Mitochondrial complex IV deficiency (cytochrome c oxidase deficiency)

Recommended panel testing at Breda Genetics for this condition:

Mitochondrial complex IV deficiency – cytochrome c oxidase deficiency (APOPT1, C12ORF62, COA3, COA5, COA6, COX10, COX14, COX15, COX20, COX6B1, FARS2, FASTKD2, LRPPRC, MTCO1, MTCO2, MTCO3, MTTL1, MTTS1, PET100, POLG, SCO1, SCO2, SURF1, TACO1)



Mitochondrial complex IV deficiency (also known as cytochrome c oxidase – COX – deficiency or simply complex IV deficiency) is a very rare genetic metabolic disorder. Complex IV – also called cytochrome c oxidase – is the terminal enzyme of the respiratory chain and consists of 14 subunits, 3 of which (named COX1, COX2 and COX3) are encoded by mitochondrial DNA. Pathogenic mutations causing COX deficiency are mostly seen in nuclear DNA encoded genes and are associated with autosomal recessive transmission (APOPT1, C12ORF62, COA3, COA5, COA6, COX10, COX14, COX15, COX20, COX6B1, FARS2 FASTKD2, LRPPRC, PET100, POLG, SCO1, SCO2, SURF1, TACO1). Rarely COX deficiency may be caused by a mutation in a mitochondrial DNA gene, showing maternal inheritance (MTCO1, MTCO2, MTCO3, MTTL1, MTTS1). The condition predominantly affect the skeletal muscles, but maybe generalized and therefore impact also heart, brain, kidney, connective tissue and liver.

COX deficiency may be found as isolated (when caused by mutations in any of the above genes) or as part of a chromosomal disorder (when caused by large deletions involving also adjacent genes – see for instance the homozygous deletion of chromosome 19q13.11 – van Bon et al. 2013).

Detailed clinical description

COX deficiency shows marked inter and intra-familial clinical variability. Disease severity ranges from the severe infantile form to the paucisymptomatic adult form at the mildest end. COX deficiency can be distinguished in at least 6 subtypes:

  • COX deficiency, benign infantile mitochondrial myopathy type
  • COX deficiency, severe infantile mitochondrial myopathy type
  • COX deficiency associated with fatal infantile cardioencephalomyopathy [CEMCOX] (caused by mutations in the SCO2, COX15, COA5 or COA6 gene)
  • COX deficiency associated with Leigh’s syndrome (caused by SURF1, COX15, TACO1 or PET100 mutation)
  • COX deficiency associated with Leigh syndrome, French-Canadian type (caused by mutation in the LRPPRC gene)
  • Adult form

Infantile mitochondrial myopathy types (benign and severe)

The benign variant of the infantile form is mainly characterized by generalized weakness of skeletal muscles (myotonia), but no other tissues/organs are involved.

In the severe form, the disorder is characterized by a generalized weakness of skeletal muscles, abnormalities of the heart and kidneys, and/or lactic acidosis. De Toni-Fanconi-Debre syndrome (a renal syndrome caused by transport defects of amino acids, monosaccharides, sodium, potassium, phosphorus, calcium, bicarbonate, uric acid, and proteins in the proximal renal tubule) may also be present and may include excessive thirst and urination.

COX deficiency associated with fatal infantile cardioencephalomyopathy [CEMCOX]

The main feature of cardioencephalomyopathy due to cytochrome c oxidase deficiency [CEMCOX] is cardiomyopathy, which can arise either in utero or in the first days of life. The following neurological stigmata are also frequently seen: abnormal breathing, nystagmus and gyral abnormalities. The disorder is usually fatal in early infancy. Those with mutations in the SCO2 gene, tend to have a more severe disease.

COX deficiency associated with Leigh syndrome

Leigh disease is a generalized clinical syndrome characterized by progressive degeneration of brain, heart, kidneys, muscles, and liver. Motor skills regression, generalized weakness with hypotonia, irritability, vomiting, seizures and lactic acidosis are typical. Onset is in infancy or early childhood with encephalopathy and failure to thrive (usually between three months and two years of age). Children with earlier disease onset, especially those with mutations in the SURF1, tend to have a more severe disease. More than half of the patients die in childhood, often within the first 18 months of life.

COX deficiency associated with Leigh syndrome, French-Canadian type

French Canadian type of Leigh syndrome is an  early-onset progressive neurodegenerative disorder with delayed psychomotor development and mental retardation, dysmorphic facial features, hypotonia, and ataxia. MRI shows lesions in the brainstem and basal ganglia. Metabolic and/or neurologic crises may often lead to early death. Strabismus may be seen in patients with COX deficiency associated with Leigh syndrome, French-Canadian type.

Adult form

In some rare cases, symptoms of COX deficiency may not develop until adolescence or adulthood. The adult form is characterized by generalized muscle aches, hypotonia and occasional twitching and stiffness of the musculature. These patients may have history of diabetes, acute hearing loss, hyperlipidemia, hyperuricemia, arterial hypertension, polyarthrosis, hypogonadism, and hypothyroidism. Weakness, myalgias, CK elevation and diabetes may be present in the family history. Clinical investigations may show postural tremor, reduced tendon reflexes, and elevated serum CK levels. Muscle biopsy is aspecific, but the biochemistry of the muscle homogenate may reveal an isolated complex IV defect and reduced amounts of coenzyme Q (CoQ).

In patients with the adult form, coenzyme Q supplementation, low-carbohydrate diet, and gluten-free diet may have a beneficial effect at least on some of the manifestations.


COX deficiency should be suspected in all infants with evocative clinical presentation and episodes of lactic acidosis. Reduced activity of cytochrome C oxidase may be confirmed in fibroblasts from connective tissue biopsy. Muscle biopsy studies may reveal “ragged-red fibers”. By special staining techniques, available in selected laboratories, it is possible to see which subunits of the COX enzyme are affected.

Genetic testing by whole exome sequencing may reveal pathogenic mutations in a known gene or detect possibly disease-causing mutations in as-yet-unknown candidate genes.

Panel testing recommended at Breda Genetics for this condition:

Mitochondrial complex IV deficiency – cytochrome c oxidase deficiency (APOPT1, C12ORF62, COA3, COA5, COA6, COX10, COX14, COX15, COX20, COX6B1, FARS2, FASTKD2, LRPPRC, MTCO1, MTCO2, MTCO3, MTTL1, MTTS1, PET100, POLG, SCO1, SCO2, SURF1, TACO1)


Nuclear Gene-Encoded Leigh Syndrome Overview. Rahman S, Thorburn D. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2015 Oct 1. PMID: 26425749

Mitochondrial cytochrome c oxidase deficiency. Rak M, Bénit P, Chrétien D, Bouchereau J, Schiff M, El-Khoury R, Tzagoloff A, Rustin P. Clin Sci (Lond). 2016 Mar;130(6):393-407. PMID: 26846578

Leigh syndrome: One disorder, more than 75 monogenic causes. Lake NJ, Compton AG, Rahman S, Thorburn DR. Ann Neurol. 2016 Feb;79(2):190-203. PMID: 26506407

Leigh syndrome: neuropathology and pathogenesis. Lake NJ, Bird MJ, Isohanni P, Paetau A. J Neuropathol Exp Neurol. 2015 Jun;74(6):482-92. PMID: 25978847

Diagnosis of mitochondrial myopathies. Milone M, Wong LJ. Mol Genet Metab. 2013 Sep-Oct;110(1-2):35-41. PMID: 23911206

Mutations in SCO2 are associated with a distinct form of hypertrophic cardiomyopathy and cytochrome c oxidase deficiency. Jaksch M, Ogilvie I, Yao J, Kortenhaus G, Bresser HG, Gerbitz KD, Shoubridge EA. Hum Mol Genet. 2000 Mar 22;9(5):795-801. PMID: 10749987

Phenotypic consequences of a novel SCO2 gene mutation. Verdijk RM, de Krijger R, Schoonderwoerd K, Tiranti V, Smeets H, Govaerts LC, de Coo R. Am J Med Genet A. 2008 Nov 1;146A(21):2822-7. PMID: 18924171

Cytochrome c oxidase deficiency associated with the first stop-codon point mutation in human mtDNA. Hanna MG, Nelson IP, Rahman S, Lane RJ, Land J, Heales S, Cooper MJ, Schapira AH, Morgan-Hughes JA, Wood NW. Am J Hum Genet. 1998 Jul;63(1):29-36. PMID: 9634511

OMIM: 516050

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