Genetic screening for mitochondrial respiratory chain defects

Mitochondrial respiratory chain defects affect metabolism in the muscle cells. Healthy people have four protein complexes that turn oxygen molecules into molecules called ATP.

ATP is a molecule that supplies energy to the muscle cells. Without it, muscle function is impaired. For the respiratory chain to function normally, all protein comprising these complexes must function properly. When one of these complexes is impaired, it can be demonstrated by measuring enzyme activity of each complex from a biopsy of muscle tissue. 

Generally, all genetic disorders leading to respiratory chain defects clinically manifest in a similar way (weakening of various muscles in the body). In these disorders, a gradual deterioration occurs, leading to outbreaks that become more severe with time. The most common types of this disorder are caused by a deficiency in complex 1 or complex 4 but may also result from deficiencies in complexes 2 or 3.


Respiratory chain disorder symptoms

Respiratory chain disorder symptoms may vary. One of the main symptoms is muscle fatigue caused by insufficient energy supply. In many cases, a significant deterioration occurs over time which leads to impairments in the heart muscles and respiratory function. Certain cases also include defects of the nervous system.

33% of cases include a deficiency in complex I, 28% of cases include a deficiency in complexes I and IV, and 28% of cases include a deficiency in complex IV.

Complex I deficiency symptoms: symptoms include death during infancy, heart defects, rapid loss of eyesight during childhood or adulthood, Parkinson’s disease, neurological disorders, and more.

Complex IV deficiency symptoms: symptoms include cardiomyopathy, liver dysfunction, kidney defects, death during early infancy, muscle weakness, and more.


How are these diseases inherited?

The complexes in the cell respiratory chain comprise various types of protein, some are coded to the genes in the chromosomes while others are coded to mitochondrial DNA (that exists exclusively in females). When the disorder is caused by a defect in the proteins originating from the cell nucleus, it will have an autosomal recessive inheritance pattern. However, when the disorder is caused by defects in the mitochondrial protein it has a mitochondrial inheritance pattern.


What is mitochondrial inheritance?

Mitochondria are organelle present in all our body’s cells, that generate energy necessary for the cell’s function. They are sometimes called “the powerhouse of the cell”. Mitochondria is inherited exclusively from one’s mother. Therefore, only mothers can pass on mitochondria defects to their children.

However, the level of manifestation depends on the number of defected mitochondria that are passed down to the fetus. In certain cases, healthy women carrying few defected mitochondria may have children with a severe form of the disease since they passed down many defected mitochondria.


Genetic screening for mutations causing mitochondrial respiratory chain disorders

Since there are many genetic components to these disorders (many of which are yet to be fully researched) there is currently no genetic screening test for carriers of the disorders in general population. For example, complex I comprises no less than 43 different proteins, 36 of which are coded by chromosomes in the cell nucleus and the rest originate in the mitochondria. Each of the sub-units produced by the genes in the nucleus is produced by a different gene, the relevant genes are yet to be discovered.

Therefore, genetic diagnosis is only possible when the specific gene mutation was detected in another family member. In addition, diagnosis is based on clinical manifestation and analysis of muscle tissue samples that show enzyme deficiency that is typical to the specific disorder.


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