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Combined oxidative phosphorylation defect type 8(COXPD8)

MedGen UID:
1377817
Concept ID:
C4518839
Disease or Syndrome
Synonyms: CARDIOMYOPATHY, HYPERTROPHIC MITOCHONDRIAL, FATAL INFANTILE; Combined oxidative phosphorylation deficiency 8
SNOMED CT: Combined oxidative phosphorylation defect type 8 (733600007); COXPD8 - combined oxidative phosphorylation defect type 8 (733600007)
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): AARS2 (6p21.1)
 
Monarch Initiative: MONDO:0013570
OMIM®: 614096
Orphanet: ORPHA319504

Definition

Combined oxidative phosphorylation deficiency-8 (COXPD8) is an autosomal recessive disorder caused by dysfunction of the mitochondrial respiratory chain. The main clinical manifestation is a lethal infantile hypertrophic cardiomyopathy, but there may also be subtle skeletal muscle and brain involvement. Biochemical studies show combined respiratory chain complex deficiencies in complexes I, III, and IV in cardiac muscle, skeletal muscle, and brain. The liver is not affected (summary by Gotz et al., 2011). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060). [from OMIM]

Clinical features

From HPO
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.
Cardiomegaly
MedGen UID:
5459
Concept ID:
C0018800
Finding
Increased size of the heart, clinically defined as an increased transverse diameter of the cardiac silhouette that is greater than or equal to 50% of the transverse diameter of the chest (increased cardiothoracic ratio) on a posterior-anterior projection of a chest radiograph or a computed tomography.
Congestive heart failure
MedGen UID:
9169
Concept ID:
C0018802
Disease or Syndrome
The presence of an abnormality of cardiac function that is responsible for the failure of the heart to pump blood at a rate that is commensurate with the needs of the tissues or a state in which abnormally elevated filling pressures are required for the heart to do so. Heart failure is frequently related to a defect in myocardial contraction.
Reduced left ventricular ejection fraction
MedGen UID:
868398
Concept ID:
C4022792
Finding
A diminution of the volumetric fraction of blood pumped out of the ventricle with each cardiac cycle.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
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.
EEG abnormality
MedGen UID:
56235
Concept ID:
C0151611
Finding
Abnormality observed by electroencephalogram (EEG), which is used to record of the brain's spontaneous electrical activity from multiple electrodes placed on the scalp.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Generalized muscle weakness
MedGen UID:
155433
Concept ID:
C0746674
Sign or Symptom
Generalized weakness or decreased strength of the muscles, affecting both distal and proximal musculature.
Increased variability in muscle fiber diameter
MedGen UID:
336019
Concept ID:
C1843700
Finding
An abnormally high degree of muscle fiber size variation. This phenotypic feature can be observed upon muscle biopsy.
Cytochrome C oxidase-negative muscle fibers
MedGen UID:
867360
Concept ID:
C4021724
Finding
An abnormally reduced activity of the enzyme cytochrome C oxidase in muscle tissue.
Pulmonary hypoplasia
MedGen UID:
78574
Concept ID:
C0265783
Congenital Abnormality
A congenital abnormality in which the lung parenchyma is not fully developed. It may be associated with other congenital abnormalities.
Lactic acidosis
MedGen UID:
1717
Concept ID:
C0001125
Disease or Syndrome
An abnormal buildup of lactic acid in the body, leading to acidification of the blood and other bodily fluids.
Metabolic acidosis
MedGen UID:
65117
Concept ID:
C0220981
Pathologic Function
Metabolic acidosis (MA) is characterized by a fall in blood pH due to a reduction of serum bicarbonate concentration. This can occur as a result of either the accumulation of acids (high anion gap MA) or the loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic MA). By definition, MA is not due to a respirary cause.
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).
Staring gaze
MedGen UID:
816157
Concept ID:
C3809827
Finding
An abnormality in which the eyes are held permanently wide open.
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 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  

Recent clinical studies

Diagnosis

Zhang Q, Ouyang Q, Xiang J, Li H, Lv H, An Y
Genes (Basel) 2023 Feb 22;14(3) doi: 10.3390/genes14030552. PMID: 36980825Free PMC Article
Trifunov S, Pyle A, Valentino ML, Liguori R, Yu-Wai-Man P, Burté F, Duff J, Kleinle S, Diebold I, Rugolo M, Horvath R, Carelli V
Sci Rep 2018 Aug 3;8(1):11682. doi: 10.1038/s41598-018-30143-z. PMID: 30076399Free PMC Article

Therapy

Dias HF, Kühtreiber WM, Nelson KJ, Ng NC, Zheng H, Faustman DL
Vaccine 2022 Mar 8;40(11):1540-1554. Epub 2021 Apr 28 doi: 10.1016/j.vaccine.2021.04.011. PMID: 33933315

Clinical prediction guides

Zhang Q, Ouyang Q, Xiang J, Li H, Lv H, An Y
Genes (Basel) 2023 Feb 22;14(3) doi: 10.3390/genes14030552. PMID: 36980825Free PMC Article
Dias HF, Kühtreiber WM, Nelson KJ, Ng NC, Zheng H, Faustman DL
Vaccine 2022 Mar 8;40(11):1540-1554. Epub 2021 Apr 28 doi: 10.1016/j.vaccine.2021.04.011. PMID: 33933315
Menezes MJ, Guo Y, Zhang J, Riley LG, Cooper ST, Thorburn DR, Li J, Dong D, Li Z, Glessner J, Davis RL, Sue CM, Alexander SI, Arbuckle S, Kirwan P, Keating BJ, Xu X, Hakonarson H, Christodoulou J
Hum Mol Genet 2015 Apr 15;24(8):2297-307. Epub 2015 Jan 2 doi: 10.1093/hmg/ddu747. PMID: 25556185
Emadali A, Nguyên DT, Rochon C, Tzimas GN, Metrakos PP, Chevet E
J Pathol 2005 Sep;207(1):111-8. doi: 10.1002/path.1798. PMID: 15912576

Recent systematic reviews

Zhang Q, Ouyang Q, Xiang J, Li H, Lv H, An Y
Genes (Basel) 2023 Feb 22;14(3) doi: 10.3390/genes14030552. PMID: 36980825Free PMC Article
Dogan AE, Yuksel C, Du F, Chouinard VA, Öngür D
Neuropsychopharmacology 2018 Jul;43(8):1681-1690. Epub 2018 Mar 14 doi: 10.1038/s41386-018-0041-9. PMID: 29581538Free PMC Article

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