What are the other Names for this Condition? (Also known as/Synonyms)

• Complex 4 Mitochondrial Respiratory Chain Deficiency
• COX Deficiency
• Mitochondrial Complex IV Deficiency

What is Cytochrome C Oxidase Deficiency? (Definition/Background Information)

• 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:
  • IBenign infantile mitochondrial type
  • French-Canadian type
  • Infantile mitochondrial myopathy type
  • Leigh syndrome
• 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
• Cytochrome C Oxidase 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

(Source: Cytochrome C Oxidase Deficiency; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Who gets Cytochrome C Oxidase Deficiency? (Age and Sex Distribution)

• Cytochrome C Oxidase Deficiency is a congenital disorder. The presentation of symptoms may occur at birth
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Cytochrome C Oxidase Deficiency? (Predisposing Factors)

• A positive family history may be an important risk factor, since Cytochrome C Oxidase Deficiency is an inherited condition

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Cytochrome C Oxidase Deficiency? (Etiology)

• Cytochrome C Oxidase Deficiency is caused by mutations in any of at least 14 genes
• The inheritance pattern depends on the gene involved

(Source: Cytochrome C Oxidase Deficiency; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

What are the Signs and Symptoms of Cytochrome C Oxidase Deficiency?

There are currently 4 known forms of Cytochrome C Oxidase 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.

In general, the signs and symptoms of Cytochrome C Oxidase Deficiency may include:

• Aminoaciduria
• Anemia, due to low red blood cell count
• Ataxia
• Cytochrome C oxidase-negative muscle fibers
• Decreased liver function
• Exercise intolerance
• Exertional dyspnea
• Failure to thrive
• Glycosuria
• Hepatomegaly or swollen liver
• Hyperphosphaturia
• Hypertrophic cardiomyopathy
• Increased CSF lactate
• Increased hepatocellular lipid droplets
• Increased intramyocellular lipid droplets
• Increased serum lactate
• Intellectual disability
• Lactic acidosis
• Motor delay
• Muscular hypotonia
• Optic atrophy
• Pigmentary retinopathy
• Proteinuria
• Ptosis or drooping eyelids
• Renal Fanconi syndrome
• Renal tubular dysfunction
• Respiratory distress
• Respiratory insufficiency due to muscle weakness
• Seizures
• Sensorineural hearing impairment

(Source: Cytochrome C Oxidase Deficiency; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is Cytochrome C Oxidase Deficiency Diagnosed?

Cytochrome C Oxidase Deficiency is diagnosed on the basis of the following information:

• Complete physical examination
• Thorough medical history evaluation
• Assessment of signs and symptoms
• Laboratory tests
• Imaging studies
• Biopsy studies, if necessary

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Cytochrome C Oxidase Deficiency?

The complications of Cytochrome C Oxidase Deficiency may include:

• Severe respiratory distress
• Failure to thrive
• Hypertrophic cardiomyopathy
• Organ dysfunction (lungs, kidney and heart)

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Cytochrome C Oxidase Deficiency Treated?

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
• 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

(Source: Cytochrome C Oxidase Deficiency; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How can Cytochrome C Oxidase Deficiency be Prevented?

Currently, Cytochrome C Oxidase Deficiency may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of Cytochrome C Oxidase Deficiency? (Outcomes/Resolutions)

There are varying degrees of severity in Cytochrome C Oxidase Deficiency. Prognosis varies depending on the form of COX Deficiency present.

• Individuals with more severe cases may die during infancy, while those with less severe cases have lived into adulthood
• 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
• It is generally not possible to predict the life expectancy of any particular child. Individuals interested in specific management recommendations should speak with their healthcare providers

(Source: Cytochrome C Oxidase Deficiency; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Additional and Relevant Useful Information for Cytochrome C Oxidase Deficiency:

Cytochrome C Oxidase Deficiency is also known by the following names:

• Complex IV Deficiency
• Deficiency of Mitochondrial Respiratory Chain Complex 4

The following DoveMed website link is a useful resource for additional information:

https://www.dovemed.com/diseases-conditions/rare-disorders/