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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
SNOMED CT: Combined oxidative phosphorylation defect type 39 (1279845005); COXPD39 - combined oxidative phosphorylation defect type 39 (1279845005); GTP dependent ribosome recycling factor mitochondrial 2-related combined oxidative phosphorylation defect (1279845005); GFM2-related combined oxidative phosphorylation defect (1279845005)
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
Ankle clonus
MedGen UID:
68672
Concept ID:
C0238651
Finding
Clonus is an involuntary tendon reflex that causes repeated flexion and extension of the foot. Ankle clonus is tested by rapidly flexing the foot upward.
Sinus bradycardia
MedGen UID:
39316
Concept ID:
C0085610
Pathologic Function
Bradycardia related to a mean resting sinus rate of less than 50 beats per minute.
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.
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.
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.
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
Upturning of the big toe (and sometimes fanning of the other toes) in response to stimulation of the sole of the foot. If the Babinski sign is present it can indicate damage to the corticospinal tract.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Macrogyria
MedGen UID:
120579
Concept ID:
C0266483
Congenital Abnormality
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.
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).
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.
Reduced eye contact
MedGen UID:
303190
Concept ID:
C1445953
Finding
A reduced frequency or duration of eye contact.
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
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.
Reduced brain N-acetyl aspartate level by MRS
MedGen UID:
868367
Concept ID:
C4022761
Finding
A decrease in the level of N-acetyl aspartate in the brain identified by magnetic resonance spectroscopy (MRS).
Elevated brain lactate level by MRS
MedGen UID:
868368
Concept ID:
C4022762
Finding
An increase in the level of lactate in the brain identified by magnetic resonance spectroscopy (MRS).
Joint contracture
MedGen UID:
3228
Concept ID:
C0009918
Anatomical Abnormality
A limitation in the passive range of motion of a joint resulting from loss of elasticity in the periarticular tissues owing to structural changes of non-bony tissues, such as muscles, tendons, ligaments, joint capsules or skin. A contracture prevents movement of the associated body part.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Congenital contracture
MedGen UID:
83066
Concept ID:
C0332878
Congenital Abnormality
One or more flexion contractures (a bent joint that cannot be straightened actively or passively) that are present at birth.
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.
Arthrogryposis multiplex congenita
MedGen UID:
1830310
Concept ID:
C5779613
Disease or Syndrome
Multiple congenital contractures in different body areas.
Recurrent respiratory infections
MedGen UID:
812812
Concept ID:
C3806482
Finding
An increased susceptibility to respiratory infections as manifested by a history of recurrent respiratory infections.
Diabetes mellitus type 1
MedGen UID:
41522
Concept ID:
C0011854
Disease or Syndrome
Type 1 diabetes mellitus (T1D), also designated insulin-dependent diabetes mellitus (IDDM), is a disorder of glucose homeostasis characterized by susceptibility to ketoacidosis in the absence of insulin therapy. It is a genetically heterogeneous autoimmune disease affecting about 0.3% of Caucasian populations (Todd, 1990). Genetic studies of T1D have focused on the identification of loci associated with increased susceptibility to this multifactorial phenotype. The classic phenotype of diabetes mellitus is polydipsia, polyphagia, and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.
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).
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.
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  
  • 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

Paul KC, Krolewski RC, Lucumi Moreno E, Blank J, Holton KM, Ahfeldt T, Furlong M, Yu Y, Cockburn M, Thompson LK, Kreymerman A, Ricci-Blair EM, Li YJ, Patel HB, Lee RT, Bronstein J, Rubin LL, Khurana V, Ritz B
Nat Commun 2023 May 16;14(1):2803. doi: 10.1038/s41467-023-38215-z. PMID: 37193692Free PMC Article
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
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

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
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

Therapy

Wang M, Li G, Jiang G, Cai J, Zhong W, Huang R, Liu Z, Huang X, Wang H
Eur J Med Chem 2024 Feb 15;266:116095. Epub 2023 Dec 25 doi: 10.1016/j.ejmech.2023.116095. PMID: 38215589
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
Herrero AJ, Martín J, Martín T, García-López D, Garatachea N, Jiménez B, Marín PJ
Clin Physiol Funct Imaging 2011 Mar;31(2):139-44. Epub 2010 Nov 15 doi: 10.1111/j.1475-097X.2010.00992.x. PMID: 21078065

Prognosis

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
Veronese N, Stubbs B, Koyanagi A, Vaona A, Demurtas J, Schofield P, Maggi S
PLoS One 2019;14(3):e0213656. Epub 2019 Mar 28 doi: 10.1371/journal.pone.0213656. PMID: 30921349Free PMC Article
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

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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