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Mitochondrial complex IV deficiency, nuclear type 1(MC4DN1)

MedGen UID:
1750917
Concept ID:
C5435656
Disease or Syndrome
Synonyms: Complex 4 mitochondrial respiratory chain deficiency; Complex IV deficiency; COX deficiency; Deficiency of mitochondrial respiratory chain complex4; Hepatic failure, early-onset, and neurologic disorder due to cytochrome C oxidase deficiency; Mitochondrial complex IV deficiency; Mitochondrial Respiratory Chain Complex IV Deficiency; Mitochondrial Respiratory Chain Complex IV Deficiency (mitochondrial genes); Mitochondrial Respiratory Chain Complex IV Deficiency (nuclear genes)
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).
Mitochondrial inheritance
MedGen UID:
165802
Concept ID:
C0887941
Genetic Function
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on the mitochondrial genome. Because the mitochondrial genome is essentially always maternally inherited, a mitochondrial condition can only be transmitted by females, although the condition can affect both sexes. The proportion of mutant mitochondria can vary (heteroplasmy).
 
Genes (locations): MT-TN; MT-TS1; SURF1 (9q34.2)
 
Monarch Initiative: MONDO:0700250
OMIM®: 220110
Orphanet: ORPHA254905

Definition

Mitochondrial complex IV deficiency nuclear type 1 (MC4DN1) is an autosomal recessive metabolic disorder characterized by rapidly progressive neurodegeneration and encephalopathy with loss of motor and cognitive skills between about 5 and 18 months of age after normal early development. Affected individuals show hypotonia, failure to thrive, loss of the ability to sit or walk, poor communication, and poor eye contact. Other features may include oculomotor abnormalities, including slow saccades, strabismus, ophthalmoplegia, and nystagmus, as well as deafness, apneic episodes, ataxia, tremor, and brisk tendon reflexes. Brain imaging shows bilateral symmetric lesions in the basal ganglia, consistent with a clinical diagnosis of Leigh syndrome (see 256000). Some patients may also have abnormalities in the brainstem and cerebellum. Laboratory studies usually show increased serum and CSF lactate and decreased levels and activity of mitochondrial respiratory complex IV in patient tissues. There is phenotypic variability, but death in childhood, often due to central respiratory failure, is common (summary by Tiranti et al., 1998; Tiranti et al., 1999; Teraoka et al., 1999; Poyau et al., 2000) Genetic Heterogeneity of Mitochondrial Complex IV Deficiency Most isolated COX deficiencies are inherited as autosomal recessive disorders caused by mutations in nuclear-encoded genes; mutations in the mtDNA-encoded COX subunit genes are relatively rare (Shoubridge, 2001; Sacconi et al., 2003). Mitochondrial complex IV deficiency caused by mutation in nuclear-encoded genes, in addition to MC4DN1, include MC4DN2 (604377), caused by mutation in the SCO2 gene (604272); MC4DN3 (619046), caused by mutation in the COX10 gene (602125); MC4DN4 (619048), caused by mutation in the SCO1 gene (603664); MC4DN5 (220111), caused by mutation in the LRPPRC gene (607544); MC4DN6 (615119), caused by mutation in the COX15 gene (603646); MC4DN7 (619051), caused by mutation in the COX6B1 gene (124089); MC4DN8 (619052), caused by mutation in the TACO1 gene (612958); MC4DN9 (616500), caused by mutation in the COA5 gene (613920); MC4DN10 (619053), caused by mutation in the COX14 gene (614478); MC4DN11 (619054), caused by mutation in the COX20 gene (614698); MC4DN12 (619055), caused by mutation in the PET100 gene (614770); MC4DN13 (616501), caused by mutation in the COA6 gene (614772); MC4DN14 (619058), caused by mutation in the COA3 gene (614775); MC4DN15 (619059), caused by mutation in the COX8A gene (123870); MC4DN16 (619060), caused by mutation in the COX4I1 gene (123864); MC4DN17 (619061), caused by mutation in the APOPT1 gene (616003); MC4DN18 (619062), caused by mutation in the COX6A2 gene (602009); MC4DN19 (619063), caused by mutation in the PET117 gene (614771); MC4DN20 (619064), caused by mutation in the COX5A gene (603773); MC4DN21 (619065), caused by mutation in the COXFA4 gene (603883); MC4DN22 (619355), caused by mutation in the COX16 gene (618064); and MC4DN23 (620275), caused by mutation in the COX11 gene (603648). Mitochondrial complex IV deficiency has been associated with mutations in several mitochondrial genes, including MTCO1 (516030), MTCO2 (516040), MTCO3 (516050), MTTS1 (590080), MTTL1 (590050), and MTTN (590010). [from OMIM]

Clinical features

From HPO
Exercise intolerance
MedGen UID:
603270
Concept ID:
C0424551
Finding
A functional motor deficit where individuals whose responses to the challenges of exercise fail to achieve levels considered normal for their age and gender.
Glycosuria
MedGen UID:
42267
Concept ID:
C0017979
Finding
An increased concentration of glucose in the urine.
Proteinuria
MedGen UID:
10976
Concept ID:
C0033687
Finding
Increased levels of protein in the urine.
Renal tubular dysfunction
MedGen UID:
57484
Concept ID:
C0151747
Disease or Syndrome
Abnormal function of the renal tubule. The basic functional unit of the kidney, the nephron, consists of a renal corpuscle attached to a renal tubule, with roughly 0.8 to 1.5 nephrons per adult kidney. The functions of the renal tubule include reabsorption of water, electrolytes, glucose, and amino acids and secretion of substances such as uric acid.
Aminoaciduria
MedGen UID:
116067
Concept ID:
C0238621
Disease or Syndrome
An increased concentration of an amino acid in the urine.
Hyperphosphaturia
MedGen UID:
78638
Concept ID:
C0268079
Disease or Syndrome
An increased excretion of phosphates in the urine.
Renal Fanconi syndrome
MedGen UID:
137960
Concept ID:
C0341703
Disease or Syndrome
An inability of the tubules in the kidney to reabsorb small molecules, causing increased urinary loss of electrolytes (sodium, potassium, bicarbonate), minerals, glucose, amino acids, and water.
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.
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.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Decreased liver function
MedGen UID:
65430
Concept ID:
C0232744
Finding
Reduced ability of the liver to perform its functions.
Increased hepatocellular lipid droplets
MedGen UID:
870573
Concept ID:
C4025021
Finding
An abnormal increase in the amount of intracellular lipid droplets in hepatocytes.
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.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
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.
Leukoencephalopathy
MedGen UID:
78722
Concept ID:
C0270612
Disease or Syndrome
This term describes abnormality of the white matter of the cerebrum resulting from damage to the myelin sheaths of nerve cells.
Truncal ataxia
MedGen UID:
96535
Concept ID:
C0427190
Sign or Symptom
Truncal ataxia is a sign of ataxia characterized by instability of the trunk. It usually occurs during sitting.
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.
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.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Brisk reflexes
MedGen UID:
382164
Concept ID:
C2673700
Finding
Tendon reflexes that are noticeably more active than usual (conventionally denoted 3+ on clinical examination). Brisk reflexes may or may not indicate a neurological lesion. They are distinguished from hyperreflexia by the fact that hyerreflexia is characterized by hyperactive repeating (clonic) reflexes, which are considered to be always abnormal.
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.
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Weakness of facial musculature
MedGen UID:
98103
Concept ID:
C0427055
Disease or Syndrome
Reduced strength of one or more muscles innervated by the facial nerve (the seventh cranial nerve).
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
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.
Exertional dyspnea
MedGen UID:
68549
Concept ID:
C0231807
Sign or Symptom
Perceived difficulty to breathe that occurs with exercise or exertion and improves with rest.
Respiratory distress
MedGen UID:
96907
Concept ID:
C0476273
Sign or Symptom
Respiratory distress is objectively observable as the physical or emotional consequences from the experience of dyspnea. The physical presentation of respiratory distress is generally referred to as labored breathing, while the sensation of respiratory distress is called shortness of breath or dyspnea.
Respiratory failure
MedGen UID:
257837
Concept ID:
C1145670
Disease or Syndrome
A severe form of respiratory insufficiency characterized by inadequate gas exchange such that the levels of oxygen or carbon dioxide cannot be maintained within normal limits.
Respiratory insufficiency due to muscle weakness
MedGen UID:
812797
Concept ID:
C3806467
Finding
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.
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).
Increased intramyocellular lipid droplets
MedGen UID:
866481
Concept ID:
C4020730
Finding
An abnormal increase in intracellular lipid droplets In a muscle. The number and size of these drops can increase with somd disorders of lipid metabolism affecting muscle. See PMID 20691590 for histological images.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Ophthalmoparesis
MedGen UID:
155551
Concept ID:
C0751401
Sign or Symptom
Ophthalmoplegia is a paralysis or weakness of one or more of the muscles that control eye movement.
Pigmentary retinopathy
MedGen UID:
1643295
Concept ID:
C4551715
Disease or Syndrome
An abnormality of the retina characterized by pigment deposition. It is typically associated with migration and proliferation of macrophages or retinal pigment epithelial cells into the retina; melanin from these cells causes the pigmentary changes. Pigmentary retinopathy is a common final pathway of many retinal conditions and is often associated with visual loss.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  

Recent clinical studies

Etiology

Hipps D, Dobson PF, Warren C, McDonald D, Fuller A, Filby A, Bulmer D, Laude A, Russell O, Deehan DJ, Turnbull DM, Lawless C
Bone 2022 May;158:116371. Epub 2022 Feb 19 doi: 10.1016/j.bone.2022.116371. PMID: 35192969
Feichtinger RG, Oláhová M, Kishita Y, Garone C, Kremer LS, Yagi M, Uchiumi T, Jourdain AA, Thompson K, D'Souza AR, Kopajtich R, Alston CL, Koch J, Sperl W, Mastantuono E, Strom TM, Wortmann SB, Meitinger T, Pierre G, Chinnery PF, Chrzanowska-Lightowlers ZM, Lightowlers RN, DiMauro S, Calvo SE, Mootha VK, Moggio M, Sciacco M, Comi GP, Ronchi D, Murayama K, Ohtake A, Rebelo-Guiomar P, Kohda M, Kang D, Mayr JA, Taylor RW, Okazaki Y, Minczuk M, Prokisch H
Am J Hum Genet 2017 Oct 5;101(4):525-538. Epub 2017 Sep 21 doi: 10.1016/j.ajhg.2017.08.015. PMID: 28942965Free PMC Article
Salminen A, Kaarniranta K, Kauppinen A, Ojala J, Haapasalo A, Soininen H, Hiltunen M
Prog Neurobiol 2013 Jul-Aug;106-107:33-54. Epub 2013 Jul 1 doi: 10.1016/j.pneurobio.2013.06.002. PMID: 23827971
Silva JP, Köhler M, Graff C, Oldfors A, Magnuson MA, Berggren PO, Larsson NG
Nat Genet 2000 Nov;26(3):336-40. doi: 10.1038/81649. PMID: 11062475
Zeviani M, Corona P, Nijtmans L, Tiranti V
Ital J Neurol Sci 1999 Dec;20(6):401-8. doi: 10.1007/s100720050059. PMID: 10937860

Diagnosis

Hipps D, Dobson PF, Warren C, McDonald D, Fuller A, Filby A, Bulmer D, Laude A, Russell O, Deehan DJ, Turnbull DM, Lawless C
Bone 2022 May;158:116371. Epub 2022 Feb 19 doi: 10.1016/j.bone.2022.116371. PMID: 35192969
Moss T, May M, Flanagan-Steet H, Caylor R, Jiang YH, McDonald M, Friez M, McConkie-Rosell A, Steet R
Cold Spring Harb Mol Case Stud 2021 Jun;7(3) Epub 2021 Jun 11 doi: 10.1101/mcs.a006081. PMID: 34117073Free PMC Article
Piro E, Serra G, Antona V, Giuffrè M, Giorgio E, Sirchia F, Schierz IAM, Brusco A, Corsello G
Ital J Pediatr 2020 Sep 24;46(1):140. doi: 10.1186/s13052-020-00903-7. PMID: 32972427Free PMC Article
Hallmann K, Kudin AP, Zsurka G, Kornblum C, Reimann J, Stüve B, Waltz S, Hattingen E, Thiele H, Nürnberg P, Rüb C, Voos W, Kopatz J, Neumann H, Kunz WS
Brain 2016 Feb;139(Pt 2):338-45. Epub 2015 Dec 17 doi: 10.1093/brain/awv357. PMID: 26685157
Abdulhag UN, Soiferman D, Schueler-Furman O, Miller C, Shaag A, Elpeleg O, Edvardson S, Saada A
Eur J Hum Genet 2015 Feb;23(2):159-64. Epub 2014 Apr 30 doi: 10.1038/ejhg.2014.85. PMID: 24781756Free PMC Article

Therapy

Possekel S, Lombes A, Ogier de Baulny H, Cheval MA, Fardeau M, Kadenbach B, Romero NB
Histochem Cell Biol 1995 Jan;103(1):59-68. doi: 10.1007/BF01464476. PMID: 7736281

Prognosis

Thompson K, Mai N, Oláhová M, Scialó F, Formosa LE, Stroud DA, Garrett M, Lax NZ, Robertson FM, Jou C, Nascimento A, Ortez C, Jimenez-Mallebrera C, Hardy SA, He L, Brown GK, Marttinen P, McFarland R, Sanz A, Battersby BJ, Bonnen PE, Ryan MT, Chrzanowska-Lightowlers ZM, Lightowlers RN, Taylor RW
EMBO Mol Med 2018 Nov;10(11) doi: 10.15252/emmm.201809060. PMID: 30201738Free PMC Article
Hallmann K, Kudin AP, Zsurka G, Kornblum C, Reimann J, Stüve B, Waltz S, Hattingen E, Thiele H, Nürnberg P, Rüb C, Voos W, Kopatz J, Neumann H, Kunz WS
Brain 2016 Feb;139(Pt 2):338-45. Epub 2015 Dec 17 doi: 10.1093/brain/awv357. PMID: 26685157
Abdulhag UN, Soiferman D, Schueler-Furman O, Miller C, Shaag A, Elpeleg O, Edvardson S, Saada A
Eur J Hum Genet 2015 Feb;23(2):159-64. Epub 2014 Apr 30 doi: 10.1038/ejhg.2014.85. PMID: 24781756Free PMC Article
Tarnopolsky MA, Bourgeois JM, Fu MH, Kataeva G, Shah J, Simon DK, Mahoney D, Johns D, MacKay N, Robinson BH
Am J Med Genet A 2004 Mar 15;125A(3):310-4. doi: 10.1002/ajmg.a.20466. PMID: 14994243
Feigenbaum A, Bergeron C, Richardson R, Wherrett J, Robinson B, Weksberg R
Am J Med Genet 1994 Jan 1;49(1):118-24. doi: 10.1002/ajmg.1320490124. PMID: 8172238

Clinical prediction guides

Hipps D, Dobson PF, Warren C, McDonald D, Fuller A, Filby A, Bulmer D, Laude A, Russell O, Deehan DJ, Turnbull DM, Lawless C
Bone 2022 May;158:116371. Epub 2022 Feb 19 doi: 10.1016/j.bone.2022.116371. PMID: 35192969
Piro E, Serra G, Antona V, Giuffrè M, Giorgio E, Sirchia F, Schierz IAM, Brusco A, Corsello G
Ital J Pediatr 2020 Sep 24;46(1):140. doi: 10.1186/s13052-020-00903-7. PMID: 32972427Free PMC Article
Abdulhag UN, Soiferman D, Schueler-Furman O, Miller C, Shaag A, Elpeleg O, Edvardson S, Saada A
Eur J Hum Genet 2015 Feb;23(2):159-64. Epub 2014 Apr 30 doi: 10.1038/ejhg.2014.85. PMID: 24781756Free PMC Article
Silva JP, Köhler M, Graff C, Oldfors A, Magnuson MA, Berggren PO, Larsson NG
Nat Genet 2000 Nov;26(3):336-40. doi: 10.1038/81649. PMID: 11062475
von Kleist-Retzow JC, Cormier-Daire V, de Lonlay P, Parfait B, Chretien D, Rustin P, Feingold J, Rötig A, Munnich A
Am J Hum Genet 1998 Aug;63(2):428-35. doi: 10.1086/301957. PMID: 9683589Free PMC Article

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