes coding for the COX subunits themselves have not been reported. 2,3 Several nuclear genes are known from yeast studies to be essential factors for assembly and maintenance of the COX complex. 4 The human homologues of four such assembly genes— SURF1, 5,6 SCO2, 7-9 COX10, 10 and SCO1 11 — have now been identified in human COX deficiency disorders. SURF1 was found to be mutated in a series of pa- tients with typical Leigh syndrome and COX deficiency. 12 Mutations in SCO2 have so far been described in six infants with a fatal disorder with hypertrophic From the Metabolic Disease Centre Munich (Drs. Jaksch, Horvath, Peters, Gerbitz, and Freisinger) and Institute of Clinical Chemistry, Molecular Diagnostics and Mitochondrial Genetics (Drs. Jaksch, Horvath, and Gerbitz), Munich; Childrens Hospital of the Technical University (Drs. Peters and Freisinger), Munich; Max Planck Institute of Psychiatry (Dr. Auer), Munich; Childrens Hospital of the Ludwig Maximilians University (Dr. Muntau), Munich; Genzentrum and Friedrich-Baur-Institut of the Ludwig-Maximilians-University (Dr. Lochmuller), Munich, Germany; The John F. Kennedy Institute (Dr. Horn), Glostrup, Denmark; Departments of Pediatrics and Neurology (Dr. Macmillan), University of Illinois, Chicago; Dept. of Neuropediatrics, Children’s Hospital (Dr. Kraegeloh-Mann), University of Tuebingen, Germany; National Institute of Public Health (Dr. Karcagi), Budapest; Department of Pediatrics II (Dr. Kalmanchy), Semmelweis University, Budapest, Hungary; and Montreal Neurological Institute and Department of Human Genetics (Dr. Shoubridge), McGill University, Montreal, Quebec, Canada. Supported by grants from the Deutsche Forschungsgemeinschaft (Ja 802/1-2) (M.J.), the Friedrich-Baur-Stiftung (M.J., H.L.), the Ernst und Berta Grimmke Stiftung (M.J., R.H.), the CIHR (E.A.S.), and the March of Dimes Birth Defects Association (E.A.S.). E.A.S. is an MNI Killam Scholar. Received January 29, 2001. Accepted in final form July 4, 2001. Address correspondence and reprint requests to Dr. M. Jaksch, Metabolic Disease Centre Munich-Schwabing, Koelner Platz 1, 80804 Muenchen, Germany; e-mail: Michaela.Jaksch@lrz.uni-muenchen.de 1440 Copyright © 2001 by AAN Enterprises, Inc.