Cytochrome c oxidase deficiency

Other Names: Mitochondrial complex IV deficiency; Complex 4 mitochondrial respiratory chain deficiency; Deficiency of mitochondrial respiratory chain complex4; COX deficiency; Complex IV deficiency

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.

Types

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.

Epidemiology

In Eastern Europe, cytochrome c oxidase deficiency is estimated to occur in 1 in 35,000 individuals. The prevalence of this condition outside this region is unknown.

Cause

• Mutations in more than 20 genes have been found to cause cytochrome c oxidase deficiency. Most genes are found in DNA in the cell's nucleus (nuclear DNA). However, some genes are found in DNA in specialized cell structures called mitochondria. This type of DNA is known as mitochondrial DNA (mtDNA). Most cases of cytochrome c oxidase deficiency are caused by mutations in genes found within nuclear DNA; however, in some rare instances, mutations in genes located within mtDNA cause this condition.
• The genes associated with cytochrome c oxidase deficiency are involved in energy production in mitochondria through a process called oxidative phosphorylation. Mutations in these genes affect an enzyme complex called cytochrome c oxidase, which is responsible for one of the last steps in oxidative phosphorylation.
• Cytochrome c oxidase is made up of two large groups of enzymes (complexes) called holoenzymes, which are each composed of multiple protein parts (subunits). Many other proteins are involved in assembling these subunits into holoenzymes.
• In most cases, cytochrome c oxidase deficiency is caused by mutations that alter the proteins that assemble the holoenzymes. As a result, the holoenzymes are either partially assembled or not assembled at all. Without complete holoenzymes, cytochrome c oxidase cannot form. Less frequently, mutations alter the holoenzyme subunits, leading to a nonfunctional version of cytochrome c oxidase. Whether cytochrome c oxidase is not formed or not functional, this missing enzyme complex disrupts the last step of oxidative phosphorylation, causing a decrease in energy production.
• Researchers believe that impaired oxidative phosphorylation can lead to cell death by reducing the amount of energy available in the cell. Certain tissues that require large amounts of energy, such as the brain, muscles, and heart, seem especially sensitive to decreases in energy. Cell death in these and other sensitive tissues likely contribute to the features of cytochrome c oxidase deficiency.

Inheritance

Cytochrome c oxidase deficiency can have different inheritance patterns depending on the gene involved.

When this condition is caused by mutations in genes within nuclear DNA, it is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

When this condition is caused by mutations in genes within mtDNA, it is inherited in a mitochondrial pattern, which is also known as maternal inheritance. This pattern of inheritance applies to genes contained in mtDNA. Because egg cells, but not sperm cells, contribute mitochondria to the developing embryo, children can only inherit disorders resulting from mtDNA mutations from their mother. These disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass traits associated with changes in mtDNA to their children.

Signs and symptoms

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.

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.

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.

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.

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

Treatment

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. Treatment generally does not reverse any damage that has already occurred.

Prognosis varies depending on the form of COX deficiency present. 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.

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. Dietary supplements including certain vitamins and cofactors have shown varying degrees of benefit in individual cases. Individuals interested in specific management recommendations for themselves or relatives should speak with their healthcare providers.

NIH genetic and rare disease info

• NIH info on Cytochrome c oxidase deficiency

Cytochrome c oxidase deficiency is a rare disease.

Cytochrome c oxidase deficiency Resources
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