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Mitochondrial complex 4 deficiency, nuclear type 8(MC4DN8)

MedGen UID:: 1765544
•Concept ID:: C5436689
•: Disease or Syndrome

Synonym:	MITOCHONDRIAL COMPLEX IV DEFICIENCY, NUCLEAR TYPE 8

Gene (location): Gene(s) directly associated with this condition or phenotype.	TACO1 (17q23.3)

Monarch Initiative:	MONDO:0033638
OMIM®:	619052

Definition

Mitochondrial complex IV deficiency nuclear type 8 (MC4DN8) is an autosomal recessive metabolic disorder characterized by the onset of neuromuscular symptoms in the first decade of life after normal early development. Affected individuals develop a slowly progressive decline in neurologic function with gait difficulties, spasticity, dysarthria, hypotonia, and variable intellectual disability. Other features may include facial hypotonia, optic atrophy with visual impairment, nystagmus, muscle rigidity, and loss of ambulation. Rare patients may have renal tubulopathy. Brain imaging shows T2-weighted hyperintensities in the basal ganglia, consistent with a clinical diagnosis of Leigh syndrome (see 256000). Serum lactate is often increased, and patient tissues show decreased levels and activity of mitochondrial respiratory complex IV (summary by Seeger et al., 2010). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110. [from OMIM]

Clinical features

From HPO

Short stature

MedGen UID:: 87607
•Concept ID:: C0349588
•: Finding

A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).

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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.

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Spastic gait

MedGen UID:: 115907
•Concept ID:: C0231687
•: Finding

Spasticity is manifested by increased stretch reflex which is intensified with movement velocity. This results in excessive and inappropriate muscle activation which can contribute to muscle hypertonia. Spastic gait is characterized by manifestations such as muscle hypertonia, stiff knee, and circumduction of the leg.

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Bradykinesia

MedGen UID:: 115925
•Concept ID:: C0233565
•: Sign or Symptom

Bradykinesia literally means slow movement, and is used clinically to denote a slowness in the execution of movement (in contrast to hypokinesia, which is used to refer to slowness in the initiation of movement).

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Abnormal pyramidal sign

MedGen UID:: 68582
•Concept ID:: C0234132
•: Sign or Symptom

Functional neurological abnormalities related to dysfunction of the pyramidal tract.

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Spastic tetraparesis

MedGen UID:: 658719
•Concept ID:: C0575059
•: Disease or Syndrome

Spastic weakness affecting all four limbs.

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Hemidystonia

MedGen UID:: 743329
•Concept ID:: C1960561
•: Disease or Syndrome

Hemidystonia refers to dystonia which involves the ipsilateral face, arm, and leg.

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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.

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Focal T2 hyperintense basal ganglia lesion

MedGen UID:: 892349
•Concept ID:: C4024926
•: Finding

A lighter than expected T2 signal on magnetic resonance imaging (MRI) of the basal ganglia. This term refers to a localized hyperintensity affecting a particular region of the basal ganglia.

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Severe temper tantrums

MedGen UID:: 1370486
•Concept ID:: C4476627
•: Mental or Behavioral Dysfunction

Temper tantrums, which occur with more severe symptomatology compared to a temper tantrum that occurs as a part of normal developmental process.

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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.

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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.

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Abnormality of the eye
- Optic atrophy
Abnormality of the musculoskeletal system
- Cytochrome C oxidase-negative muscle fibers
Abnormality of the nervous system
Growth abnormality
- Short stature

Recent clinical studies

Etiology

Donation of mitochondria by iPSC-derived mesenchymal stem cells protects retinal ganglion cells against mitochondrial complex I defect-induced degeneration.

Jiang D, Xiong G, Feng H, Zhang Z, Chen P, Yan B, Chen L, Gandhervin K, Ma C, Li C, Han S, Zhang Y, Liao C, Lee TL, Tse HF, Fu QL, Chiu K, Lian Q
Theranostics 2019;9(8):2395-2410. Epub 2019 Apr 13 doi: 10.7150/thno.29422. PMID: 31149051 Free PMC Article

Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor.

Killian JK, Kim SY, Miettinen M, Smith C, Merino M, Tsokos M, Quezado M, Smith WI Jr, Jahromi MS, Xekouki P, Szarek E, Walker RL, Lasota J, Raffeld M, Klotzle B, Wang Z, Jones L, Zhu Y, Wang Y, Waterfall JJ, O'Sullivan MJ, Bibikova M, Pacak K, Stratakis C, Janeway KA, Schiffman JD, Fan JB, Helman L, Meltzer PS
Cancer Discov 2013 Jun;3(6):648-57. Epub 2013 Apr 2 doi: 10.1158/2159-8290.CD-13-0092. PMID: 23550148 Free PMC Article

UV-induced apoptosis in XPG-deficient fibroblasts involves activation of CD95 and caspases but not p53.

Clément V, Dunand-Sauthier I, Wiznerowicz M, Clarkson SG
DNA Repair (Amst) 2007 May 1;6(5):602-14. Epub 2007 Jan 5 doi: 10.1016/j.dnarep.2006.11.010. PMID: 17208056

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Diagnosis

Loss of NOR-1 represses muscle metabolism through mTORC1-mediated signaling and mitochondrial gene expression in C2C12 myotubes.

Paez HG, Ferrandi PJ, Pitzer CR, Mohamed JS, Alway SE
FASEB J 2023 Aug;37(8):e23050. doi: 10.1096/fj.202202029R. PMID: 37389860

Defective mitochondrial rRNA methyltransferase MRM2 causes MELAS-like clinical syndrome.

Garone C, D'Souza AR, Dallabona C, Lodi T, Rebelo-Guiomar P, Rorbach J, Donati MA, Procopio E, Montomoli M, Guerrini R, Zeviani M, Calvo SE, Mootha VK, DiMauro S, Ferrero I, Minczuk M
Hum Mol Genet 2017 Nov 1;26(21):4257-4266. doi: 10.1093/hmg/ddx314. PMID: 28973171 Free PMC Article

Loss of the smallest subunit of cytochrome c oxidase, COX8A, causes Leigh-like syndrome and epilepsy.

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

A novel deficiency of mitochondrial ATPase of nuclear origin.

Houstek J, Klement P, Floryk D, Antonická H, Hermanská J, Kalous M, Hansíková H, Hout'ková H, Chowdhury SK, Rosipal T, Kmoch S, Stratilová L, Zeman J
Hum Mol Genet 1999 Oct;8(11):1967-74. doi: 10.1093/hmg/8.11.1967. PMID: 10484764

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