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Combined oxidative phosphorylation deficiency 29(COXPD29)

MedGen UID:
1799030
Concept ID:
C5567607
Disease or Syndrome
Synonyms: Combined oxidative phosphorylation defect type 29; COXPD29
SNOMED CT: Combined oxidative phosphorylation defect type 29 (1172843003); COXPD29 - combined oxidative phosphorylation defect type 29 (1172843003)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): TXN2 (22q12.3)
 
Monarch Initiative: MONDO:0014781
OMIM®: 616811
Orphanet: ORPHA478029

Definition

A rare mitochondrial oxidative phosphorylation disorder with characteristics of microcephaly, global developmental delay, spastic-dystonic movement disorder, intractable seizures, optic atrophy, autonomic dysfunction and peripheral neuropathy. Serum lactate is increased, and muscle biopsy shows decreased activity of mitochondrial respiratory complexes I and III. Brain imaging reveals progressive cerebellar atrophy and delayed myelination. [from SNOMEDCT_US]

Clinical features

From HPO
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Peripheral neuropathy
MedGen UID:
18386
Concept ID:
C0031117
Disease or Syndrome
Peripheral neuropathy is a general term for any disorder of the peripheral nervous system. The main clinical features used to classify peripheral neuropathy are distribution, type (mainly demyelinating versus mainly axonal), duration, and course.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Global brain atrophy
MedGen UID:
66840
Concept ID:
C0241816
Pathologic Function
Unlocalized atrophy of the brain with decreased total brain matter volume and increased ventricular size.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Increased CSF lactate
MedGen UID:
257904
Concept ID:
C1167918
Finding
Increased concentration of lactate in the cerebrospinal fluid.
Increased CSF protein concentration
MedGen UID:
329971
Concept ID:
C1806780
Finding
Increased concentration of protein in the cerebrospinal fluid.
Subependymal cysts
MedGen UID:
318876
Concept ID:
C1833431
Anatomical Abnormality
Cerebral cysts, usually located in the wall of the caudate nucleus or in the caudothalamic groove. They are found in up to 5.2% of all neonates, using transfontanellar ultrasound in the first days of life.
Severe global developmental delay
MedGen UID:
332436
Concept ID:
C1837397
Finding
A severe delay in the achievement of motor or mental milestones in the domains of development of a child.
Axonal degeneration
MedGen UID:
332464
Concept ID:
C1837496
Finding
Delayed CNS myelination
MedGen UID:
867393
Concept ID:
C4021758
Anatomical Abnormality
Delayed myelination in the central nervous system.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Increased circulating lactate concentration
MedGen UID:
332209
Concept ID:
C1836440
Finding
Abnormally increased level of blood lactate (2-hydroxypropanoic acid). Lactate is produced from pyruvate by lactate dehydrogenase during normal metabolism. The terms lactate and lactic acid are often used interchangeably but lactate (the component measured in blood) is strictly a weak base whereas lactic acid is the corresponding acid. Lactic acidosis is often used clinically to describe elevated lactate but should be reserved for cases where there is a corresponding acidosis (pH below 7.35).
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Retinopathy
MedGen UID:
11209
Concept ID:
C0035309
Disease or Syndrome
Any noninflammatory disease of the retina. This nonspecific term is retained here because of its wide use in the literature, but if possible new annotations should indicate the precise type of retinal abnormality.
Optic neuropathy
MedGen UID:
854546
Concept ID:
C3887709
Disease or Syndrome
Disorder of the optic nerve.
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.

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
Fertil Steril 2021 Jun;115(6):1521-1532. Epub 2021 Mar 19 doi: 10.1016/j.fertnstert.2021.01.026. PMID: 33745725
Stroes ES, Thompson PD, Corsini A, Vladutiu GD, Raal FJ, Ray KK, Roden M, Stein E, Tokgözoğlu L, Nordestgaard BG, Bruckert E, De Backer G, Krauss RM, Laufs U, Santos RD, Hegele RA, Hovingh GK, Leiter LA, Mach F, März W, Newman CB, Wiklund O, Jacobson TA, Catapano AL, Chapman MJ, Ginsberg HN; European Atherosclerosis Society Consensus Panel
Eur Heart J 2015 May 1;36(17):1012-22. Epub 2015 Feb 18 doi: 10.1093/eurheartj/ehv043. PMID: 25694464Free PMC Article
Maisch B, Hufnagel G, Kölsch S, Funck R, Richter A, Rupp H, Herzum M, Pankuweit S
Herz 2004 Sep;29(6):624-36. doi: 10.1007/s00059-004-2628-7. PMID: 15912438

Recent clinical studies

Etiology

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
Chen J, Stimpson SE, Fernandez-Bueno GA, Mathews CE
Antioxid Redox Signal 2018 Nov 10;29(14):1361-1372. Epub 2018 Feb 15 doi: 10.1089/ars.2017.7346. PMID: 29295631Free PMC Article
Kearney M, Orrell RW, Fahey M, Brassington R, Pandolfo M
Cochrane Database Syst Rev 2016 Aug 30;2016(8):CD007791. doi: 10.1002/14651858.CD007791.pub4. PMID: 27572719Free PMC Article
Stroes ES, Thompson PD, Corsini A, Vladutiu GD, Raal FJ, Ray KK, Roden M, Stein E, Tokgözoğlu L, Nordestgaard BG, Bruckert E, De Backer G, Krauss RM, Laufs U, Santos RD, Hegele RA, Hovingh GK, Leiter LA, Mach F, März W, Newman CB, Wiklund O, Jacobson TA, Catapano AL, Chapman MJ, Ginsberg HN; European Atherosclerosis Society Consensus Panel
Eur Heart J 2015 May 1;36(17):1012-22. Epub 2015 Feb 18 doi: 10.1093/eurheartj/ehv043. PMID: 25694464Free PMC Article
Popovici D, Hertoghe J
Endocrinologie 1991;29(3-4):119-36. PMID: 1821070

Diagnosis

François-Heude MC, Lebigot E, Roze E, Warde MTA, Cances C, Damaj L, Espil C, Fluss J, de Lonlay P, Kern I, Lenaers G, Munnich A, Meyer P, Spitz MA, Torre S, Doummar D, Touati G, Leboucq N, Roubertie A
Eur J Neurol 2022 Nov;29(11):3229-3242. Epub 2022 Aug 9 doi: 10.1111/ene.15515. PMID: 36200804
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
Stroes ES, Thompson PD, Corsini A, Vladutiu GD, Raal FJ, Ray KK, Roden M, Stein E, Tokgözoğlu L, Nordestgaard BG, Bruckert E, De Backer G, Krauss RM, Laufs U, Santos RD, Hegele RA, Hovingh GK, Leiter LA, Mach F, März W, Newman CB, Wiklund O, Jacobson TA, Catapano AL, Chapman MJ, Ginsberg HN; European Atherosclerosis Society Consensus Panel
Eur Heart J 2015 May 1;36(17):1012-22. Epub 2015 Feb 18 doi: 10.1093/eurheartj/ehv043. PMID: 25694464Free PMC Article
Gorman GS, Schaefer AM, Ng Y, Gomez N, Blakely EL, Alston CL, Feeney C, Horvath R, Yu-Wai-Man P, Chinnery PF, Taylor RW, Turnbull DM, McFarland R
Ann Neurol 2015 May;77(5):753-9. Epub 2015 Mar 28 doi: 10.1002/ana.24362. PMID: 25652200Free PMC Article
Popovici D, Hertoghe J
Endocrinologie 1991;29(3-4):119-36. PMID: 1821070

Therapy

Mohan A, Griffith KA, Wuchu F, Zhen DB, Kumar-Sinha C, Crysler O, Hsiehchen D, Enzler T, Dippman D, Gunchick V, Achreja A, Animasahun O, Choppara S, Nenwani M, Chinnaiyan AM, Nagrath D, Zalupski MM, Sahai V
Clin Cancer Res 2023 Jul 5;29(13):2394-2400. doi: 10.1158/1078-0432.CCR-23-0036. PMID: 37115501Free 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
Kearney M, Orrell RW, Fahey M, Brassington R, Pandolfo M
Cochrane Database Syst Rev 2016 Aug 30;2016(8):CD007791. doi: 10.1002/14651858.CD007791.pub4. PMID: 27572719Free PMC Article
Stroes ES, Thompson PD, Corsini A, Vladutiu GD, Raal FJ, Ray KK, Roden M, Stein E, Tokgözoğlu L, Nordestgaard BG, Bruckert E, De Backer G, Krauss RM, Laufs U, Santos RD, Hegele RA, Hovingh GK, Leiter LA, Mach F, März W, Newman CB, Wiklund O, Jacobson TA, Catapano AL, Chapman MJ, Ginsberg HN; European Atherosclerosis Society Consensus Panel
Eur Heart J 2015 May 1;36(17):1012-22. Epub 2015 Feb 18 doi: 10.1093/eurheartj/ehv043. PMID: 25694464Free PMC Article
Clay HB, Sillivan S, Konradi C
Int J Dev Neurosci 2011 May;29(3):311-24. Epub 2010 Sep 15 doi: 10.1016/j.ijdevneu.2010.08.007. PMID: 20833242Free PMC Article

Prognosis

Li Y, Yu J, Li R, Zhou H, Chang X
Cell Mol Biol Lett 2024 Jan 30;29(1):21. doi: 10.1186/s11658-024-00536-2. PMID: 38291374Free PMC Article
Kadirvelu B, Gavriel C, Nageshwaran S, Chan JPK, Nethisinghe S, Athanasopoulos S, Ricotti V, Voit T, Giunti P, Festenstein R, Faisal AA
Nat Med 2023 Jan;29(1):86-94. Epub 2023 Jan 19 doi: 10.1038/s41591-022-02159-6. PMID: 36658420Free PMC Article
Imai-Okazaki A, Matsunaga A, Yatsuka Y, Nitta KR, Kishita Y, Sugiura A, Sugiyama Y, Fushimi T, Shimura M, Ichimoto K, Tajika M, Ogawa-Tominaga M, Ebihara T, Matsuhashi T, Tsuruoka T, Kohda M, Hirata T, Harashima H, Nojiri S, Takeda A, Nakaya A, Kogaki S, Sakata Y, Ohtake A, Murayama K, Okazaki Y
Int J Cardiol 2021 Oct 15;341:48-55. Epub 2021 Jul 21 doi: 10.1016/j.ijcard.2021.06.042. PMID: 34298071
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
Papp M, Lakatos PL, Harsfalvi J, Farkas G, Palatka K, Udvardy M, Molnar T, Farkas K, Nagy F, Veres G, Lakatos L, Kovacs A, Dinya T, Kocsis AK, Papp J; Hungarian IBD Study Group, Altorjay I
Hum Immunol 2010 Apr;71(4):407-13. Epub 2010 Jan 26 doi: 10.1016/j.humimm.2010.01.012. PMID: 20079790

Clinical prediction guides

Mohan A, Griffith KA, Wuchu F, Zhen DB, Kumar-Sinha C, Crysler O, Hsiehchen D, Enzler T, Dippman D, Gunchick V, Achreja A, Animasahun O, Choppara S, Nenwani M, Chinnaiyan AM, Nagrath D, Zalupski MM, Sahai V
Clin Cancer Res 2023 Jul 5;29(13):2394-2400. doi: 10.1158/1078-0432.CCR-23-0036. PMID: 37115501Free PMC Article
Kadirvelu B, Gavriel C, Nageshwaran S, Chan JPK, Nethisinghe S, Athanasopoulos S, Ricotti V, Voit T, Giunti P, Festenstein R, Faisal AA
Nat Med 2023 Jan;29(1):86-94. Epub 2023 Jan 19 doi: 10.1038/s41591-022-02159-6. PMID: 36658420Free PMC Article
Chen J, Stimpson SE, Fernandez-Bueno GA, Mathews CE
Antioxid Redox Signal 2018 Nov 10;29(14):1361-1372. Epub 2018 Feb 15 doi: 10.1089/ars.2017.7346. PMID: 29295631Free PMC Article
Kearney M, Orrell RW, Fahey M, Brassington R, Pandolfo M
Cochrane Database Syst Rev 2016 Aug 30;2016(8):CD007791. doi: 10.1002/14651858.CD007791.pub4. PMID: 27572719Free PMC Article
Stroes ES, Thompson PD, Corsini A, Vladutiu GD, Raal FJ, Ray KK, Roden M, Stein E, Tokgözoğlu L, Nordestgaard BG, Bruckert E, De Backer G, Krauss RM, Laufs U, Santos RD, Hegele RA, Hovingh GK, Leiter LA, Mach F, März W, Newman CB, Wiklund O, Jacobson TA, Catapano AL, Chapman MJ, Ginsberg HN; European Atherosclerosis Society Consensus Panel
Eur Heart J 2015 May 1;36(17):1012-22. Epub 2015 Feb 18 doi: 10.1093/eurheartj/ehv043. PMID: 25694464Free PMC Article

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
Kearney M, Orrell RW, Fahey M, Brassington R, Pandolfo M
Cochrane Database Syst Rev 2016 Aug 30;2016(8):CD007791. doi: 10.1002/14651858.CD007791.pub4. PMID: 27572719Free PMC Article

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