Mitochondrial complex III deficiency

Alternate names

Complex 3 mitochondrial respiratory chain deficiency

Definition

Mitochondrial complex III deficiency is a genetic condition that can affect several parts of the body, including the brain, kidneys, liver, heart, and the muscles used for movement (skeletal muscles).

Epidemiology

The prevalence of mitochondrial complex III deficiency is unknown, although the condition is thought to be rare.

Onset

Signs and symptoms of mitochondrial complex III deficiency usually begin in infancy but can appear later.

Cause

• Mitochondrial complex III deficiency can be caused by mutations in one of several genes. The proteins produced from these genes either are a part of or help assemble a group of proteins called complex III.
• The two most commonly mutated genes involved in mitochondrial complex III deficiency are MT-CYB and BCS1L.
• It is likely that genes that have not been identified are also involved in this condition.
• Cytochrome b, produced from the MT-CYB gene, is one component of complex III, and the protein produced from the BCS1L gene is critical for the formation of the complex.
• Complex III is found in cell structures called mitochondria, which convert the energy from food into a form that cells can use.
• Complex III is one of several complexes that carry out a multistep process called oxidative phosphorylation, through which cells derive much of their energy.
• As a byproduct of its action in oxidative phosphorylation, complex III produces reactive oxygen species, which are harmful molecules that can damage DNA and tissues.

Gene mutations

• MT-CYB and BCS1L gene mutations impair the formation of complex III molecules.
• As a result, complex III activity and oxidative phosphorylation are reduced.
• Researchers believe that impaired oxidative phosphorylation can lead to cell death by reducing the amount of energy available in the cell.
• It is thought that tissues and organs that require a lot of energy, such as the brain, liver, kidneys, and skeletal muscles, are most affected by a reduction in oxidative phosphorylation.
• In addition, for unknown reasons, BCS1L gene mutations lead to increased overall production of reactive oxygen species, although production by complex III is reduced.
• Damage from reduced energy and from reactive oxygen species likely contributes to the signs and symptoms of mitochondrial complex III deficiency.
• Unlike most genes, the MT-CYB gene is found in DNA located in mitochondria, called mitochondrial DNA (mtDNA). This location may help explain why some people have more severe features of the condition than others. Most of the body's cells contain thousands of mitochondria, each with one or more copies of mtDNA.
• These cells can have a mix of mitochondria containing mutated and unmutated DNA (heteroplasmy).
• When caused by MT-CYB gene mutations, the severity of mitochondrial complex III deficiency is thought to be associated with the percentage of mitochondria with the gene mutation.
• The other genes known to be involved in this condition are found in DNA packaged in chromosomes within the cell nucleus (nuclear DNA). It is not clear why the severity of the condition varies in people with mutations in these other genes.

Inheritance

• Mitochondrial complex III deficiency is usually 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.
• In some cases caused by mutations in the MT-CYB gene, the condition is not inherited; it is caused by new mutations in the gene that occur in people with no history of the condition in their family.
• Other cases caused by mutations in the MT-CYB gene are 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

• The signs and symptoms of mitochondrial complex III deficiency are not the same for each affected individual, because a person with mitochondrial disease can have a unique mixture of healthy and defective mitochondria, with a unique distribution in the body.
• Several forms of mitochondrial complex III deficiency have been identified, and they are generally grouped based on the age of onset, nature and severity of symptoms.
• The most severe form begins in infancy and causes life-threatening muscle and nervous system dysfunction (encephalomyopathy), lactic acidosis at birth, hypotonia (poor muscle tone), dystrophic posturing, seizures, and coma. Ragged-red fibers, a characteristic microscopic abnormality observed in muscle biopsy, are commonly present with this form.
• In some individuals, encephalomyopathy does not begin until childhood or adulthood. For these individuals, symptoms may include various combinations of weakness, short stature, ataxia (inability to coordinate muscle movements), dementia, hearing loss, sensory neuropathy, pigmentary retinopathy (a disorder of the retina characterized by deposits of pigment and vision loss), and possible lactic acidosis or other features. Ragged-red fibers are common in these individuals as well.
• Individuals with a less severe type may have myopathy with exercise intolerance that progresses to general weakness. Ragged-red fibers and lactic acidosis may be present.
• A fourth described form is characterized by infantile histiocytoid cardiomyopathy. This is a condition characterized by cardiomegaly (enlarged heart), severe cardiac arrhythmias or sudden death, and the presence of histiocyte-like cells within the heart muscle.

NIH genetic and rare disease info

• NIH info on Mitochondrial complex III deficiency

Mitochondrial complex III deficiency is a rare disease.

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