Mitochondrial chain respiratory complex IV

What else is it called?

Mitochondrial chain respiratory complex IV (MCRIV) is also known as: 

  • Mitochondrial complex IV deficiency  
  • Complex 4 mitochondrial respiratory chain deficiency  
  • Deficiency of mitochondrial respiratory chain complex 4 
  • COX deficiency  
  • Complex IV deficiency  
  • Lethal neonatal cardiomyopathy hypertrophic due to cytochrome c oxidase deficiency  

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What causes it?

MCRIV is caused by a problem in at least 14 genes. These genes provide the instructions for the production of the cytochrome C oxidase enzyme. This enzyme is needed in the mitochondria in order to convert food into energy for your body to use in order to do every-day tasks. If you have a problem in these genes, then you will not be able to produce enough of the cytochrome C oxidase enzyme, therefore you will be unable to convert food into energy for your body and MCRIV develops. 

How common is it?

The overall incidence rate of all of the forms of this disorder is unknown but the French-Canadian form of the disorder has an estimated occurrence of 1 in 2,473 births 

What are the signs and symptoms?

This disorder usually can present during infancy to childhood. There are currently four known forms of MCRIV, each form has a range of different signs and symptoms. This is because there is a unique distribution of healthy mitochondria to defective mitochondria in each affected person. The current four forms are: 

  • Benign Infantile mitochondrial myopathy  
  • Infantile mitochondrial myopathy  
  • Leighs disease  
  • COX deficiency French-canadian type 


Benign Infantile mitochondrial myopathy may present many of the same symptoms as those with the more severe infantile form of this disorder as this the COX deficiency is generally found in the skeletal muscles. However, those with this form of the disorder do not have heart or kidney dysfunction. 


Infantile mitochondrial myopathy affects the muscles in the body, and it is usually characterised by muscle weakness and heart and kidney abnormalities and high levels of lactic acid in the blood. This disorder is usually coupled with De Toni Fanconi Debre syndrome which adds addition symptoms such as: excessive thirst and excessive urination. 


Leighs disease is a progressive illness which is characterised by progressive degeneration of the brain and progressive dysfunction of the other organs within the body, for example the heart, kidneys, muscles and the liver. Other symptoms can include loss of motor skills, loss of appetite, vomiting, irritability, high lactic acid in the blood and seizures.  

COX French Canadian type deficiency affects the brain, liver and muscles. Children and infants with this disease may present developmental delays for example, failure to thrive, diminished muscle tone, crossing of the eyes, lactic acid in the blood. 

The general signs and symptoms of MCRIV are:  

  • Enlarged liver (hepatomegaly)
  • Glycosuria   
  • High palate 
  • Anaemia  
  • Decreased liver function 
  • Intellectual disability  
  • Increased lactate in the body  
  • Motor delay  
  • Decreased muscle tone 
  • Seizures  
  • Muscle weakness  
  • Drooping upper eyelid 

If untreated this disorder can become life-threatening, also depending on the age of the individual with the disease the more severe the condition will be. Unfortunately, individuals with more severe cases of this disease usually die during infancy, but people with less severe cases live onto adulthood. However, unfortunately life expectancy cannot be predicted for a particular child.  

How is it diagnosed?

A doctor can diagnose MCRIV using an individual’s medical history, symptoms, nature of disease and the doctor may also take bodily samples to take to do laboratory tests. There are a number of countries that are currently running diagnostic tests on this form of the mitochondrial disease, these countries are:  

  • Austria 
  • Belgium 
  • Canada 
  • Estonia  
  • France 
  • Germany  
  • Italy  
  • Netherlands 
  • Portugal 
  • Spain 
  • Sweden  
  • Switzerland 
  • United Kingdom 

Can it be treated?

MCRIV can be treated using an orphan drug known as alpha-tocotrienol quinone which is also known as vatiquinone, which is currently available in Europe and the USA. In the USA this orphan drug is being used to treat mitochondrial membrane transport disorders and the mitochondrial oxidative phosphorylation disorder and in Europe this orphan drug is being used to treat leigh syndrome. 

Do my family need to be tested?

Depending on the gene affected this disorder can either be an autosomal recessive inherited metabolic disease or mitochondrial inherited.  

As an autosomal recessive inherited metabolic disorder which means that for a person to inherit this disorder, they will need to inherit it from their parents. Humans are made up of 46 chromosomes and we inherit 23 chromosomes from each parent, in the form of the egg and sperm which combine to determine the characteristics of the child. Every human being has two copies of the genes which are needed in order to produce the cytochrome C oxidase enzyme. If both of these genes are faulty then MCRIV will develop. The parents do not necessarily need to suffer from MCRIV they can be carriers, carriers are people who carry one faulty gene for a particular protein, and they do not develop the disease because the other gene works correctly.  

In the event that both of the parents are carriers of MCRIV. There is a: 

  • 25% chance that one of the children will be unaffected by MCRIV and will not be a carrier. 
  • 25% chance that the child will inherit MCRIV.  
  • 50% chance that the child will be unaffected by MCRIV and will be a carrier.     

As a mitochondrial inherited disease. Each mitochondrion (a single celled mitochondria) is made up of DNA which is known as mitochondrial DNA which has genes that provide information to make proteins. If these genes are faulty then the mitochondrial proteins will not be made correctly, or possibly not at all. For a child to inherit a disease via mitochondria inheritance they will need to inherit faulty genes from their mother. If the father has been affected with the mitochondrial disorder, he will be unable to pass the disease onto the children.  

Relevant Organisations


References are available on request. Please contact Helen Morris by phoning 0845 241 2173 or emailing [Resource Library No: AAP002]. 

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