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Muscle diseases arising from disorders in the muscle respiratory chain complexes

These are metabolic disorders of the muscle arising from a defect in the complexes that provide the energy for the muscle. These complexes are composed of a large number of different proteins, and the activity of the complex depends on the correct functioning of all these proteins. The metabolic activity can be demonstrated by testing the activity of the complexes constituting the enzymes of the muscle respiratory chain, which turns oxygen from the air that is breathed into a chemical molecule called ATP, which delivers energy to the muscles.

This is a group of diseases with similar clinical presentations. There is progressive muscle weakness and also involvement of other systems in the body. Paroxysmal episodes of metabolic acidosis that follow regression in function, both motor and developmental, sometimes occur following a feverish disease or even a regular infection.

There are a number of major types:
  • Complex 1 deficiency

  • Complex 4 deficiency

  • Deficiency in other complexes (complex 2 or 3) and other muscle metabolism disorders. These are less common.

Clinical signs

There are a wide variety of clinical signs in these diseases.

Most types of deficiencies in the muscle respiratory chain enzymes eventually manifest as muscular weakness.

In a large proportion of cases there is significant exacerbation over time, and some types progress to respiratory muscle disorders and the need for permanent supportive therapy and prolonged ventilation.

In other patients there is advanced impairment of the function of the heart muscle. Sometimes the disease has a systemic effect, manifesting as severe metabolic acidosis and extensive neurological involvement progressing through to death.

The clinical presentation of complex 1 deficiency is diverse, and differing clinical pictures are described, as follows:

  • Severe course leading to death in infancy - in some cases there is metabolic acidosis (increased levels of lactic and pyruvic acid in the blood), dysfunction of the heart muscle, etc.

  • Degenerative disorders of the nervous system, appearing at different ages (known as LEIGH syndrome).

  • Rapid loss of vision (within 1-2 weeks) in childhood to adolescence (known as LHON syndrome).

  • Parkinsonism.

The clinical presentation of complex 4 deficiency is also diverse, and differing clinical pictures are described, as follows:
  • Severe course leading to death in infancy - in some cases there is metabolic acidosis (increased levels of lactic and pyruvic acid in the blood), dysfunction of the heart muscle, etc.

  • Muscle weakness only.

  • Cardiomyopathy (dysfunction of the heart muscle within an increased heart muscle mass, etc.).

  • Degenerative disorders of the nervous system, appearing at different ages (known as LEIGH syndrome).

  • Hepatic insufficiency and secondary loss of consciousness (hepatic encephalopathy).

  • Abnormal kidney function causing problems in concentration of the urine.

Due to the diverse clinical presentations, many of which can be caused by other conditions that have nothing to do with defects in the muscle respiratory chain, diagnosis is not easy, and a muscle biopsy should be performed.

A precise diagnosis is important, and a diagnosis made in the past is not always accurate by today's standards. Because of this, the diagnosis must always be confirmed in a genetic institute by examining the patient, or at least by reviewing the results of neurological tests, laboratory and/or EMG results, and other data.

Even though we know a lot about the inheritance patterns, the risk of recurrence, the mechanism of the manifestations of the disease, etc., most of these diseases have exceptions, and each case/family must be examined individually in a genetic institute. It must be remembered that a diagnosis of disorders in the muscle respiratory chain is very difficult to make, and even if the clinical criteria stated above are present, the diagnosis cannot necessarily be confirmed by the diagnostic methods and techniques available today.

Inheritance pattern

As noted above, the muscle respiratory chain complexes are composed of more proteins than the other enzymes in our body. This impedes our understanding of the genetic basis of these diseases. Essentially, the proteins and genes comprising these complexes are derived from 2 main sources:
  1. The nucleus of the cell.

  2. The mitochondria.

These organelles are the respiratory organs of the cell that provide the energy for muscle cells.

Depending on in which of these sources the genetic defect is located, the inheritance pattern of the diseases can be established.

In diseases in which the defect is in proteins/genes originating from the cell nucleus, the disease is transmitted by autosomal recessive inheritance. It appears that most diseases in this group are caused by a defect in the nuclear component of the complex, i.e. the inheritance is autosomal recessive rather than mitochondrial.

In diseases in which the defect is in the proteins/genes originating from the mitochondria, the disease is transmitted by mitochondrial inheritance. Each cell has organelles known as mitochondria, which are responsible for important cellular activities. Their main function is to generate energy for the cell. Each cell has an average of 100 mitochondria. Most of the genetic material of the cell is concentrated in the nucleus, but mitochondria also have a small number of genes. The mitochondrial genes produce proteins that function in the mitochondria only, providing energy for the cell. During fertilization, only the mother contributes mitochondria to the embryo; the sperm cell contains only a nucleus and no mitochondria. Therefore the genes present in the mitochondria in the male will not be transmitted to the next generation since all the mitochondria in both male and female embryos are of maternal origin. The expression of a defect in the genetic material in the mitochondria also depends on the percentage of mitochondria that contain the defect. This means that a situation may arise in which a woman with only a few defective mitochondria will be healthy, but she may give birth to a number of affected children because they have received a high percentage of the mitochondria containing the defect.

Penetrance

The penetrance of the disease is usually full, although there are patients in whom the disease may be mild and not always expressed. This depends on the percentage of affected mitochondria the patient has as compared to normal ones.

Associated features that can be demonstrated in tests performed during pregnancy

In the autosomal recessive types, the presence of an abnormal gene can be demonstrated by an enzyme activity test by taking a biopsy from the patient's skin. If the enzyme is absent in the patient's skin, it is recommended that the mother undergo amniocentesis in each subsequent pregnancy in order to measure the enzyme activity in the amniotic fluid cells. In families in whom the genetic defect has been identified at the DNA level, i.e. the mutation in a specific gene has been found, a reliable test can be performed in the fetus if the geneticist assesses that there is a high risk that the fetus will be affected. The condition cannot be diagnosed by ultrasound examination in pregnancy or by regular amniocentesis.

In the types transmitted by mitochondrial inheritance, the risk of recurrence in a couple who has or has had an affected child is up to 100%, and it is not possible to test for this in subsequent pregnancies. In these cases it is possible at the present time to offer ovum donation. Attempts are currently underway to insert the nucleus of the mother's ovum into the cytoplasm of the ovum of another healthy woman with normal mitochondria. If this procedure will be possible in the future, it will be the ideal solution, for the couple's genetic constitution will remain their own, and their children will not inherit the mother's abnormal mitochondrial genes.

What is the risk of recurrence in a subsequent pregnancy?

In the type transmitted by autosomal recessive inheritance, a couple that has already had an affected child has a 25% recurrence risk in every pregnancy. Other family members do not have a high risk (usually less than 1%); this can be determined within genetic counseling for each person individually according to their pedigree.

In the type transmitted by mitochondrial inheritance, every couple that already has an affected child has a risk of up to 100% of having another child with the same condition. Other female relatives who are maternally related to the affected patient are also at a certain risk of having an affected child.

In each type, the exact risk for distant relatives of patients depends on the number of patients in the family, the degree of relatedness of the applicants to affected family members, consanguinity (blood relationship) between the partners, if present, etc., and can be ascertained in genetic counseling.

Molecular genetic information:

The gene for the diseases and the location of the genes
For a deletion in complex 1:
  • 36 subunits in this complex originate from the cell nucleus - each of these is encoded by another gene situated in the nucleus. A defect in the genes of these 36 subunits causes a decrease in the activity of complex 1, which is transmitted by autosomal recessive inheritance. Genes in which mutations have been found that are responsible for the defects in complex 1 include: NDUFV1, NDUFS1, NDUFS2, NDUFS4, NDUFS7, NDUFV2, NDUFS8, etc.

  • 7 subunits in this complex originate from the mitochondria in the cytoplasm - each of these is encoded by a different gene in the mitochondria, and a defect in them causes a decrease in the activity of complex 1 that is transmitted by mitochondrial inheritance: mitochondrial genes containing mutations responsible for the defects in complex 1 are called subunits ND1-7.

For a deletion in complex 4:
  • 10 subunits in this complex are encoded by genes in the cell nucleus - a defect in them causes a decrease in the activity of complex 4 that is transmitted by autosomal recessive inheritance. Mutations have not yet been found in the genes for these 10 subunits.

  • Apparently there are a number of genes in the cell nucleus that participate in the complex 4 assembling and building process, even though they are not part of the complex itself. It has been found that a defect in them causes a decrease in the activity of complex 4 that is transmitted by autosomal recessive inheritance. The majority of the cases of complex 4 deficiency result from this. The genes that have been found to be involved in the complex 4 defect in this group are: COX10, SCO1, SCO2 and SURF1.

  • 3 subunits in this complex are encoded by genes in the mitochondria, and a defect in them causes a decrease in the activity of complex 4 that is transmitted by mitochondrial inheritance. Genes in which mutations that are responsible for the complex 4 defect have been found are called subunits CO1-3. Defects in the mitochondrial subunits are relatively rare in sporadic cases (a single case in a family).

It appears that the clinical manifestations of this complex also differ among the different groups; the autosomal recessive inheritance types where the gene is in the nucleus of the cell are more severe, and usually lead to death in infancy.

Diagnostic testing

It is possible to carry out testing in some cases by measuring the level of activity of the enzymes in the muscle respiratory chain. For patients with the muscular defect, those with the autosomal recessive type usually demonstrate the enzyme defect in the skin too, whereas those with the mitochondrial inheritance type do not usually demonstrate the enzyme defect in the skin. The identification of the genetic defect at the DNA level, i.e. finding the mutation in the specific gene responsible for the disease in a specific patient, is still complex and complicated, because there are many possible genes. This is currently carried out in a research setting in a number of centers in the world, and the tests can be performed through genetic institutes. See: Indirect testing of genetic markers with a number of patients in the family - when there are a number of different genes, each of which can cause the disease - all the genes have been located / detected / mapped - autosomal recessive disease

Carrier testing

In families in whom the gene responsible for the disease has been located and the mutation identified, other family members can be examined for signs of the disease or carrier status.

Fetal testing

As for diagnostic testing. If a reduced level of the enzyme has been found in the skin of the affected child in a family, the same enzyme activity level test can be performed on the amniotic fluid cells of the fetus, in which case the test is fairly reliable, although not completely definitive. If the genetic defect itself has been found, reliable prenatal testing can be performed in each subsequent pregnancy of a couple with an affected child, and carrier tests may also be performed on all other family members if required.

 
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