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Combined oxidative phosphorylation deficiency 33(COXPD33)

MedGen UID:
1623699
Concept ID:
C4540209
Disease or Syndrome
Synonym: COXPD33
 
Gene (location): C1QBP (17p13.2)
 
Monarch Initiative: MONDO:0054677
OMIM®: 617713

Definition

COXPD33 is an autosomal recessive multisystem disorder resulting from a defect in mitochondrial energy metabolism. The phenotype is highly variable, ranging from death in infancy to adult-onset progressive external ophthalmoplegia (PEO) and myopathy. A common finding is cardiomyopathy and increased serum lactate (summary by Feichtinger et al., 2017). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060). [from OMIM]

Clinical features

From HPO
Fatigue
MedGen UID:
41971
Concept ID:
C0015672
Sign or Symptom
A subjective feeling of tiredness characterized by a lack of energy and motivation.
Exercise intolerance
MedGen UID:
603270
Concept ID:
C0424551
Finding
A functional motor deficit where individuals whose responses to the challenges of exercise fail to achieve levels considered normal for their age and gender.
Nephrotic syndrome
MedGen UID:
10308
Concept ID:
C0027726
Disease or Syndrome
Nephrotic syndrome is a collection of findings resulting from glomerular dysfunction with an increase in glomerular capillary wall permeability associated with pronounced proteinuria. Nephrotic syndrome refers to the constellation of clinical findings that result from severe renal loss of protein, with Proteinuria and hypoalbuminemia, edema, and hyperlipidemia.
Cardiac arrest
MedGen UID:
5456
Concept ID:
C0018790
Finding
An abrupt loss of heart function.
Cardiomegaly
MedGen UID:
5459
Concept ID:
C0018800
Finding
Increased size of the heart, clinically defined as an increased transverse diameter of the cardiac silhouette that is greater than or equal to 50% of the transverse diameter of the chest (increased cardiothoracic ratio) on a posterior-anterior projection of a chest radiograph or a computed tomography.
Left ventricular hypertrophy
MedGen UID:
57442
Concept ID:
C0149721
Disease or Syndrome
Enlargement or increased size of the heart left ventricle.
Cardiomyopathy
MedGen UID:
209232
Concept ID:
C0878544
Disease or Syndrome
A myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality.
Fetal growth restriction
MedGen UID:
4693
Concept ID:
C0015934
Pathologic Function
An abnormal restriction of fetal growth with fetal weight below the tenth percentile for gestational age.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Sensorineural hearing loss disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Cerebral edema
MedGen UID:
2337
Concept ID:
C0006114
Pathologic Function
Abnormal accumulation of fluid in the brain.
EEG with burst suppression
MedGen UID:
369943
Concept ID:
C1969156
Finding
The burst suppression pattern in electroencephalography refers to a characteristic periodic pattern of low voltage (<10 microvolts) suppressed background and a relatively shorter pattern of higher amplitude slow, sharp, and spiking complexes.
Myopathy
MedGen UID:
10135
Concept ID:
C0026848
Disease or Syndrome
A disorder of muscle unrelated to impairment of innervation or neuromuscular junction.
Lactic acidosis
MedGen UID:
1717
Concept ID:
C0001125
Disease or Syndrome
An abnormal buildup of lactic acid in the body, leading to acidification of the blood and other bodily fluids.
Elevated circulating creatine kinase concentration
MedGen UID:
69128
Concept ID:
C0241005
Finding
An elevation of the level of the enzyme creatine kinase (also known as creatine phosphokinase (CK; EC 2.7.3.2) in the blood. CK levels can be elevated in a number of clinical disorders such as myocardial infarction, rhabdomyolysis, and muscular dystrophy.
Elevated hepatic transaminase
MedGen UID:
338525
Concept ID:
C1848701
Finding
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.
Oligohydramnios
MedGen UID:
86974
Concept ID:
C0079924
Pathologic Function
Diminished amniotic fluid volume in pregnancy.
Hypothyroidism
MedGen UID:
6991
Concept ID:
C0020676
Disease or Syndrome
Deficiency of thyroid hormone.
Amblyopia
MedGen UID:
8009
Concept ID:
C0002418
Disease or Syndrome
Reduced visual acuity that is uncorrectable by lenses in the absence of detectable anatomic defects in the eye or visual pathways.
Astigmatism
MedGen UID:
2473
Concept ID:
C0004106
Disease or Syndrome
Astigmatism (from the Greek 'a' meaning absence and 'stigma' meaning point) is a condition in which the parallel rays of light entering the eye through the refractive media are not focused on a single point. Both corneal and noncorneal factors contribute to refractive astigmatism. Corneal astigmatism is mainly the result of an aspheric anterior surface of the cornea, which can be measured readily by means of a keratometer; in a small fraction of cases (approximately 1 in 10) the effect is neutralized by the back surface. The curvature of the back surface of the cornea is not considered in most studies, because it is more difficult to measure; moreover, in the case of severe corneal astigmatism, there is evidence that both surfaces have the same configuration. Noncorneal factors are errors in the curvature of the 2 surfaces of the crystalline lens, irregularity in the refractive index of the lens, and an eccentric lens position. Since the cornea is the dominant component of the eye's refracting system, a highly astigmatic cornea is likely to result in a similarly astigmatic ocular refraction (summary by Clementi et al., 1998).
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).
Progressive external ophthalmoplegia
MedGen UID:
102439
Concept ID:
C0162674
Disease or Syndrome
Progressive external ophthalmoplegia is a condition characterized by weakness of the eye muscles. The condition typically appears in adults between ages 18 and 40 and slowly worsens over time. The first sign of progressive external ophthalmoplegia is typically drooping eyelids (ptosis), which can affect one or both eyelids. As ptosis worsens, affected individuals may use the forehead muscles to try to lift the eyelids, or they may lift up their chin in order to see. Another characteristic feature of progressive external ophthalmoplegia is weakness or paralysis of the muscles that move the eye (ophthalmoplegia). Affected individuals have to turn their head to see in different directions, especially as the ophthalmoplegia worsens. People with progressive external ophthalmoplegia may also have general weakness of the muscles used for movement (myopathy), particularly those in the neck, arms, or legs. The weakness may be especially noticeable during exercise (exercise intolerance). Muscle weakness may also cause difficulty swallowing (dysphagia).\n\nWhen the muscle cells of affected individuals are stained and viewed under a microscope, these cells usually appear abnormal. These abnormal muscle cells contain an excess of cell structures called mitochondria and are known as ragged-red fibers.\n\nAlthough muscle weakness is the primary symptom of progressive external ophthalmoplegia, this condition can be accompanied by other signs and symptoms. In these instances, the condition is referred to as progressive external ophthalmoplegia plus (PEO+). Additional signs and symptoms can include hearing loss caused by nerve damage in the inner ear (sensorineural hearing loss), weakness and loss of sensation in the limbs due to nerve damage (neuropathy), impaired muscle coordination (ataxia), a pattern of movement abnormalities known as parkinsonism, and depression.\n\nProgressive external ophthalmoplegia is part of a spectrum of disorders with overlapping signs and symptoms. Similar disorders include ataxia neuropathy spectrum and Kearns-Sayre syndrome. Like progressive external ophthalmoplegia, the other conditions in this spectrum can involve weakness of the eye muscles. However, these conditions have many additional features not shared by most people with progressive external ophthalmoplegia.
Decreased activity of mitochondrial complex I
MedGen UID:
393796
Concept ID:
C2677650
Finding
A reduction in the activity of the mitochondrial respiratory chain complex I, which is part of the electron transport chain in mitochondria.
Decreased activity of mitochondrial complex III
MedGen UID:
460434
Concept ID:
C3149083
Finding
A reduction in the activity of the mitochondrial respiratory chain complex III, which is part of the electron transport chain in mitochondria.
Decreased activity of mitochondrial complex IV
MedGen UID:
866520
Concept ID:
C4020800
Finding
A reduction in the activity of the mitochondrial respiratory chain complex IV, which is part of the electron transport chain in mitochondria.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  

Professional guidelines

PubMed

Spath K, Babariya D, Konstantinidis M, Lowndes J, Child T, Grifo JA, Poulton J, Wells D
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Lindner M, Hoffmann GF, Matern D
J Inherit Metab Dis 2010 Oct;33(5):521-6. Epub 2010 Apr 7 doi: 10.1007/s10545-010-9076-8. PMID: 20373143
Hanisch F, Müller T, Muser A, Deschauer M, Zierz S
J Neurol 2006 Apr;253(4):417-23. Epub 2006 Apr 20 doi: 10.1007/s00415-006-0987-0. PMID: 16619117

Recent clinical studies

Etiology

Tein I
Epilepsy Behav 2023 Aug;145:109338. Epub 2023 Jul 13 doi: 10.1016/j.yebeh.2023.109338. PMID: 37453291
Martínez-Reyes I, Cardona LR, Kong H, Vasan K, McElroy GS, Werner M, Kihshen H, Reczek CR, Weinberg SE, Gao P, Steinert EM, Piseaux R, Budinger GRS, Chandel NS
Nature 2020 Sep;585(7824):288-292. Epub 2020 Jul 8 doi: 10.1038/s41586-020-2475-6. PMID: 32641834Free PMC Article
Voet NB, van der Kooi EL, van Engelen BG, Geurts AC
Cochrane Database Syst Rev 2019 Dec 6;12(12):CD003907. doi: 10.1002/14651858.CD003907.pub5. PMID: 31808555Free PMC Article
Smith AM, Depp C, Ryan BJ, Johnston GI, Alegre-Abarrategui J, Evetts S, Rolinski M, Baig F, Ruffmann C, Simon AK, Hu MTM, Wade-Martins R
Mov Disord 2018 Oct;33(10):1580-1590. Epub 2018 Oct 7 doi: 10.1002/mds.104. PMID: 30294923Free PMC Article
Schapira AH
Neurochem Res 2008 Dec;33(12):2502-9. Epub 2008 Nov 8 doi: 10.1007/s11064-008-9855-x. PMID: 18998208

Diagnosis

Tein I
Epilepsy Behav 2023 Aug;145:109338. Epub 2023 Jul 13 doi: 10.1016/j.yebeh.2023.109338. PMID: 37453291
Zech M, Jech R, Boesch S, Škorvánek M, Weber S, Wagner M, Zhao C, Jochim A, Necpál J, Dincer Y, Vill K, Distelmaier F, Stoklosa M, Krenn M, Grunwald S, Bock-Bierbaum T, Fečíková A, Havránková P, Roth J, Příhodová I, Adamovičová M, Ulmanová O, Bechyně K, Danhofer P, Veselý B, Haň V, Pavelekova P, Gdovinová Z, Mantel T, Meindl T, Sitzberger A, Schröder S, Blaschek A, Roser T, Bonfert MV, Haberlandt E, Plecko B, Leineweber B, Berweck S, Herberhold T, Langguth B, Švantnerová J, Minár M, Ramos-Rivera GA, Wojcik MH, Pajusalu S, Õunap K, Schatz UA, Pölsler L, Milenkovic I, Laccone F, Pilshofer V, Colombo R, Patzer S, Iuso A, Vera J, Troncoso M, Fang F, Prokisch H, Wilbert F, Eckenweiler M, Graf E, Westphal DS, Riedhammer KM, Brunet T, Alhaddad B, Berutti R, Strom TM, Hecht M, Baumann M, Wolf M, Telegrafi A, Person RE, Zamora FM, Henderson LB, Weise D, Musacchio T, Volkmann J, Szuto A, Becker J, Cremer K, Sycha T, Zimprich F, Kraus V, Makowski C, Gonzalez-Alegre P, Bardakjian TM, Ozelius LJ, Vetro A, Guerrini R, Maier E, Borggraefe I, Kuster A, Wortmann SB, Hackenberg A, Steinfeld R, Assmann B, Staufner C, Opladen T, Růžička E, Cohn RD, Dyment D, Chung WK, Engels H, Ceballos-Baumann A, Ploski R, Daumke O, Haslinger B, Mall V, Oexle K, Winkelmann J
Lancet Neurol 2020 Nov;19(11):908-918. doi: 10.1016/S1474-4422(20)30312-4. PMID: 33098801Free PMC Article
Fatehi F, Okhovat AA, Nilipour Y, Mroczek M, Straub V, Töpf A, Palibrk A, Peric S, Rakocevic Stojanovic V, Najmabadi H, Nafissi S
Eur J Neurol 2020 Nov;27(11):2257-2266. Epub 2020 Jul 24 doi: 10.1111/ene.14402. PMID: 32558070Free PMC Article
Voet NB, van der Kooi EL, van Engelen BG, Geurts AC
Cochrane Database Syst Rev 2019 Dec 6;12(12):CD003907. doi: 10.1002/14651858.CD003907.pub5. PMID: 31808555Free PMC Article
Bianchi MC, Sgandurra G, Tosetti M, Battini R, Cioni G
Biosci Rep 2007 Jun;27(1-3):69-85. doi: 10.1007/s10540-007-9046-z. PMID: 17510789

Therapy

Tein I
Epilepsy Behav 2023 Aug;145:109338. Epub 2023 Jul 13 doi: 10.1016/j.yebeh.2023.109338. PMID: 37453291
Voet NB, van der Kooi EL, van Engelen BG, Geurts AC
Cochrane Database Syst Rev 2019 Dec 6;12(12):CD003907. doi: 10.1002/14651858.CD003907.pub5. PMID: 31808555Free PMC Article
Otten ABC, Sallevelt SCEH, Carling PJ, Dreesen JCFM, Drüsedau M, Spierts S, Paulussen ADC, de Die-Smulders CEM, Herbert M, Chinnery PF, Samuels DC, Lindsey P, Smeets HJM
Hum Reprod 2018 Jul 1;33(7):1331-1341. doi: 10.1093/humrep/dey114. PMID: 29850888Free PMC Article
Jao J, Abrams EJ
Pediatr Infect Dis J 2014 Jul;33(7):734-40. doi: 10.1097/INF.0000000000000224. PMID: 24378947Free PMC Article
Saccà F, Puorro G, Antenora A, Marsili A, Denaro A, Piro R, Sorrentino P, Pane C, Tessa A, Brescia Morra V, Cocozza S, De Michele G, Santorelli FM, Filla A
PLoS One 2011 Mar 11;6(3):e17627. doi: 10.1371/journal.pone.0017627. PMID: 21412413Free PMC Article

Prognosis

Bautista-Aguilera ÓM, Alonso JM, Catto M, Iriepa I, Knez D, Gobec S, Marco-Contelles J
Molecules 2022 Nov 1;27(21) doi: 10.3390/molecules27217437. PMID: 36364263Free PMC Article
Zech M, Jech R, Boesch S, Škorvánek M, Weber S, Wagner M, Zhao C, Jochim A, Necpál J, Dincer Y, Vill K, Distelmaier F, Stoklosa M, Krenn M, Grunwald S, Bock-Bierbaum T, Fečíková A, Havránková P, Roth J, Příhodová I, Adamovičová M, Ulmanová O, Bechyně K, Danhofer P, Veselý B, Haň V, Pavelekova P, Gdovinová Z, Mantel T, Meindl T, Sitzberger A, Schröder S, Blaschek A, Roser T, Bonfert MV, Haberlandt E, Plecko B, Leineweber B, Berweck S, Herberhold T, Langguth B, Švantnerová J, Minár M, Ramos-Rivera GA, Wojcik MH, Pajusalu S, Õunap K, Schatz UA, Pölsler L, Milenkovic I, Laccone F, Pilshofer V, Colombo R, Patzer S, Iuso A, Vera J, Troncoso M, Fang F, Prokisch H, Wilbert F, Eckenweiler M, Graf E, Westphal DS, Riedhammer KM, Brunet T, Alhaddad B, Berutti R, Strom TM, Hecht M, Baumann M, Wolf M, Telegrafi A, Person RE, Zamora FM, Henderson LB, Weise D, Musacchio T, Volkmann J, Szuto A, Becker J, Cremer K, Sycha T, Zimprich F, Kraus V, Makowski C, Gonzalez-Alegre P, Bardakjian TM, Ozelius LJ, Vetro A, Guerrini R, Maier E, Borggraefe I, Kuster A, Wortmann SB, Hackenberg A, Steinfeld R, Assmann B, Staufner C, Opladen T, Růžička E, Cohn RD, Dyment D, Chung WK, Engels H, Ceballos-Baumann A, Ploski R, Daumke O, Haslinger B, Mall V, Oexle K, Winkelmann J
Lancet Neurol 2020 Nov;19(11):908-918. doi: 10.1016/S1474-4422(20)30312-4. PMID: 33098801Free PMC Article
Ashar FN, Zhang Y, Longchamps RJ, Lane J, Moes A, Grove ML, Mychaleckyj JC, Taylor KD, Coresh J, Rotter JI, Boerwinkle E, Pankratz N, Guallar E, Arking DE
JAMA Cardiol 2017 Nov 1;2(11):1247-1255. doi: 10.1001/jamacardio.2017.3683. PMID: 29049454Free PMC Article
Vadakkadath Meethal S, Atwood CS
Neurobiol Aging 2012 Mar;33(3):569-81. Epub 2010 Jun 11 doi: 10.1016/j.neurobiolaging.2010.04.012. PMID: 20541840
Lindner M, Hoffmann GF, Matern D
J Inherit Metab Dis 2010 Oct;33(5):521-6. Epub 2010 Apr 7 doi: 10.1007/s10545-010-9076-8. PMID: 20373143

Clinical prediction guides

Zech M, Jech R, Boesch S, Škorvánek M, Weber S, Wagner M, Zhao C, Jochim A, Necpál J, Dincer Y, Vill K, Distelmaier F, Stoklosa M, Krenn M, Grunwald S, Bock-Bierbaum T, Fečíková A, Havránková P, Roth J, Příhodová I, Adamovičová M, Ulmanová O, Bechyně K, Danhofer P, Veselý B, Haň V, Pavelekova P, Gdovinová Z, Mantel T, Meindl T, Sitzberger A, Schröder S, Blaschek A, Roser T, Bonfert MV, Haberlandt E, Plecko B, Leineweber B, Berweck S, Herberhold T, Langguth B, Švantnerová J, Minár M, Ramos-Rivera GA, Wojcik MH, Pajusalu S, Õunap K, Schatz UA, Pölsler L, Milenkovic I, Laccone F, Pilshofer V, Colombo R, Patzer S, Iuso A, Vera J, Troncoso M, Fang F, Prokisch H, Wilbert F, Eckenweiler M, Graf E, Westphal DS, Riedhammer KM, Brunet T, Alhaddad B, Berutti R, Strom TM, Hecht M, Baumann M, Wolf M, Telegrafi A, Person RE, Zamora FM, Henderson LB, Weise D, Musacchio T, Volkmann J, Szuto A, Becker J, Cremer K, Sycha T, Zimprich F, Kraus V, Makowski C, Gonzalez-Alegre P, Bardakjian TM, Ozelius LJ, Vetro A, Guerrini R, Maier E, Borggraefe I, Kuster A, Wortmann SB, Hackenberg A, Steinfeld R, Assmann B, Staufner C, Opladen T, Růžička E, Cohn RD, Dyment D, Chung WK, Engels H, Ceballos-Baumann A, Ploski R, Daumke O, Haslinger B, Mall V, Oexle K, Winkelmann J
Lancet Neurol 2020 Nov;19(11):908-918. doi: 10.1016/S1474-4422(20)30312-4. PMID: 33098801Free PMC Article
Rana P, Kogut S, Wen X, Akhlaghi F, Aleo MD
Chem Res Toxicol 2020 Jul 20;33(7):1780-1790. Epub 2020 May 8 doi: 10.1021/acs.chemrestox.0c00040. PMID: 32338883
Feichtinger RG, Brunner-Krainz M, Alhaddad B, Wortmann SB, Kovacs-Nagy R, Stojakovic T, Erwa W, Resch B, Windischhofer W, Verheyen S, Uhrig S, Windpassinger C, Locker F, Makowski C, Strom TM, Meitinger T, Prokisch H, Sperl W, Haack TB, Mayr JA
Oxid Med Cell Longev 2017;2017:7202589. Epub 2017 Jul 19 doi: 10.1155/2017/7202589. PMID: 28804536Free PMC Article
Vadakkadath Meethal S, Atwood CS
Neurobiol Aging 2012 Mar;33(3):569-81. Epub 2010 Jun 11 doi: 10.1016/j.neurobiolaging.2010.04.012. PMID: 20541840
Lindner M, Hoffmann GF, Matern D
J Inherit Metab Dis 2010 Oct;33(5):521-6. Epub 2010 Apr 7 doi: 10.1007/s10545-010-9076-8. PMID: 20373143

Recent systematic reviews

Chang X, Wu Y, Zhou J, Meng H, Zhang W, Guo J
Medicine (Baltimore) 2020 Jan;99(5):e18634. doi: 10.1097/MD.0000000000018634. PMID: 32000367Free PMC Article
Voet NB, van der Kooi EL, van Engelen BG, Geurts AC
Cochrane Database Syst Rev 2019 Dec 6;12(12):CD003907. doi: 10.1002/14651858.CD003907.pub5. PMID: 31808555Free PMC Article
Jao J, Abrams EJ
Pediatr Infect Dis J 2014 Jul;33(7):734-40. doi: 10.1097/INF.0000000000000224. PMID: 24378947Free PMC Article

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