|
|
|
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:
- The nucleus of the cell.
- 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.
|
|
|