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Combined oxidative phosphorylation deficiency 54(COXPD54)

MedGen UID:
1812715
Concept ID:
C5676912
Disease or Syndrome
Synonym: COXPD54
 
Gene (location): PRORP (14q13.2)
 
Monarch Initiative: MONDO:0030543
OMIM®: 619737

Definition

Combined oxidative phosphorylation deficiency-54 (COXPD54) is an autosomal recessive disorder with pleiotropic multisystem presentations resulting from a disruption in mitochondrial transcription and translation. The phenotype is highly variable. Many patients have early-onset sensorineural hearing loss, sometimes in isolation, and sometimes associated with global developmental delay or primary ovarian failure. Other features may include peripheral hypertonia, seizures, muscle weakness, behavioral abnormalities, and leukoencephalopathy on brain imaging. Serum lactate may or may not be elevated (summary by Hochberg et al., 2021). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060). [from OMIM]

Clinical features

From HPO
Asthenia
MedGen UID:
2107
Concept ID:
C0004093
Sign or Symptom
A state characterized by a feeling of weakness and loss of strength leading to a generalized weakness of the body.
Myalgia
MedGen UID:
68541
Concept ID:
C0231528
Sign or Symptom
Pain in muscle.
Primary amenorrhea
MedGen UID:
115918
Concept ID:
C0232939
Disease or Syndrome
Abnormally late or absent menarche in a female with normal secondary sexual characteristics.
Lower limb muscle weakness
MedGen UID:
324478
Concept ID:
C1836296
Finding
Weakness of the muscles of the legs.
Tachycardia
MedGen UID:
21453
Concept ID:
C0039231
Finding
A rapid heartrate that exceeds the range of the normal resting heartrate for age.
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.
Obesity
MedGen UID:
18127
Concept ID:
C0028754
Disease or Syndrome
Accumulation of substantial excess body fat.
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.
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.
Absence of acoustic reflex
MedGen UID:
322049
Concept ID:
C1832834
Finding
Absence of the acoustic reflex, an involuntary contraction of the stapedius muscle that occurs in response to high-intensity sound stimuli.
Headache
MedGen UID:
9149
Concept ID:
C0018681
Sign or Symptom
Cephalgia, or pain sensed in various parts of the head, not confined to the area of distribution of any nerve.
Hemiparesis
MedGen UID:
6783
Concept ID:
C0018989
Finding
Loss of strength in the arm, leg, and sometimes face on one side of the body. Hemiplegia refers to a complete loss of strength, whereas hemiparesis refers to an incomplete loss of strength.
Hypoesthesia
MedGen UID:
6974
Concept ID:
C0020580
Finding
Decreased ability to perceive touch.
Psychotic disorder
MedGen UID:
19568
Concept ID:
C0033975
Mental or Behavioral Dysfunction
A condition characterized by changes in personality and thought patterns, often accompanied by hallucinations and delusional beliefs, is known as psychosis.
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.
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
Migraine
MedGen UID:
57451
Concept ID:
C0149931
Disease or Syndrome
Migraine is a chronic neurological disorder characterized by episodic attacks of headache and associated symptoms.
Memory impairment
MedGen UID:
68579
Concept ID:
C0233794
Mental or Behavioral Dysfunction
An impairment of memory as manifested by a reduced ability to remember things such as dates and names, and increased forgetfulness.
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
Absence of neurologic reflexes such as the knee-jerk reaction.
Generalized-onset seizure
MedGen UID:
115963
Concept ID:
C0234533
Disease or Syndrome
A generalized-onset seizure is a type of seizure originating at some point within, and rapidly engaging, bilaterally distributed networks. The networks may include cortical and subcortical structures but not necessarily the entire cortex.
Dysplastic corpus callosum
MedGen UID:
98128
Concept ID:
C0431369
Congenital Abnormality
Dysplasia and dysgenesis of the corpus callosum are nonspecific descriptions that imply defective development of the corpus callosum. The term dysplasia is applied when the morphology of the corpus callosum is altered as a congenital trait. For instance, the corpus callosum may be hump-shaped, kinked, or a striped corpus callosum that lacks an anatomically distinct genu and splenium.
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.
Autistic behavior
MedGen UID:
163547
Concept ID:
C0856975
Mental or Behavioral Dysfunction
Persistent deficits in social interaction and communication and interaction as well as a markedly restricted repertoire of activity and interest as well as repetitive patterns of behavior.
Impaired vibratory sensation
MedGen UID:
220959
Concept ID:
C1295585
Finding
A decrease in the ability to perceive vibration. Clinically, this is usually tested with a tuning fork which vibrates at 128 Hz and is applied to bony prominences such as the malleoli at the ankles or the metacarpal-phalangeal joints. There is a slow decay of vibration from the tuning fork. The degree of vibratory sense loss can be crudely estimated by counting the number of seconds that the examiner can perceive the vibration longer than the patient.
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.
Periventricular nodular heterotopia
MedGen UID:
358387
Concept ID:
C1868720
Disease or Syndrome
Nodules of heterotopia along the ventricular walls. There can be a single nodule or a large number of nodules, they can exist on either or both sides of the brain at any point along the higher ventricle margins, they can be small or large, single or multiple.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Periventricular white matter hyperintensities
MedGen UID:
927595
Concept ID:
C4293686
Finding
Areas of brighter than expected signal on magnetic resonance imaging emanating from the cerebral white matter that surrounds the cerebral ventricles.
Thrombophlebitis
MedGen UID:
11799
Concept ID:
C0040046
Pathologic Function
Inflammation of a vein associated with venous thrombosis (blood clot formation within the vein).
Hypertonia
MedGen UID:
10132
Concept ID:
C0026826
Finding
A condition in which there is increased muscle tone so that arms or legs, for example, are stiff and difficult to move.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Secondary microcephaly
MedGen UID:
608952
Concept ID:
C0431352
Finding
Head circumference which falls below 2 standard deviations below the mean for age and gender because of insufficient head growth after birth.
Microretrognathia
MedGen UID:
326907
Concept ID:
C1839546
Finding
A form of developmental hypoplasia of the mandible in which the mandible is mislocalised posteriorly.
Retrobulbar optic neuritis
MedGen UID:
39312
Concept ID:
C0085582
Disease or Syndrome
Optic neuritis that occurs in the section of the optic nerve located behind the eyeball.
Hyperglycemia
MedGen UID:
5689
Concept ID:
C0020456
Disease or Syndrome
An increased concentration of glucose in the blood.
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).
Elevated lactate:pyruvate ratio
MedGen UID:
1717835
Concept ID:
C5397670
Finding
An abnormal increase in the molar ratio of lactate to pyruvate in the blood circulation.
Thin vermilion border
MedGen UID:
108294
Concept ID:
C0578038
Finding
Height of the vermilion of the medial part of the lip more than 2 SD below the mean, or apparently reduced height of the vermilion of the lip in the frontal view. The vermilion is the red part of the lips (and confusingly, the vermilion itself is also often referred to as being equivalent the lips).
Epicanthus
MedGen UID:
151862
Concept ID:
C0678230
Congenital Abnormality
Epicanthus is a condition in which a fold of skin stretches from the upper to the lower eyelid, partially covering the inner canthus. Usher (1935) noted that epicanthus is a normal finding in the fetus of all races. Epicanthus also occurs in association with hereditary ptosis (110100).
Hypergonadotropic hypogonadism
MedGen UID:
184926
Concept ID:
C0948896
Disease or Syndrome
Reduced function of the gonads (testes in males or ovaries in females) associated with excess pituitary gonadotropin secretion and resulting in delayed sexual development and growth delay.
Hemianopia
MedGen UID:
9193
Concept ID:
C0018979
Finding
Partial or complete loss of vision in one half of the visual field of one or both eyes.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
Tonic pupil
MedGen UID:
52779
Concept ID:
C0040416
Sign or Symptom
An abnormality of the pupillary light reaction characterized by a marked slowing of the light reaction of usually just one pupil. The pupil tends to be relatively dilated, and there is reduced accommodation.
Optic disc pallor
MedGen UID:
108218
Concept ID:
C0554970
Finding
A pale yellow discoloration of the optic disc (the area of the optic nerve head in the retina). The optic disc normally has a pinkish hue with a central yellowish depression.

Professional guidelines

PubMed

Zhiping W, Quwen L, Hai Z, Jian Z, Peiyi G
Folia Neuropathol 2016;54(1):66-71. doi: 10.5114/fn.2016.58917. PMID: 27179223

Recent clinical studies

Etiology

Liu MY, Shao HD, Wu YY, Peng DL, Yu JW, Jia JP, Peng H, Li CR, Sulaiman A, Yu XY, Li CH, Huang WK
Plant Dis 2023 Jul;107(7):2070-2080. Epub 2023 Jul 6 doi: 10.1094/PDIS-08-22-1796-RE. PMID: 36691277
Meunier I, Bocquet B, Defoort-Dhellemmes S, Smirnov V, Arndt C, Picot MC, Dollfus H, Charif M, Audo I, Huguet H, Zanlonghi X, Lenaers G
Sci Rep 2021 Sep 21;11(1):18703. doi: 10.1038/s41598-021-98150-1. PMID: 34548540Free 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
Sanders LH, Paul KC, Howlett EH, Lawal H, Boppana S, Bronstein JM, Ritz B, Greenamyre JT
Toxicol Sci 2017 Jul 1;158(1):188-198. doi: 10.1093/toxsci/kfx086. PMID: 28460087Free PMC Article
Haug SJ, Wong RW, Day S, Choudhry N, Sneed S, Prasad P, Read S, McDonald RH, Agarwal A, Davis J, Sarraf D
Retina 2016 Dec;36 Suppl 1:S159-S167. doi: 10.1097/IAE.0000000000001267. PMID: 28005674

Diagnosis

Jha RK, Dawar C, Hasan Q, Pujar A, Gupta G, Vishnu VY, Kekunnaya R, Thangaraj K
Genes (Basel) 2021 Aug 24;12(9) doi: 10.3390/genes12091300. PMID: 34573281Free PMC Article
Shurtleff H, Barry D, Chanprasert S, Firman T, Warner M, Saneto RP
Epilepsy Behav 2018 Nov;88:235-243. Epub 2018 Oct 11 doi: 10.1016/j.yebeh.2018.09.013. PMID: 30316150
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
Rahman S
Dev Med Child Neurol 2012 May;54(5):397-406. Epub 2012 Jan 28 doi: 10.1111/j.1469-8749.2011.04214.x. PMID: 22283595
Ma YY, Zhang XL, Wu TF, Liu YP, Wang Q, Zhang Y, Song JQ, Wang YJ, Yang YL
J Child Neurol 2011 Aug;26(8):974-9. Epub 2011 May 3 doi: 10.1177/0883073811399905. PMID: 21540367

Therapy

Liu Y, Zhang L, Zhao J, Lu R, Shao X, Xu K, Li J, Tian Y
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Madeddu G, Fiore V, Melis M, Ortu S, Mannu F, Muredda AA, Garrucciu G, Bandiera F, Zaru S, Bagella P, Calvisi DF, Babudieri S
Sci Rep 2020 Feb 6;10(1):2014. doi: 10.1038/s41598-020-58837-3. PMID: 32029790Free PMC Article
Haug SJ, Wong RW, Day S, Choudhry N, Sneed S, Prasad P, Read S, McDonald RH, Agarwal A, Davis J, Sarraf D
Retina 2016 Dec;36 Suppl 1:S159-S167. doi: 10.1097/IAE.0000000000001267. PMID: 28005674
Franik S, Huidekoper HH, Visser G, de Vries M, de Boer L, Hermans-Peters M, Rodenburg R, Verhaak C, Vlieger AM, Smeitink JA, Janssen MC, Wortmann SB
J Inherit Metab Dis 2015 May;38(3):477-82. Epub 2014 Oct 11 doi: 10.1007/s10545-014-9773-9. PMID: 25303853
Robinson MM, Soop M, Sohn TS, Morse DM, Schimke JM, Klaus KA, Nair KS
J Clin Endocrinol Metab 2014 Dec;99(12):E2574-83. doi: 10.1210/jc.2014-2736. PMID: 25222757Free PMC Article

Prognosis

Ceperuelo-Mallafré V, Reverté L, Peraire J, Madeira A, Maymó-Masip E, López-Dupla M, Gutierrez-Valencia A, Ruiz-Mateos E, Buzón MJ, Jorba R, Vendrell J, Auguet T, Olona M, Vidal F, Rull A, Fernández-Veledo S
Front Immunol 2022;13:912579. Epub 2022 Sep 14 doi: 10.3389/fimmu.2022.912579. PMID: 36189213Free 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
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
Rahman S
Dev Med Child Neurol 2012 May;54(5):397-406. Epub 2012 Jan 28 doi: 10.1111/j.1469-8749.2011.04214.x. PMID: 22283595
Yang Y, Yao Z, Song J, Hasegawa Y, Kimura M, Yamaguchi S, Jiang Y, Qin J, Wu X
Ann Acad Med Singap 2008 Dec;37(12 Suppl):120-3. PMID: 19904473

Clinical prediction guides

Smith TB, Rea A, Thomas HB, Thompson K, Oláhová M, Maroofian R, Zamani M, He L, Sadeghian S, Galehdari H, Lotan NS, Gilboa T, Herman KC, McCorvie TJ, Yue WW, Houlden H, Taylor RW, Newman WG, O'Keefe RT
Eur J Hum Genet 2023 Oct;31(10):1190-1194. Epub 2023 Aug 9 doi: 10.1038/s41431-023-01437-2. PMID: 37558808Free PMC Article
Jha RK, Dawar C, Hasan Q, Pujar A, Gupta G, Vishnu VY, Kekunnaya R, Thangaraj K
Genes (Basel) 2021 Aug 24;12(9) doi: 10.3390/genes12091300. PMID: 34573281Free 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
Sanders LH, Paul KC, Howlett EH, Lawal H, Boppana S, Bronstein JM, Ritz B, Greenamyre JT
Toxicol Sci 2017 Jul 1;158(1):188-198. doi: 10.1093/toxsci/kfx086. PMID: 28460087Free PMC Article
Haug SJ, Wong RW, Day S, Choudhry N, Sneed S, Prasad P, Read S, McDonald RH, Agarwal A, Davis J, Sarraf D
Retina 2016 Dec;36 Suppl 1:S159-S167. doi: 10.1097/IAE.0000000000001267. PMID: 28005674

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