Genotypes and Clinical Phenotypes in Children with Cytochrome-c Oxidase Deficiency

Abstract

Cytochrome c oxidase (COX) deficiency has been associated with a wide spectrum of clinical features and may be caused by mutations in different genes of both the mitochondrial and the nuclear DNA. In an attempt to correlate the clinical phenotype with the genotype in 16 childhood cases, mtDNA was analysed for deletion, depletion, and mutations in the three genes encoding COX subunits and the 22 tRNA genes. Furthermore, nuclear DNA was analysed for mutations in the SURF1, SCO2, COX10, and COX17 genes and cases with mtDNA depletion were analysed for mutations in the TK2 gene. SURF1-mutations were identified in three out of four cases with Leigh syndrome while a mutation in the mitochondrial tRNA^trp gene was identified in the fourth. One case with mtDNA depletion had mutations in the TK2 gene. In two cases with leukoencephalopathy, one case with encephalopathy, five cases with fatal infantile myopathy and cardiomyopathy, two cases with benign infantile myopathy, and one case with mtDNA depletion, no mutations were identified. We conclude that COX deficiency in childhood should be suspected in a wide range of clinical settings and although an increasing number of genetic defects have been identified, the underlying mutations remain unclear in the majority of the cases.

Key words

Cytochrome-c oxidase deficiency - SURFI - tRNA^trp - mtDNA depletion - TK2

References

• 1 Absalon M J, Harding C O, Fain D R, Li L, Mack K J. Leigh syndrome in an infant resulting from mitochondrial DNA depletion.  Pediatr Neurol. 2001;  24 60-63
• 2 Angelini C, Bresolin N, Pegolo G, Bet L, Rinaldo P, Trevisan C. et al . Childhood encephalomyopathy with cytochrome c oxidase deficiency, ataxia, muscle wasting, and mental impairment.  Neurology. 1986;  36 1048-1052
• 3 Antonicka H, Mattman A, Carlson C G, Glerum D M, Hoffbuhr K C, Leary S C. et al . Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy.  Am J Hum Genet. 2003;  72 101-114
• 4 Boustany R N, Aprille J R, Halperin J, Levy H, DeLong G R. Mitochondrial cytochrome deficiency presenting as a myopathy with hypotonia, external ophthalmoplegia, and lactic acidosis in an infant and as fatal hepatopathy in a second cousin.  Ann Neurol. 1983;  14 462-470
• 5 Bruno C, Martinuzzi A, Tang Y, Andreu A L, Pallotti F, Bonilla E. et al . A stop-codon mutation in the human mtDNA cytochrome c oxidase I gene disrupts the functional structure of complex IV.  Am J Hum Genet. 1999;  65 611-620
• 6 Campos Y, Garcia-Redondo A, Fernandez-Moreno M A, Martinez-Pardo M, Goda G, Rubio J C. et al . Early-onset multisystem mitochondrial disorder caused by a nonsense mutation in the mitochondrial DNA cytochrome C oxidase II gene.  Ann Neurol. 2001;  50 409-413
• 7 Darin N, Holme E, Moslemi A R, Oldfors A, Tulinius M. The incidence of mitochondrial encephalomyopathies in childhood; clinical features, morphological, biochemical and DNA-abnormalities.  Ann Neurol. 2001;  49 377-383
• 8 Davis P C, Hoffman Jr J C, Braun I F, Ahmann P, Krawiecki N. MR of Leigh's disease (subacute necrotizing encephalomyelopathy).  Am J Neuroradiol. 1987;  8 71-75
• 9 DiMauro S, Nicholson J F, Hays A P, Eastwood A B, Papadimitriou A, Koenigsberger R. et al . Benign infantile mitochondrial myopathy due to reversible cytochrome c oxidase deficiency.  Ann Neurol. 1983;  14 226-234
• 10 Doriguzzi C, Palmucci L, Mongini T, Bresolin N, Bet L, Comi G. et al . Endocrine involvement in mitochondrial encephalomyopathy with partial cytochrome c oxidase deficiency.  J Neurol Neurosurg Psychiatry. 1989;  52 122-125
• 11 Dubowitz V, Brooke M H. Muscle Biopsy: A Modern Approach. London; W. B. Saunders 1973
• 12 Eshel G, Lahat E, Fried K, Barr J, Barash V, Gutman A. et al . Autosomal recessive lethal infantile cytochrome C oxidase deficiency.  Am J Dis Child. 1991;  145 661-664
• 13 Glerum D M, Shtanko A, Tzagoloff A. Characterization of COX17, a yeast gene involved in copper metabolism and assembly of cytochrome oxidase.  J Biol Chem. 1996;  271 14504-14509
• 14 Glerum D M, Shtanko A, Tzagoloff A. SCO1 and SCO2 act as high copy suppressors of a mitochondrial copper recruitment defect in Saccharomyces cerevisiae.  J Biol Chem. 1996;  271 20531-20535
• 15 Haftel L T, Lev D, Barash V, Gutman A, Bujanover Y, Lerman-Sagie T. Familial mitochondrial intestinal pseudo-obstruction and neurogenic bladder.  J Child Neurol. 2000;  15 386-389
• 16 Hanna M G, Nelson I P, Rahman S, Lane R J, Land J, Heales S. et al . Cytochrome c oxidase deficiency associated with the first stop-codon point mutation in human mtDNA.  Am J Hum Genet. 1998;  63 29-36
• 17 Harpey J P, Heron D, Prudent M, Charpentier C, Rustin P, Ponsot G. et al . Diffuse leukodystrophy in an infant with cytochrome-c oxidase deficiency.  J Inherit Metab Dis. 1998;  21 748-752
• 18 Horvath R, Lochmuller H, Stucka R, Yao J, Shoubridge E A, Kim S H. et al . Characterization of human SCO1 and COX17 genes in mitochondrial cytochrome-c-oxidase deficiency.  Biochem Biophys Res Commun. 2000;  276 530-533
• 19 Houshmand M, Larsson N G, Holme E, Oldfors A, Tulinius M H, Andersen O. Automatic sequencing of mitochondrial tRNA genes in patients with mitochondrial encephalomyopathy.  Biochim Biophys Acta. 1994;  1226 49-55
• 20 Jaksch M, Horvath R, Horn N, Auer D P, Macmillan C, Peters J. et al . Homozygosity (E140 K) in SCO2 causes delayed infantile onset of cardiomyopathy and neuropathy.  Neurology. 2001;  57 1140-1446
• 21 Jaksch M, Ogilvie I, Yao J, Kortenhaus G, Bresser H G, Gerbitz K D. et al . Mutations in SCO2 are associated with a distinct form of hypertrophic cardiomyopathy and cytochrome c oxidase deficiency.  Hum Mol Genet. 2000;  9 795-801
• 22 Jinnai K, Yamada H, Kanda F, Masui Y, Tanaka M, Ozawa T. et al . A case of mitochondrial myopathy, encephalopathy and lactic acidosis due to cytochrome c oxidase deficiency with neurogenic muscular changes.  Eur Neurol. 1990;  30 56-60
• 23 Kaido M, Fujimura H, Taniike M, Yoshikawa H, Toyooka K, Yorifuji S. et al . Focal cytochrome c oxidase deficiency in the brain and dorsal root ganglia in a case with mitochondrial encephalomyopathy (tRNA(Ile) 4269 mutation): histochemical, immunohistochemical, and ultrastructural study.  J Neurol Sci. 1995;  131 170-176
• 24 Keightley J A, Hoffbuhr K C, Burton M D, Salas V M, Johnston W S, Penn A M. et al . A microdeletion in cytochrome c oxidase (COX) subunit III associated with COX deficiency and recurrent myoglobinuria.  Nat Genet. 1996;  12 410-416
• 25 Keppler K, Cunniff C. Variable presentation of cytochrome c oxidase deficiency.  Am J Dis Child. 1992;  146 1349-1352
• 26 Kuwertz-Broking E, Koch H G, Marquardt T, Rossi R, Helmchen U, Muller-Hocker J. et al . Renal Fanconi syndrome: first sign of partial respiratory chain complex IV deficiency.  Pediatr Nephrol. 2000;  14 495-498
• 27 Larsson N G, Oldfors A, Holme E, Clayton D A. Low levels of mitochondrial transcription factor A in mitochondrial DNA depletion.  Biochem Biophys Res Commun. 1994;  200 1374-1381
• 28 Leigh D. Subacute necrotizing encephalomyelopathy in an infant.  J Neurol Neurosurg Psychiatry. 1951;  14 216-221
• 29 Lincke C R, van den Bogert C, Nijtmans L G, Wanders R J, Tamminga P, Barth P G. Cerebellar hypoplasia in respiratory chain dysfunction.  Neuropediatrics. 1996;  27 216-218
• 30 Lombes A, Mendell J R, Nakase H, Barohn R J, Bonilla E, Zeviani M. et al . Myoclonic epilepsy and ragged-red fibers with cytochrome oxidase deficiency: neuropathology, biochemistry, and molecular genetics.  Ann Neurol. 1989;  26 20-33
• 31 Macmillan C J, Shoubridge E A. Mitochondrial DNA depletion: prevalence in a pediatric population referred for neurologic evaluation.  Pediatr Neurol. 1996;  14 203-210
• 32 Mancuso M, Salviati L, Sacconi S, Otaegui D, Camano P, Marina A. et al . Mitochondrial DNA depletion: mutations in thymidine kinase gene with myopathy and SMA.  Neurology. 2002;  59 1197-1202
• 33 Mandel H, Szargel R, Labay V, Elpeleg O, Saada A, Shalata A. et al . The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA.  Nat Genet. 2001;  29 337-341
• 34 Manfredi G, Schon E A, Moraes C T, Bonilla E, Berry G T, Sladky J T. et al . A new mutation associated with MELAS is located in a mitochondrial DNA polypeptide-coding gene.  Neuromuscul Disord. 1995;  5 391-398
• 35 Morin C, Mitchell G, Larochelle J, Lambert M, Ogier H, Robinson B H. et al . Clinical, metabolic, and genetic aspects of cytochrome C oxidase deficiency in Saguenay-Lac-Saint-Jean.  Am J Hum Genet. 1993;  53 488-496
• 36 Moslemi A R, Melberg A, Holme E, Oldfors A. Autosomal dominant progressive external ophthalmoplegia: distribution of multiple mitochondrial DNA deletions.  Neurology. 1999;  53 79-84
• 37 Moslemi A R, Tulinius M, Darin N, Åman P, Holme E, Oldfors A. SURF1 gene mutations in three cases of Leigh syndrome with cytochrome-c oxidase deficiency.  Neurology. 2003;  61 991-993
• 38 Naviaux R K, Nyhan W L, Barshop B A, Poulton J, Markusic D, Karpinski N C. et al . Mitochondrial DNA polymerase gamma deficiency and mtDNA depletion in a child with Alpers' syndrome.  Ann Neurol. 1999;  45 54-58
• 39 Nijtmans L G, Barth P G, Lincke C R, Van-Galen M J, Zwart R, Klement P. et al . Altered kinetics of cytochrome c oxidase in a patient with severe mitochondrial encephalomyopathy.  Biochim Biophys Acta. 1995;  1270 193-201
• 40 Nobrega M P, Nobrega F G, Tzagoloff A. COX10 codes for a protein homologous to the ORF1 product of Paracoccus denitrificans and is required for the synthesis of yeast cytochrome oxidase.  J Biol Chem. 1990;  265 14220-14226
• 41 Oldfors A, Sommerland H, Holme E, Tulinius M, Kristiansson B. Cytochrome c oxidase deficiency in infancy.  Acta Neuropathol (Berl). 1989;  77 267-275
• 42 Papadopoulou L C, Sue C M, Davidson M M, Tanji K, Nishino I, Sadlock J E. et al . Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene.  Nat Genet. 1999;  23 333-337
• 43 Parfait B, Percheron A, Chretien D, Rustin P, Munnich A, Rotig A. No mitochondrial cytochrome oxidase (COX) gene mutations in 18 cases of COX deficiency.  Hum Genet. 1997;  101 247-250
• 44 Prick M J, Gabreels F J, Trijbels J M, Janssen A J, le Coultre R, van Dam K. et al . Progressive poliodystrophy (Alpers' disease) with a defect in cytochrome aa3 in muscle: a report of two unrelated patients.  Clin Neurol Neurosurg. 1983;  85 57-70
• 45 Rahman S, Blok R B, Dahl H H, Danks D M, Kirby D M, Chow C W. et al . Leigh syndrome: clinical features and biochemical and DNA abnormalities.  Ann Neurol. 1996;  39 343-351
• 46 Rahman S, Taanman J W, Cooper J M, Nelson I, Hargreaves I, Meunier B. et al . A missense mutation of cytochrome oxidase subunit II causes defective assembly and myopathy.  Am J Hum Genet. 1999;  65 1030-1039
• 47 Rimoldi M, Bottacchi E, Rossi L, Cornelio F, Uziel G, Di Donato S. Cytochrome-C-oxidase deficiency in muscles of a floppy infant without mitochondrial myopathy.  J Neurol. 1982;  227 201-207
• 48 Rubio-Gozalbo M E, Smeitink J A, Ruitenbeek W, Ter Laak H, Mullaart R A, Schuelke M. et al . Spinal muscular atrophy-like picture, cardiomyopathy, and cytochrome c oxidase deficiency.  Neurology. 1999;  52 383-386
• 49 Saada A, Shaag A, Mandel H, Nevo Y, Eriksson S, Elpeleg O. Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy.  Nat Genet. 2001;  29 342-344
• 50 Sacconi S, Salviati L, Sue C M, Shanske S, Davidson M M, Bonilla E. et al . Mutation screening in patients with isolated cytochrome c oxidase deficiency.  Pediatr Res. 2003;  53 224-230
• 51 Santorelli F M, Gagliardi M G, Dionisi-Vici C, Parisi F, Tessa A, Carrozzo R. et al . Hypertrophic cardiomyopathy and mtDNA depletion. Successful treatment with heart transplantation.  Neuromuscul Disord. 2002;  12 56-59
• 52 Santorelli F M, Tanji K, Sano M, Shanske S, El-Shahawi M, Kranz-Eble P. et al . Maternally inherited encephalopathy associated with a single-base insertion in the mitochondrial tRNATrp gene.  Ann Neurol. 1997;  42 256-260
• 53 Saunier P, Chretien D, Wood C, Rotig A, Bonnefont J P, Saudubray J M. et al . Cytochrome c oxidase deficiency presenting as recurrent neonatal myoglobinuria.  Neuromuscul Disord. 1995;  5 285-289
• 54 Seligman A M, Karnovsky M J, Wasserkrug H L, Hanker J S. Non droplet ultrastructural demonstration of cytochrome oxidase activity with a polymerizing osmiophilic reagent, diaminobenzidine (DAB).  J Cell Biol. 1968;  38 1-14
• 55 Shoubridge E A. Cytochrome C oxidase deficiency.  Am J Med Genet. 2001;  106 46-52
• 56 Silvestri G, Mongini T, Odoardi F, Modoni A, deRosa G, Doriguzzi C. et al . A new mtDNA mutation associated with a progressive encephalopathy and cytochrome c oxidase deficiency.  Neurology. 2000;  54 1693-1696
• 57 Sue C M, Karadimas C, Checcarelli N, Tanji K, Papadopoulou L C, Pallotti F. et al . Differential features of patients with mutations in two COX assembly genes, SURF-1 and SCO2.  Ann Neurol. 2000;  47 589-595
• 58 Takayanagi T, Inoue M, Tomimasu K, Shimomura C, Matsuzaka T, Tsuji Y. et al . Infantile cytochrome c oxidase deficiency with neonatal death.  Pediatr Neurol. 1989;  5 179-181
• 59 Taniike M, Fukushima H, Yanagihara I, Tsukamoto H, Tanaka J, Fujimura H. et al . Mitochondrial tRNA(Ile) mutation in fatal cardiomyopathy.  Biochem Biophys Res Commun. 1992;  186 47-53
• 60 Tanji K, Bonilla E. Neuropathologic aspects of cytochrome C oxidase deficiency.  Brain Pathol. 2000;  10 422-430
• 61 Tiranti V, Corona P, Greco M, Taanman J W, Carrara F, Lamantea E. et al . A novel frameshift mutation of the mtDNA COIII gene leads to impaired assembly of cytochrome c oxidase in a patient affected by Leigh-like syndrome.  Hum Mol Genet. 2000;  9 2733-2742
• 62 Tiranti V, Hoertnagel K, Carrozzo R, Galimberti C, Munaro M, Granatiero M. et al . Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency.  Am J Hum Genet. 1998;  63 1609-1621
• 63 Tiranti V, Jaksch M, Hofmann S, Galimberti C, Hoertnagel K, Lulli L. et al . Loss-of-function mutations of SURF-1 are specifically associated with Leigh syndrome with cytochrome c oxidase deficiency.  Ann Neurol. 1999;  46 161-166
• 64 Tsao C Y, Mendell J R, Luquette M, Dixon B, Morrow 3rd G. Mitochondrial DNA depletion in children.  J Child Neurol. 2000;  15 822-824
• 65 Tulinius M, Moslemi A R, Darin N, Westerberg B, Holme E, Oldfors A. Leigh syndrome with cytochrome-c oxidase deficiency and a single T insertion nt 5537 in the mitochondrial tRNA^Trp gene. A second case.  Neuropediatrics. 2003;  34 87-91
• 66 Tulinius M H, Holme E, Kristiansson B, Larsson N G, Oldfors A. Mitochondrial encephalomyopathies in childhood. I. Biochemical and morphologic investigations.  J Pediatr. 1991;  119 242-250
• 67 Uusimaa J, Finnila S, Vainionpaa L, Karppa M, Herva R, Rantala H. et al . A mutation in mitochondrial DNA-encoded cytochrome c oxidase II gene in a child with Alpers-Huttenlocher-like disease.  Pediatrics. 2003;  111 E262-E268
• 68 Valnot I, Osmond S, Gigarel N, Mehaye B, Amiel J, Cormier-Daire V. et al . Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase deficiency with neonatal-onset hepatic failure and encephalopathy.  Am J Hum Genet. 2000;  67 1104-1109
• 69 Valnot I, von Kleist-Retzow J C, Barrientos A, Gorbatyuk M, Taanman J W, Mehaye B. et al . A mutation in the human heme A:farnesyltransferase gene (COX10) causes cytochrome c oxidase deficiency.  Hum Mol Genet. 2000;  9 1245-1249
• 70 Van Biervliet J P, Bruinvis L, Ketting D, De Bree P K, Van der Heiden C, Wadman S K. Hereditary mitochondrial myopathy with lactic acidemia, a De Toni-Fanconi-Debré syndrome, and a defective respiratory chain in voluntary striated muscles.  Pediatr Res. 1977;  11 1088-1093
• 71 Willems J L, Monnens L A, Trijbels J M, Veerkamp J H, Meyer A E, van Dam K. et al . Leigh's encephalomyelopathy in a patient with cytochrome c oxidase deficiency in muscle tissue.  Pediatrics. 1977;  60 850-857
• 72 Williams A N, Gray R G, Poulton K, Ramani P, Whitehouse W P. A case of Ohtahara syndrome with cytochrome oxidase deficiency.  Dev Med Child Neurol. 1998;  40 568-570
• 73 Willis T A, Davidson J, Gray R G, Poulton K, Ramani P, Whitehouse W. Cytochrome oxidase deficiency presenting as birth asphyxia.  Dev Med Child Neurol. 2000;  42 414-417
• 74 Wong L J, Dai P, Tan D, Lipson M, Grix A, Sifry-Platt M. et al . Severe lactic acidosis caused by a novel frame-shift mutation in mitochondrial-encoded cytochrome c oxidase subunit II.  Am J Med Genet. 2001;  102 95-99
• 75 Vu T H, Sciacco M, Tanji K, Nichter C, Bonilla E, Chatkupt S. et al . Clinical manifestations of mitochondrial DNA depletion.  Neurology. 1998;  50 1783-1790
• 76 Zhu Z, Yao J, Johns T, Fu K, De Bie, Macmillan C. et al . SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome.  Nat Genet. 1998;  20 337-343