Rare Pulmonology News

Disease Profile

Cytochrome c oxidase deficiency

Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.


US Estimated

Europe Estimated

Age of onset





Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease.


Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype.


dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.


recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.


Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.


Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.


Not applicable


Other names (AKA)

Mitochondrial complex IV deficiency; Complex 4 mitochondrial respiratory chain deficiency; Deficiency of mitochondrial respiratory chain complex4;


Metabolic disorders


Cytochrome C oxidase deficiency (COX deficiency) is a condition that can affect several parts of the body including the skeletal muscles, heart, brain and liver. There are four types of COX deficiency differentiated by symptoms and age of onset: benign infantile mitochondrial type, French-Canadian type, infantile mitochondrial myopathy type, and Leigh syndrome.[1] The range and severity of signs and symptoms can vary widely among affected individuals (even within the same subtype and same family) and depend on the form of the condition present. Features in mildly affected individuals may include muscle weakness and hypotonia; in more severely affected individuals, brain dysfunction; heart problems; an enlarged liver; lactic acidosis; and/or a specific group of features known as Leigh syndrome may also be present. COX deficiency is caused by mutations in any of at least 14 genes; the inheritance pattern depends on the gene involved. The condition is frequently fatal in childhood, but mildly affected individuals may survive into adolescence or adulthood.[2]


There are currently 4 known forms of COX deficiency. The range and severity of signs and symptoms can vary widely from case to case.

In one form, referred to as the benign infantile mitochondrial myopathy type, symptoms may be limited to the skeletal muscles. Episodes of lactic acidosis may occur and can cause life-threatening complications if left untreated. However, with appropriate treatment, individuals with this form of the condition may spontaneously recover within the first few years of life.[1]

In the second form of the disorder, referred to as the infantile mitochondrial myopathy type, the skeletal muscles as well as several other tissues (such as the heart, kidney, liver, brain, and/or connective tissue) are affected. Symptoms associated with this form typically begin within the first few weeks of life and may include muscle weakness; heart problems; kidney dysfunction; failure to thrive; difficulties sucking, swallowing, and/or breathing; and/or hypotonia. Affected infants may also have episodes of lactic acidosis.[1]

The third form of COX deficiency is thought to be a systemic form of the condition and is referred to as Leigh's disease. This form is characterized by progressive degeneration of the brain as well as dysfunction of several other organs including the heart, kidneys, muscles, and/or liver. Symptoms of this form, which predominantly involve the central nervous system, may begin between three months and two years of age and may include loss of previously acquired motor skills and/or head control; poor sucking ability; loss of appetite; vomiting; irritability; and possible seizures. Intellectual disability may also occur.[1]

In the fourth form of COX deficiency, the French-Canadian type, the brain (as in Leigh's disease) and liver are particularly affected in addition to the skeletal muscles and connective tissues. However, in this form, the kidneys and heart appear to have near-normal enzyme activity. Individuals with this form may have developmental delay; hypotonia; slight facial abnormalities; Leigh's disease; strabismus; ataxia; liver degeneration; and/or episodes of lactic acidosis.[1]

Although some mildly affected individuals survive into adolescence or adulthood, this condition is often fatal in childhood.[2]

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
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Percent of people who have these symptoms is not available through HPO
High urine amino acid levels
Increased levels of animo acids in urine

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Low number of red blood cells or hemoglobin
Autosomal recessive inheritance
Cytochrome C oxidase-negative muscle fibers
Decreased liver function
Liver dysfunction
Exercise intolerance
Decreased ability to exercise
Inability to exercise

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Exertional dyspnea
Failure to thrive
Faltering weight
Weight faltering

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Generalized hypotonia
Decreased muscle tone
Low muscle tone

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Global developmental delay
Glucose in urine
Enlarged liver
High palate
Elevated palate
Increased palatal height

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High urine phosphate levels
Hypertrophic cardiomyopathy
Enlarged and thickened heart muscle
Increased CSF lactate
Increased hepatocellular lipid droplets
Increased intramyocellular lipid droplets
Increased serum lactate
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific

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Lactic acidosis
Increased lactate in body
Mitochondrial inheritance
Motor delay
Muscular hypotonia
Low or weak muscle tone
Optic atrophy
Pigmentary retinopathy
High urine protein levels
Protein in urine

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Drooping upper eyelid
Renal Fanconi syndrome
Respiratory distress
Breathing difficulties
Difficulty breathing

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Respiratory insufficiency due to muscle weakness
Decreased lung function due to weak breathing muscles
Sensorineural hearing impairment
Weakness of facial musculature
Decreased facial muscle strength
Decreased strength of facial muscles
Face weakness
Facial muscle weakness
Facial weakness
Reduced facial muscle strength
Weakness of face

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There is currently no cure for cytochrome C oxidase (COX) deficiency. Management of all forms of COX deficiency generally focuses on the specific symptoms present in the affected individual and is largely supportive. The goals of treatment are to improve symptoms and slow progression of the disease; the effectiveness of treatment varies with each individual.[3][4] Treatment generally does not reverse any damage that has already occurred.[3] Prognosis varies depending on the form of COX deficiency present.[4] Individuals with benign infantile mitochondrial myopathy may experience spontaneous recovery (although early diagnosis and intensive treatment is still needed until this point), while there may be rapid demise in individuals with Leigh syndrome.[4]

It is often recommended that individuals with mitochondrial disorders such as COX deficiency avoid fasting. Dehydration due to vomiting or illness may be treated with intravenous fluid if the individual is not able to take fluids orally. Seizures are typically controlled with anticonvulsants. Some affected individuals may benefit from physical, occupational, and speech therapies that are specifically tailored to their needs.[3] Dietary supplements including certain vitamins and cofactors have shown varying degrees of benefit in individual cases.[4]

Individuals interested in specific management recommendations for themselves or relatives should speak with their healthcare providers.


Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Providing General Support

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    These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

    Where to Start

      In-Depth Information

      • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
      • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
      • PubMed is a searchable database of medical literature and lists journal articles that discuss Cytochrome c oxidase deficiency. Click on the link to view a sample search on this topic.


        1. Cytochrome C Oxidase Deficiency. NORD. 2015; https://www.rarediseases.org/rare-disease-information/rare-diseases/byID/1088/viewAbstract. Accessed 4/17/2013.
        2. Cytochrome c oxidase deficiency. Genetics Home Reference. October 2012; https://ghr.nlm.nih.gov/condition/cytochrome-c-oxidase-deficiency. Accessed 4/17/2013.
        3. Gropman AL. Diagnosis and treatment of childhood mitochondrial diseases. Curr Neurol Neurosci Rep. March 2001; 1(2):185-194.
        4. PATRICK F. CHINNERY. Chapter 429: Muscle Diseases. GOLDMAN'S CECIL MEDICINE, 24TH EDITION. Philadelphia, PA: Saunders; 2011;

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