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Combined oxidative phosphorylation deficiency 44(COXPD44)

MedGen UID:
1718899
Concept ID:
C5394293
Disease or Syndrome
Synonyms: COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 44; COXPD44
 
Gene (location): FASTKD2 (2q33.3)
 
Monarch Initiative: MONDO:0030020
OMIM®: 618855

Definition

Combined oxidative phosphorylation deficiency-44 (COXPD44) is an autosomal recessive mitochondrial disorder with multisystemic manifestations. Most affected individuals present in infancy or early childhood with global developmental delay, hypotonia, and abnormal movements. Most patients develop seizures, often associated with status epilepticus, and some patients may have optic atrophy. One patient with hypertrophic cardiomyopathy has been reported. Serum lactate may be increased, although that finding is inconsistent. Detailed biochemical analysis shows variable combined deficiencies of mitochondrial oxidative complexes that appear to be tissue-specific (summary by Wei et al., 2020). For discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060). [from OMIM]

Clinical features

From HPO
Hyporeflexia of lower limbs
MedGen UID:
371881
Concept ID:
C1834696
Finding
Reduced intensity of muscle tendon reflexes in the lower limbs. Reflexes are elicited by stretching the tendon of a muscle, e.g., by tapping.
Hypertrophic cardiomyopathy
MedGen UID:
2881
Concept ID:
C0007194
Disease or Syndrome
Hypertrophic cardiomyopathy (HCM) is defined by the presence of increased ventricular wall thickness or mass in the absence of loading conditions (hypertension, valve disease) sufficient to cause the observed abnormality.
Dyskinesia
MedGen UID:
8514
Concept ID:
C0013384
Disease or Syndrome
A movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements.
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.
Slurred speech
MedGen UID:
65885
Concept ID:
C0234518
Finding
Abnormal coordination of muscles involved in speech.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Delayed ability to walk
MedGen UID:
66034
Concept ID:
C0241726
Finding
A failure to achieve the ability to walk at an appropriate developmental stage. Most children learn to walk in a series of stages, and learn to walk short distances independently between 12 and 15 months.
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.
Abnormal basal ganglia MRI signal intensity
MedGen UID:
868351
Concept ID:
C4022745
Anatomical Abnormality
A deviation from normal signal on magnetic resonance imaging (MRI) of the basal ganglia.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
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).
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.

Professional guidelines

PubMed

Esmaeili Y, Yarjanli Z, Pakniya F, Bidram E, Łos MJ, Eshraghi M, Klionsky DJ, Ghavami S, Zarrabi A
J Control Release 2022 May;345:147-175. Epub 2022 Mar 3 doi: 10.1016/j.jconrel.2022.03.001. PMID: 35248646
Gureev AP, Popov VN
Neurochem Res 2019 Oct;44(10):2273-2279. Epub 2019 Jan 7 doi: 10.1007/s11064-018-02711-2. PMID: 30617864
Christensen CL, Wulff Helge J, Krasnik A, Kriegbaum M, Rasmussen LJ, Hickson ID, Liisberg KB, Oxlund B, Bruun B, Lau SR, Olsen MN, Andersen JS, Heltberg AS, Kuhlman AB, Morville TH, Dohlmann TL, Larsen S, Dela F
Scand J Public Health 2016 Jul;44(5):534-9. Epub 2016 Mar 3 doi: 10.1177/1403494816636304. PMID: 26939591

Recent clinical studies

Etiology

Mincarone P, Bodini A, Tumolo MR, Sabina S, Colella R, Mannini L, Sabato E, Leo CG
JMIR Public Health Surveill 2024 Mar 18;10:e49772. doi: 10.2196/49772. PMID: 38498040Free PMC Article
Rafehi H, Read J, Szmulewicz DJ, Davies KC, Snell P, Fearnley LG, Scott L, Thomsen M, Gillies G, Pope K, Bennett MF, Munro JE, Ngo KJ, Chen L, Wallis MJ, Butler EG, Kumar KR, Wu KH, Tomlinson SE, Tisch S, Malhotra A, Lee-Archer M, Dolzhenko E, Eberle MA, Roberts LJ, Fogel BL, Brüggemann N, Lohmann K, Delatycki MB, Bahlo M, Lockhart PJ
Am J Hum Genet 2023 Jan 5;110(1):105-119. Epub 2022 Dec 8 doi: 10.1016/j.ajhg.2022.11.015. PMID: 36493768Free PMC Article
Altay O, Arif M, Li X, Yang H, Aydın M, Alkurt G, Kim W, Akyol D, Zhang C, Dinler-Doganay G, Turkez H, Shoaie S, Nielsen J, Borén J, Olmuscelik O, Doganay L, Uhlén M, Mardinoglu A
Adv Sci (Weinh) 2021 Sep;8(17):e2101222. Epub 2021 Jun 28 doi: 10.1002/advs.202101222. PMID: 34180141Free 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

Diagnosis

Leotta C, Hernandez L, Tothova L, Arefin S, Ciceri P, Cozzolino MG, Barany P, Chromek M, Stenvinkel P, Kublickiene K
Cells 2023 Dec 6;12(24) doi: 10.3390/cells12242774. PMID: 38132094Free PMC Article
Rafehi H, Read J, Szmulewicz DJ, Davies KC, Snell P, Fearnley LG, Scott L, Thomsen M, Gillies G, Pope K, Bennett MF, Munro JE, Ngo KJ, Chen L, Wallis MJ, Butler EG, Kumar KR, Wu KH, Tomlinson SE, Tisch S, Malhotra A, Lee-Archer M, Dolzhenko E, Eberle MA, Roberts LJ, Fogel BL, Brüggemann N, Lohmann K, Delatycki MB, Bahlo M, Lockhart PJ
Am J Hum Genet 2023 Jan 5;110(1):105-119. Epub 2022 Dec 8 doi: 10.1016/j.ajhg.2022.11.015. PMID: 36493768Free PMC Article
Zhang J, Yin X, Li C, Yin X, Xue Q, Ding L, Ju J, Ma J, Zhu Y, Du D, Reis RL, Wang Y
Adv Mater 2022 May;34(19):e2110690. Epub 2022 Apr 6 doi: 10.1002/adma.202110690. PMID: 35275432
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
Pfeffer G, Burke A, Yu-Wai-Man P, Compston DA, Chinnery PF
Neurology 2013 Dec 10;81(24):2073-81. Epub 2013 Nov 6 doi: 10.1212/01.wnl.0000437308.22603.43. PMID: 24198293Free PMC Article

Therapy

Chen Z, Li Y, Xie Y, Nie S, Chen B, Wu Z
J Dermatol Sci 2023 May;110(2):44-52. Epub 2023 Apr 3 doi: 10.1016/j.jdermsci.2023.04.001. PMID: 37069030
Altay O, Arif M, Li X, Yang H, Aydın M, Alkurt G, Kim W, Akyol D, Zhang C, Dinler-Doganay G, Turkez H, Shoaie S, Nielsen J, Borén J, Olmuscelik O, Doganay L, Uhlén M, Mardinoglu A
Adv Sci (Weinh) 2021 Sep;8(17):e2101222. Epub 2021 Jun 28 doi: 10.1002/advs.202101222. PMID: 34180141Free 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
Voet NB, van der Kooi EL, Riphagen II, Lindeman E, van Engelen BG, Geurts AC
Cochrane Database Syst Rev 2013 Jul 9;(7):CD003907. doi: 10.1002/14651858.CD003907.pub4. PMID: 23835682

Prognosis

Mincarone P, Bodini A, Tumolo MR, Sabina S, Colella R, Mannini L, Sabato E, Leo CG
JMIR Public Health Surveill 2024 Mar 18;10:e49772. doi: 10.2196/49772. PMID: 38498040Free PMC Article
Napierala JS, Rajapakshe K, Clark A, Chen YY, Huang S, Mesaros C, Xu P, Blair IA, Hauser LA, Farmer J, Lynch DR, Edwards DP, Coarfa C, Napierala M
Mol Cell Proteomics 2021;20:100094. Epub 2021 May 13 doi: 10.1016/j.mcpro.2021.100094. PMID: 33991687Free PMC Article
Herman I, Lopez MA, Marafi D, Pehlivan D, Calame DG, Abid F, Lotze TE
Muscle Nerve 2021 Mar;63(3):304-310. Epub 2020 Nov 13 doi: 10.1002/mus.27112. PMID: 33146414
Peyravi A, Yazdanpanahi N, Nayeri H, Hosseini SA
J Food Biochem 2020 Feb;44(2):e13125. Epub 2019 Dec 17 doi: 10.1111/jfbc.13125. PMID: 31849103
Alis R, Santos-Lozano A, Sanchis-Gomar F, Pareja-Galeano H, Fiuza-Luces C, Garatachea N, Lucia A, Emanuele E
J Trace Elem Med Biol 2016 May;35:103-6. Epub 2016 Feb 12 doi: 10.1016/j.jtemb.2016.02.002. PMID: 27049133

Clinical prediction guides

Mincarone P, Bodini A, Tumolo MR, Sabina S, Colella R, Mannini L, Sabato E, Leo CG
JMIR Public Health Surveill 2024 Mar 18;10:e49772. doi: 10.2196/49772. PMID: 38498040Free PMC Article
Chen Z, Li Y, Xie Y, Nie S, Chen B, Wu Z
J Dermatol Sci 2023 May;110(2):44-52. Epub 2023 Apr 3 doi: 10.1016/j.jdermsci.2023.04.001. PMID: 37069030
Rafehi H, Read J, Szmulewicz DJ, Davies KC, Snell P, Fearnley LG, Scott L, Thomsen M, Gillies G, Pope K, Bennett MF, Munro JE, Ngo KJ, Chen L, Wallis MJ, Butler EG, Kumar KR, Wu KH, Tomlinson SE, Tisch S, Malhotra A, Lee-Archer M, Dolzhenko E, Eberle MA, Roberts LJ, Fogel BL, Brüggemann N, Lohmann K, Delatycki MB, Bahlo M, Lockhart PJ
Am J Hum Genet 2023 Jan 5;110(1):105-119. Epub 2022 Dec 8 doi: 10.1016/j.ajhg.2022.11.015. PMID: 36493768Free 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
Pfeffer G, Burke A, Yu-Wai-Man P, Compston DA, Chinnery PF
Neurology 2013 Dec 10;81(24):2073-81. Epub 2013 Nov 6 doi: 10.1212/01.wnl.0000437308.22603.43. PMID: 24198293Free PMC Article

Recent systematic reviews

Mincarone P, Bodini A, Tumolo MR, Sabina S, Colella R, Mannini L, Sabato E, Leo CG
JMIR Public Health Surveill 2024 Mar 18;10:e49772. doi: 10.2196/49772. PMID: 38498040Free 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
Greising SM, Corona BT, McGann C, Frankum JK, Warren GL
Tissue Eng Part B Rev 2019 Dec;25(6):510-525. Epub 2019 Nov 11 doi: 10.1089/ten.TEB.2019.0207. PMID: 31578930
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
Voet NB, van der Kooi EL, Riphagen II, Lindeman E, van Engelen BG, Geurts AC
Cochrane Database Syst Rev 2013 Jul 9;(7):CD003907. doi: 10.1002/14651858.CD003907.pub4. PMID: 23835682

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