Complex IV Deficiency

Mitochondria are parts of a cell that help turn the energy we get from food into energy that the body can use. They are also important in the communication between body parts and creating other materials the body needs. Mitochondrial conditions can cause a variety of signs and symptoms in many parts of the body, particularly those that use a lot of energy like muscles and the brain.

The respiratory chain, also called the electron transport chain (ETC), helps a cell create energy (in the form of ATP) using oxygen. Mitochondrial respiratory chain disorders (MRCDs) are a group of conditions that happen when one of the five complexes, or pieces, of the respiratory chain doesn’t work as well as it should. Complex IV deficiency is related to the fourth step in the ETC. To learn more about the respiratory chain, please click here.

• Complex 4 deficiency
• Cytochrome C Oxidase Deficiency
• COX deficiency
• Deficiency of mitochondrial respiratory chain complex IV

Changes in over 20 genes have been associated with complex IV deficiency, both in the DNA inherited from both parents (nuclear DNA) and genes inherited in the mitochondria (mitochondrial DNA). Both males and females can have complex IV deficiency. People with the same genetic cause for complex IV deficiency can also have different symptoms or be more severely affected than others, even in the same family.

Complex IV deficiency usually happens when there are changes in both copies of a related gene (autosomal recessive inheritance). Someone who has a change in only one copy of a related gene is called a carrier. Carriers for some genes related to complex IV deficiency can be at an increased risk for certain types of cancer. If both parents are carriers, there is a 1 in IV chance with each pregnancy that their child will have complex IV deficiency.

When complex IV deficiency is caused by a change in one of the related mitochondrial genes, it is mitochondrially inherited. Mitochondria are inherited from the mother through her eggs. People typically do not inherit any mitochondria from sperm, making it very unlikely for mitochondrial conditions to be passed down from a father.

In Eastern Europe, around 1 in 35,000 people has complex IV deficiency. In the French-Canadian population of the Saguenay-Lac-Saint-Jean region of northeastern Quebec around 1 in 2,573 babies has the French-Canadian type of complex IV deficiency. The number of people who have complex IV deficiency in other parts of the world is unknown.

Complex IV deficiency causes a range of signs and symptoms. These may differ greatly, so always check with your provider if new symptoms appear or you are concerned.

There are four main types of complex IV deficiency:

Infantile mitochondrial myopathy type
This severe form of complex IV deficiency causes skeletal muscle features as well as heart disease, kidney disease, and high levels of lactate in the blood (lactic acidosis). Some babies have De Toni-Fanconi-Debre syndrome which can cause extreme thirst, urination and loss of sugars and other substances in the urine.

Benign infantile mitochondrial myopathy type
Babies with this type of complex IV deficiency have skeletal muscle symptoms but do not typically have heart or kidney disease.

French-Canadian type
This type of complex IV deficiency affects skeletal muscles, connective tissues, the brain and the liver. Children can also have delays, low muscle tone (hypotonia), eye features (strabismus), Leigh’s disease, and episodes of lactic acidosis.

Leigh’s syndrome (subacute necrotizing encephalomyelopathy)
This regressive form of complex IV deficiency causes degeneration of many organs in the body including the muscles, heart, kidneys, and liver. More details about Leigh’s Syndrome.

Complex IV deficiency can be diagnosed by:

• Blood tests looking at the activity of complex IV, levels of lactate, overall metabolic function and others
• Taking a small piece of muscle to look for changes in the mitochondria (muscle biopsy)
• Genetic testing for genes known to cause complex IV deficiency
• A detailed physical exam and medical history
• Imaging tests like MRIs or CTs to look for changes in the brain and other parts of the body

Complex IV deficiency is not included on newborn screening panels.

No

Before beginning any treatment or therapy, please consult with your physician.

There is currently no FDA-approved therapy for complex IV deficiency. Treatment and management of complex IV deficiency is symptomatic and supportive. This may include:

• Physical therapy
• Medications and/or surgeries based on symptoms
• Avoidance of mitochondrial toxins like certain drugs, tobacco and alcohol
• Mitochondrial supplements
• Special schooling arrangements

Individuals living with complex IV deficiency typically work with several healthcare providers regularly based on their symptoms, which may include:

• Metabolic specialist or geneticist
• Dieticians (diet and nutrition)
• Physical, speech, and occupational therapists
• Neurologists (muscles and brain)
• Cardiologists (heart)
• Pulmonologists (lungs)
• Nephrologists (kidneys)
• Hepatologists (liver)

It is important that all those living with or caring for someone with complex IV deficiency have an emergency protocol letter. These letters, which are written and signed by a doctor, share details about prescribed treatment during a crisis and in emergency room settings.

• Cardiology
• Hematology
• Neurology
• Nutritionist
• Physical and occupational therapy
• Registered dietitian

• Cytochrome C Oxidase Deficiency – Symptoms, Causes, Treatment | NORD
• Cytochrome c oxidase deficiency: MedlinePlus Genetics

Connecting with others impacted by a rare disease allows for vital information to be shared about day-to-day life, prevents isolation, and gives hope. Please contact MitoAction for peer support opportunities at 888-MITO-411 or email mito411@mitoaction.org.

Other resources we recommend are:

• New Patient Kit for Mitochondrial Conditions
• Planning and Preparation
• Monthly Expert Series
• Energy in Action Podcast