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Combined oxidative phosphorylation deficiency 39(COXPD39)

MedGen UID:
1683958
Concept ID:
C5193075
Disease or Syndrome
Synonyms: COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 39; COXPD39
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): GFM2 (5q13.3)
 
Monarch Initiative: MONDO:0032726
OMIM®: 618397
Orphanet: ORPHA565624

Definition

Combined oxidative phosphorylation deficiency-39 (COXPD39) is an autosomal recessive multisystem disorder resulting from a defect in mitochondrial energy metabolism. Affected individuals show global developmental delay, sometimes with regression after normal early development, axial hypotonia with limb spasticity or abnormal involuntary movements, and impaired intellectual development with poor speech. More variable features may include hypotonia, seizures, and features of Leigh syndrome (256000) on brain imaging. There are variable deficiencies of the mitochondrial respiratory chain enzyme complexes in patient tissues (summary by Glasgow et al., 2017). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060). [from OMIM]

Clinical features

From HPO
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.
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
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.
Involuntary movements
MedGen UID:
140884
Concept ID:
C0427086
Sign or Symptom
Involuntary contractions of muscle leading to involuntary movements of extremities, neck, trunk, or face.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
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.
Hypsarrhythmia
MedGen UID:
195766
Concept ID:
C0684276
Finding
Hypsarrhythmia is abnormal interictal high amplitude waves and a background of irregular spikes. There is continuous (during wakefulness), high-amplitude (>200 Hz), generalized polymorphic slowing with no organized background and multifocal spikes demonstrated by electroencephalography (EEG).
Increased CSF lactate
MedGen UID:
257904
Concept ID:
C1167918
Finding
Increased concentration of lactate in the cerebrospinal fluid.
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Abnormal cerebellum morphology
MedGen UID:
400925
Concept ID:
C1866129
Anatomical Abnormality
Any structural abnormality of the cerebellum.
Simplified gyral pattern
MedGen UID:
413664
Concept ID:
C2749675
Finding
An abnormality of the cerebral cortex with fewer gyri but with normal cortical thickness. This pattern is usually often associated with congenital microcephaly.
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
Pachygyria
MedGen UID:
504794
Concept ID:
CN001193
Finding
Pachygyria is a malformation of cortical development with abnormally wide gyri with sulci 1,5-3 cm apart and abnormally thick cortex measuring more than 5 mm (radiological definition). See also neuropathological definitions for 2-, 3-, and 4-layered lissencephaly.
Arthrogryposis multiplex congenita
MedGen UID:
2455
Concept ID:
C0003886
Finding
Multiple congenital contractures in different body areas.
Flexion contracture
MedGen UID:
83069
Concept ID:
C0333068
Anatomical Abnormality
A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Increased serum lactate
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).
Drooling
MedGen UID:
8484
Concept ID:
C0013132
Finding
Habitual flow of saliva out of the mouth.
Myopathic facies
MedGen UID:
90695
Concept ID:
C0332615
Finding
A facial appearance characteristic of myopathic conditions. The face appears expressionless with sunken cheeks, bilateral ptosis, and inability to elevate the corners of the mouth, due to muscle weakness.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVCombined oxidative phosphorylation deficiency 39

Professional guidelines

PubMed

Naftali J, Mermelstein M, Landau YE, Barnea R, Shelly S, Auriel E, Peretz S
Acta Neurol Belg 2023 Jun;123(3):1019-1028. Epub 2023 Feb 15 doi: 10.1007/s13760-023-02196-z. PMID: 36792807
Carrozzo R, Verrigni D, Rasmussen M, de Coo R, Amartino H, Bianchi M, Buhas D, Mesli S, Naess K, Born AP, Woldseth B, Prontera P, Batbayli M, Ravn K, Joensen F, Cordelli DM, Santorelli FM, Tulinius M, Darin N, Duno M, Jouvencel P, Burlina A, Stangoni G, Bertini E, Redonnet-Vernhet I, Wibrand F, Dionisi-Vici C, Uusimaa J, Vieira P, Osorio AN, McFarland R, Taylor RW, Holme E, Ostergaard E
J Inherit Metab Dis 2016 Mar;39(2):243-52. Epub 2015 Oct 16 doi: 10.1007/s10545-015-9894-9. PMID: 26475597
Thuillier L, Rostane H, Droin V, Demaugre F, Brivet M, Kadhom N, Prip-Buus C, Gobin S, Saudubray JM, Bonnefont JP
Hum Mutat 2003 May;21(5):493-501. doi: 10.1002/humu.10201. PMID: 12673791

Recent clinical studies

Etiology

Mendham AE, Goedecke JH, Zeng Y, Larsen S, George C, Hauksson J, Fortuin-de Smidt MC, Chibalin AV, Olsson T, Chorell E
Diabetologia 2021 Jul;64(7):1642-1659. Epub 2021 Mar 26 doi: 10.1007/s00125-021-05430-6. PMID: 33770195Free PMC Article
Carrozzo R, Verrigni D, Rasmussen M, de Coo R, Amartino H, Bianchi M, Buhas D, Mesli S, Naess K, Born AP, Woldseth B, Prontera P, Batbayli M, Ravn K, Joensen F, Cordelli DM, Santorelli FM, Tulinius M, Darin N, Duno M, Jouvencel P, Burlina A, Stangoni G, Bertini E, Redonnet-Vernhet I, Wibrand F, Dionisi-Vici C, Uusimaa J, Vieira P, Osorio AN, McFarland R, Taylor RW, Holme E, Ostergaard E
J Inherit Metab Dis 2016 Mar;39(2):243-52. Epub 2015 Oct 16 doi: 10.1007/s10545-015-9894-9. PMID: 26475597
Berdoukas V, Coates TD, Cabantchik ZI
Free Radic Biol Med 2015 Nov;88(Pt A):3-9. Epub 2015 Jul 26 doi: 10.1016/j.freeradbiomed.2015.07.019. PMID: 26216855
Hanna JS
JPEN J Parenter Enteral Nutr 2015 Mar;39(3):273-81. Epub 2015 Jan 15 doi: 10.1177/0148607114567710. PMID: 25591973
Jomova K, Vondrakova D, Lawson M, Valko M
Mol Cell Biochem 2010 Dec;345(1-2):91-104. Epub 2010 Aug 22 doi: 10.1007/s11010-010-0563-x. PMID: 20730621

Diagnosis

Pardo B, Herrada-Soler E, Satrústegui J, Contreras L, Del Arco A
Int J Mol Sci 2022 Jan 4;23(1) doi: 10.3390/ijms23010528. PMID: 35008954Free PMC Article
Mendham AE, Goedecke JH, Zeng Y, Larsen S, George C, Hauksson J, Fortuin-de Smidt MC, Chibalin AV, Olsson T, Chorell E
Diabetologia 2021 Jul;64(7):1642-1659. Epub 2021 Mar 26 doi: 10.1007/s00125-021-05430-6. PMID: 33770195Free PMC Article
Li N, Zhan X
Mass Spectrom Rev 2020 Sep;39(5-6):471-498. Epub 2020 Feb 4 doi: 10.1002/mas.21618. PMID: 32020673
Tranchant C, Koob M, Anheim M
Parkinsonism Relat Disord 2017 Jun;39:4-16. Epub 2017 Feb 22 doi: 10.1016/j.parkreldis.2017.02.025. PMID: 28256436
Carrozzo R, Verrigni D, Rasmussen M, de Coo R, Amartino H, Bianchi M, Buhas D, Mesli S, Naess K, Born AP, Woldseth B, Prontera P, Batbayli M, Ravn K, Joensen F, Cordelli DM, Santorelli FM, Tulinius M, Darin N, Duno M, Jouvencel P, Burlina A, Stangoni G, Bertini E, Redonnet-Vernhet I, Wibrand F, Dionisi-Vici C, Uusimaa J, Vieira P, Osorio AN, McFarland R, Taylor RW, Holme E, Ostergaard E
J Inherit Metab Dis 2016 Mar;39(2):243-52. Epub 2015 Oct 16 doi: 10.1007/s10545-015-9894-9. PMID: 26475597

Therapy

Tian Z, Wang P, Huang K, Yu J, Zhang M, Liu Y, Zhao H, Zhu B, Huang X, Tong Z
Lasers Med Sci 2023 Jan 12;38(1):39. doi: 10.1007/s10103-022-03692-z. PMID: 36633696Free PMC Article
Mendham AE, Goedecke JH, Zeng Y, Larsen S, George C, Hauksson J, Fortuin-de Smidt MC, Chibalin AV, Olsson T, Chorell E
Diabetologia 2021 Jul;64(7):1642-1659. Epub 2021 Mar 26 doi: 10.1007/s00125-021-05430-6. PMID: 33770195Free PMC Article
Berdoukas V, Coates TD, Cabantchik ZI
Free Radic Biol Med 2015 Nov;88(Pt A):3-9. Epub 2015 Jul 26 doi: 10.1016/j.freeradbiomed.2015.07.019. PMID: 26216855
Ohkubo K, Ihara K, Ohga S, Ishimura M, Hara T
Thyroid 2012 Oct;22(10):1080-3. Epub 2012 Sep 4 doi: 10.1089/thy.2011.0521. PMID: 22947348Free PMC Article
Driessen J, Willems S, Dercksen S, Giele J, van der Staak F, Smeitink J
Paediatr Anaesth 2007 Jan;17(1):16-21. doi: 10.1111/j.1460-9592.2006.02043.x. PMID: 17184426

Prognosis

Mendham AE, Goedecke JH, Zeng Y, Larsen S, George C, Hauksson J, Fortuin-de Smidt MC, Chibalin AV, Olsson T, Chorell E
Diabetologia 2021 Jul;64(7):1642-1659. Epub 2021 Mar 26 doi: 10.1007/s00125-021-05430-6. PMID: 33770195Free PMC Article
Li N, Zhan X
Mass Spectrom Rev 2020 Sep;39(5-6):471-498. Epub 2020 Feb 4 doi: 10.1002/mas.21618. PMID: 32020673
Bruni F, Di Meo I, Bellacchio E, Webb BD, McFarland R, Chrzanowska-Lightowlers ZMA, He L, Skorupa E, Moroni I, Ardissone A, Walczak A, Tyynismaa H, Isohanni P, Mandel H, Prokisch H, Haack T, Bonnen PE, Enrico B, Pronicka E, Ghezzi D, Taylor RW, Diodato D
Hum Mutat 2018 Apr;39(4):563-578. Epub 2018 Feb 7 doi: 10.1002/humu.23398. PMID: 29314548Free PMC Article
Tranchant C, Koob M, Anheim M
Parkinsonism Relat Disord 2017 Jun;39:4-16. Epub 2017 Feb 22 doi: 10.1016/j.parkreldis.2017.02.025. PMID: 28256436
Driessen J, Willems S, Dercksen S, Giele J, van der Staak F, Smeitink J
Paediatr Anaesth 2007 Jan;17(1):16-21. doi: 10.1111/j.1460-9592.2006.02043.x. PMID: 17184426

Clinical prediction guides

Naftali J, Mermelstein M, Landau YE, Barnea R, Shelly S, Auriel E, Peretz S
Acta Neurol Belg 2023 Jun;123(3):1019-1028. Epub 2023 Feb 15 doi: 10.1007/s13760-023-02196-z. PMID: 36792807
Pardo B, Herrada-Soler E, Satrústegui J, Contreras L, Del Arco A
Int J Mol Sci 2022 Jan 4;23(1) doi: 10.3390/ijms23010528. PMID: 35008954Free PMC Article
Gojanovich GS, Jacobson DL, Jao J, Russell JS, Van Dyke RB, Libutti DE, Sharma TS, Geffner ME, Gerschenson M
AIDS Res Hum Retroviruses 2020 Sep;36(9):703-711. Epub 2020 Jul 20 doi: 10.1089/AID.2020.0067. PMID: 32586116Free 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
Li N, Zhan X
Mass Spectrom Rev 2020 Sep;39(5-6):471-498. Epub 2020 Feb 4 doi: 10.1002/mas.21618. PMID: 32020673

Recent systematic reviews

Tranchant C, Koob M, Anheim M
Parkinsonism Relat Disord 2017 Jun;39:4-16. Epub 2017 Feb 22 doi: 10.1016/j.parkreldis.2017.02.025. PMID: 28256436

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