KEGG DISEASE: Cytochrome c oxidase (COX) deficiency

DISEASE: Cytochrome c oxidase (COX) deficiency

Entry

H01368                      Disease

Name

Cytochrome c oxidase (COX) deficiency;
Mitochondrial complex IV deficiency (MT-C4D)

Subgroup

Fatal infantile cardioencephalomyopathy (CEMCOX) [DS:H01200]
Leigh syndrome, French-Canadian type (LSFC)

Supergrp

Mitochondrial disease [DS:H01427]

Description

Cytochrome c oxidase (COX) deficiency is a mitochondrial disease that is caused by the lack of the COX. Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial respiratory chain (complex IV). Since COX is encoded by nuclear and mitochondrial genes, COX deficiency can be inherited in either an autosomal recessive or a maternal pattern. Patients can present with a number of different clinical phenotypes, including Leigh syndrome, Fatal infantile cardioencephalomyopathy, and Leber hereditary optic neuropathy.

Category

Inherited metabolic disorder, Mitochondrial disease

Brite

Human diseases in ICD-11 classification [BR:br08403]
05 Endocrine, nutritional or metabolic diseases
  Metabolic disorders
   Inborn errors of metabolism
    5C53  Inborn errors of energy metabolism
     H01368  Cytochrome c oxidase (COX) deficiency
Pathway-based classification of diseases [BR:br08402]
Cellular process
  nt06529  Thermogenesis
   H01368  Cytochrome c oxidase (COX) deficiency

Pathway

hsa04714

Thermogenesis

hsa00190

Oxidative phosphorylation

hsa00860

Porphyrin metabolism

hsa04260

Cardiac muscle contraction

Network

nt06529 Thermogenesis

Gene

(MC4DN1) SURF1 [HSA:6834] [KO:K14998]
(MC4DN2) SCO2 [HSA:9997] [KO:K23755]
(MC4DN3) COX10 [HSA:1352] [KO:K02257]
(MC4DN4) SCO1 [HSA:6341] [KO:K07152]
(MC4DN5) LRPPRC [HSA:10128] [KO:K17964]
(MC4DN6) COX15 [HSA:1355] [KO:K02259]
(MC4DN7) COX6B1 [HSA:1340] [KO:K02267]
(MC4DN8) TACO1 [HSA:51204] [KO:K18189]
(MC4DN9) COA5 [HSA:493753] [KO:K18178]
(MC4DN10) COX14 [HSA:84987] [KO:K18181]
(MC4DN11) COX20 [HSA:116228] [KO:K18184]
(MC4DN12) PET100 [HSA:100131801] [KO:K18186]
(MC4DN13) COA6 [HSA:388753] [KO:K18179]
(MC4DN14) COA3 [HSA:28958] [KO:K18175]
(MC4DN15) COX8A [HSA:1351] [KO:K02273]
(MC4DN16) COX4I1 [HSA:1327] [KO:K02263]
(MC4DN17) COA8 [HSA:84334] [KO:K23506]
(MC4DN18) COX6A2 [HSA:1339] [KO:K02266]
(MC4DN19) PET117 [HSA:100303755] [KO:K18188]
(MC4DN20) COX5A [HSA:9377] [KO:K02264]
(MC4DN21) NDUFA4 [HSA:4697] [KO:K03948]
(MC4DN22) COX16 [HSA:51241] [KO:K18182]
(MC4DN23) COX11 [HSA:1353] [KO:K02258]
(COXPD44) FASTKD2 [HSA:22868] [KO:K18190]
(MT-C4D) COX1 [HSA:4512] [KO:K02256]
(MT-C4D) COX2 [HSA:4513] [KO:K02261]
(MT-C4D) COX3 [HSA:4514] [KO:K02262]

Other DBs

ICD-11:

5C53.2Y

ICD-10:

G71.3

MeSH:

D030401

OMIM:

604377 619046 619048 220110 220111 615119 619051 619052 616500 619053 619054 619055 616501 619058 619059 619060 619061 619062 619063 619064 619065 618855 619355 620275

Reference

PMID:11579424

Authors

Shoubridge EA

Title

Cytochrome c oxidase deficiency.

Journal

Am J Med Genet 106:46-52 (2001)
DOI:10.1002/ajmg.1378

Reference

PMID:9843204 (SURF1)

Authors

Zhu Z, Yao J, Johns T, Fu K, De Bie I, Macmillan C, Cuthbert AP, Newbold RF, Wang J, Chevrette M, Brown GK, Brown RM, Shoubridge EA

Title

SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome.

Journal

Nat Genet 20:337-43 (1998)
DOI:10.1038/3804

Reference

PMID:10545952 (SCO2)

Authors

Papadopoulou LC, Sue CM, Davidson MM, Tanji K, Nishino I, Sadlock JE, Krishna S, Walker W, Selby J, Glerum DM, Coster RV, Lyon G, Scalais E, Lebel R, Kaplan P, Shanske S, De Vivo DC, Bonilla E, Hirano M, DiMauro S, Schon EA

Title

Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene.

Journal

Nat Genet 23:333-7 (1999)
DOI:10.1038/15513

Reference

PMID:10767350 (COX10)

Authors

Valnot I, von Kleist-Retzow JC, Barrientos A, Gorbatyuk M, Taanman JW, Mehaye B, Rustin P, Tzagoloff A, Munnich A, Rotig A

Title

A mutation in the human heme A:farnesyltransferase gene (COX10 ) causes cytochrome c oxidase deficiency.

Journal

Hum Mol Genet 9:1245-9 (2000)
DOI:10.1093/hmg/9.8.1245

Reference

PMID:11013136 (SCO1)

Authors

Valnot I, Osmond S, Gigarel N, Mehaye B, Amiel J, Cormier-Daire V, Munnich A, Bonnefont JP, Rustin P, Rotig A

Title

Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase deficiency with neonatal-onset hepatic failure and encephalopathy.

Journal

Am J Hum Genet 67:1104-9 (2000)
DOI:10.1016/S0002-9297(07)62940-1

Reference

PMID:12529507 (LRPPRC)

Authors

Mootha VK, Lepage P, Miller K, Bunkenborg J, Reich M, Hjerrild M, Delmonte T, Villeneuve A, Sladek R, Xu F, Mitchell GA, Morin C, Mann M, Hudson TJ, Robinson B, Rioux JD, Lander ES

Title

Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics.

Journal

Proc Natl Acad Sci U S A 100:605-10 (2003)
DOI:10.1073/pnas.242716699

Reference

PMID:21412973 (COX15)

Authors

Alfadhel M, Lillquist YP, Waters PJ, Sinclair G, Struys E, McFadden D, Hendson G, Hyams L, Shoffner J, Vallance HD

Title

Infantile cardioencephalopathy due to a COX15 gene defect: report and review.

Journal

Am J Med Genet A 155A:840-4 (2011)
DOI:10.1002/ajmg.a.33881

Reference

PMID:18499082 (COX6B1)

Authors

Massa V, Fernandez-Vizarra E, Alshahwan S, Bakhsh E, Goffrini P, Ferrero I, Mereghetti P, D'Adamo P, Gasparini P, Zeviani M

Title

Severe infantile encephalomyopathy caused by a mutation in COX6B1, a nucleus-encoded subunit of cytochrome c oxidase.

Journal

Am J Hum Genet 82:1281-9 (2008)
DOI:10.1016/j.ajhg.2008.05.002

Reference

PMID:19503089 (TACO1)

Authors

Weraarpachai W, Antonicka H, Sasarman F, Seeger J, Schrank B, Kolesar JE, Lochmuller H, Chevrette M, Kaufman BA, Horvath R, Shoubridge EA

Title

Mutation in TACO1, encoding a translational activator of COX I, results in cytochrome c oxidase deficiency and late-onset Leigh syndrome.

Journal

Nat Genet 41:833-7 (2009)
DOI:10.1038/ng.390

Reference

PMID:21457908 (COA5)

Authors

Huigsloot M, Nijtmans LG, Szklarczyk R, Baars MJ, van den Brand MA, Hendriksfranssen MG, van den Heuvel LP, Smeitink JA, Huynen MA, Rodenburg RJ

Title

A mutation in C2orf64 causes impaired cytochrome c oxidase assembly and mitochondrial cardiomyopathy.

Journal

Am J Hum Genet 88:488-93 (2011)
DOI:10.1016/j.ajhg.2011.03.002

Reference

PMID:22243966 (COX14)

Authors

Weraarpachai W, Sasarman F, Nishimura T, Antonicka H, Aure K, Rotig A, Lombes A, Shoubridge EA

Title

Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.

Journal

Am J Hum Genet 90:142-51 (2012)
DOI:10.1016/j.ajhg.2011.11.027

Reference

PMID:23125284 (COX20)

Authors

Szklarczyk R, Wanschers BF, Nijtmans LG, Rodenburg RJ, Zschocke J, Dikow N, van den Brand MA, Hendriks-Franssen MG, Gilissen C, Veltman JA, Nooteboom M, Koopman WJ, Willems PH, Smeitink JA, Huynen MA, van den Heuvel LP

Title

A mutation in the FAM36A gene, the human ortholog of COX20, impairs cytochrome c oxidase assembly and is associated with ataxia and muscle hypotonia.

Journal

Hum Mol Genet 22:656-67 (2013)
DOI:10.1093/hmg/dds473

Reference

PMID:24462369 (PET100)

Authors

Lim SC, Smith KR, Stroud DA, Compton AG, Tucker EJ, Dasvarma A, Gandolfo LC, Marum JE, McKenzie M, Peters HL, Mowat D, Procopis PG, Wilcken B, Christodoulou J, Brown GK, Ryan MT, Bahlo M, Thorburn DR

Title

A founder mutation in PET100 causes isolated complex IV deficiency in Lebanese individuals with Leigh syndrome.

Journal

Am J Hum Genet 94:209-22 (2014)
DOI:10.1016/j.ajhg.2013.12.015

Reference

PMID:25339201 (COA6)

Authors

Baertling F, A M van den Brand M, Hertecant JL, Al-Shamsi A, P van den Heuvel L, Distelmaier F, Mayatepek E, Smeitink JA, Nijtmans LG, Rodenburg RJ

Title

Mutations in COA6 cause cytochrome c oxidase deficiency and neonatal hypertrophic cardiomyopathy.

Journal

Hum Mutat 36:34-8 (2015)
DOI:10.1002/humu.22715

Reference

PMID:25604084 (COA3)

Authors

Ostergaard E, Weraarpachai W, Ravn K, Born AP, Jonson L, Duno M, Wibrand F, Shoubridge EA, Vissing J

Title

Mutations in COA3 cause isolated complex IV deficiency associated with neuropathy, exercise intolerance, obesity, and short stature.

Journal

J Med Genet 52:203-7 (2015)
DOI:10.1136/jmedgenet-2014-102914

Reference

PMID:26685157 (COX8A)

Authors

Hallmann K, Kudin AP, Zsurka G, Kornblum C, Reimann J, Stuve B, Waltz S, Hattingen E, Thiele H, Nurnberg P, Rub C, Voos W, Kopatz J, Neumann H, Kunz WS

Title

Loss of the smallest subunit of cytochrome c oxidase, COX8A, causes Leigh-like syndrome and epilepsy.

Journal

Brain 139:338-45 (2016)
DOI:10.1093/brain/awv357

Reference

PMID:28766551 (COX4I1)

Authors

Abu-Libdeh B, Douiev L, Amro S, Shahrour M, Ta-Shma A, Miller C, Elpeleg O, Saada A

Title

Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia.

Journal

Eur J Hum Genet 25:1142-1146 (2017)
DOI:10.1038/ejhg.2017.112

Reference

PMID:25175347 (COA8)

Authors

Melchionda L, Haack TB, Hardy S, Abbink TE, Fernandez-Vizarra E, Lamantea E, Marchet S, Morandi L, Moggio M, Carrozzo R, Torraco A, Diodato D, Strom TM, Meitinger T, Tekturk P, Yapici Z, Al-Murshedi F, Stevens R, Rodenburg RJ, Lamperti C, Ardissone A, Moroni I, Uziel G, Prokisch H, Taylor RW, Bertini E, van der Knaap MS, Ghezzi D, Zeviani M

Title

Mutations in APOPT1, encoding a mitochondrial protein, cause cavitating leukoencephalopathy with cytochrome c oxidase deficiency.

Journal

Am J Hum Genet 95:315-25 (2014)
DOI:10.1016/j.ajhg.2014.08.003

Reference

PMID:31155743 (COX6A2)

Authors

Inoue M, Uchino S, Iida A, Noguchi S, Hayashi S, Takahashi T, Fujii K, Komaki H, Takeshita E, Nonaka I, Okada Y, Yoshizawa T, Van Lommel L, Schuit F, Goto YI, Mimaki M, Nishino I

Title

COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.

Journal

Ann Neurol 86:193-202 (2019)
DOI:10.1002/ana.25517

Reference

PMID:28386624 (PET117)

Authors

Renkema GH, Visser G, Baertling F, Wintjes LT, Wolters VM, van Montfrans J, de Kort GAP, Nikkels PGJ, van Hasselt PM, van der Crabben SN, Rodenburg RJT

Title

Mutated PET117 causes complex IV deficiency and is associated with neurodevelopmental regression and medulla oblongata lesions.

Journal

Hum Genet 136:759-769 (2017)
DOI:10.1007/s00439-017-1794-7

Reference

PMID:28247525 (COX5A)

Authors

Baertling F, Al-Murshedi F, Sanchez-Caballero L, Al-Senaidi K, Joshi NP, Venselaar H, van den Brand MA, Nijtmans LG, Rodenburg RJ

Title

Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia, and failure to thrive.

Journal

Hum Mutat 38:692-703 (2017)
DOI:10.1002/humu.23210

Reference

PMID:23746447 (NDUFA4)

Authors

Pitceathly RD, Rahman S, Wedatilake Y, Polke JM, Cirak S, Foley AR, Sailer A, Hurles ME, Stalker J, Hargreaves I, Woodward CE, Sweeney MG, Muntoni F, Houlden H, Taanman JW, Hanna MG

Title

NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease.

Journal

Cell Rep 3:1795-805 (2013)
DOI:10.1016/j.celrep.2013.05.005

Reference

PMID:33169484 (COX16)

Authors

Wintjes LTM, Kava M, van den Brandt FA, van den Brand MAM, Lapina O, Bliksrud YT, Kulseth MA, Amundsen SS, Selberg TR, Ybema-Antoine M, Tutakhel OAZ, Greed L, Thorburn DR, Tangeraas T, Balasubramaniam S, Rodenburg RJT

Title

A novel variant in COX16 causes cytochrome c oxidase deficiency, severe fatal neonatal lactic acidosis, encephalopathy, cardiomyopathy, and liver dysfunction.

Journal

Hum Mutat 42:135-141 (2021)
DOI:10.1002/humu.24137

Reference

PMID:36030551 (COX11)

Authors

Rius R, Bennett NK, Bhattacharya K, Riley LG, Yuksel Z, Formosa LE, Compton AG, Dale RC, Cowley MJ, Gayevskiy V, Al Tala SM, Almehery AA, Ryan MT, Thorburn DR, Nakamura K, Christodoulou J

Title

Biallelic pathogenic variants in COX11 are associated with an infantile-onset mitochondrial encephalopathy.

Journal

Hum Mutat 43:1970-1978 (2022)
DOI:10.1002/humu.24453

Reference

PMID:18771761 (FASTKD2)

Authors

Ghezzi D, Saada A, D'Adamo P, Fernandez-Vizarra E, Gasparini P, Tiranti V, Elpeleg O, Zeviani M

Title

FASTKD2 nonsense mutation in an infantile mitochondrial encephalomyopathy associated with cytochrome c oxidase deficiency.

Journal

Am J Hum Genet 83:415-23 (2008)
DOI:10.1016/j.ajhg.2008.08.009

Reference

PMID:10441567 (COX1)

Authors

Bruno C, Martinuzzi A, Tang Y, Andreu AL, Pallotti F, Bonilla E, Shanske S, Fu J, Sue CM, Angelini C, DiMauro S, Manfredi G

Title

A stop-codon mutation in the human mtDNA cytochrome c oxidase I gene disrupts the functional structure of complex IV.

Journal

Am J Hum Genet 65:611-20 (1999)
DOI:10.1086/302546

Reference

PMID:10205264 (COX2)

Authors

Clark KM, Taylor RW, Johnson MA, Chinnery PF, Chrzanowska-Lightowlers ZM, Andrews RM, Nelson IP, Wood NW, Lamont PJ, Hanna MG, Lightowlers RN, Turnbull DM

Title

An mtDNA mutation in the initiation codon of the cytochrome C oxidase subunit II gene results in lower levels of the protein and a mitochondrial encephalomyopathy.

Journal

Am J Hum Genet 64:1330-9 (1999)
DOI:10.1086/302361

Reference

PMID:8630495 (COX3)

Authors

Keightley JA, Hoffbuhr KC, Burton MD, Salas VM, Johnston WS, Penn AM, Buist NR, Kennaway NG

Title

A microdeletion in cytochrome c oxidase (COX) subunit III associated with COX deficiency and recurrent myoglobinuria.

Journal

Nat Genet 12:410-6 (1996)
DOI:10.1038/ng0496-410

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