Generality
Duchenne muscular dystrophy ( DMD ) is a genetic disorder, sometimes inherited, that affects the muscles. Patients lose muscle tone due to the absence of a fundamental protein: dystrophin .
Unfortunately, there is no cure for Duchenne muscular dystrophy. Current treatments can only alleviate symptoms and delay progression. However, the trial is active to find a specific therapy.
Chromosomes
To understand Duchenne muscular dystrophy, a premise is needed that describes the human chromosome set.
Every cell of a healthy human being contains 23 pairs of chromosomes. A pair of these chromosomes is sexual, that is, it determines the sex of the individual; the remaining 22 pairs, instead, are composed of autosomal chromosomes . In all, therefore, the human genome has 46 chromosomes.
CHROMOSOMAL ALTERATIONS
Each pair of chromosomes contains certain genes .
When a mutation occurs in a chromosome, a gene can be defective. This defective gene consequently expresses a defective protein.
When, on the contrary, the number of chromosomes varies, we speak of aneuploidy . In this case, instead of two, the chromosomes can be three (trisomy) or only one (monosomy).
THE SEXUAL CHROMOSOMES
Sexual chromosomes are essential in determining a person's gender, male or female. The woman has, in the cells of her body, two copies of the so-called X chromosome ; the man, on the contrary, presents an X chromosome and a Y chromosome . As for the autosomal chromosomes, also the sexual ones are inherited from the parents: a copy is given by the father, another by the mother. There are several genetic pathologies due to sexual chromosomes. They present either alterations in the chromosomal structure or changes in the number of chromosomes.
What is that?
Duchenne muscular dystrophy ( DMD ) is an inherited genetic disorder that weakens the body's muscles, which are responsible for movement. In medicine, this muscle weakness is called hyposthenia .
Although the patient is born with DMD, it appears during early childhood, between 2 and 5 years of age. At the beginning, the symptoms are mild and bearable; over the years, however, they become more serious and debilitating: the smooth muscles of the respiratory and circulatory systems are also involved.
WHAT ARE THE MUSCLES AFFECTED?
The targets of Duchenne muscular dystrophy are the voluntary muscles of the lower and upper limbs, having a part (proximal insertion) located close to the trunk. More precisely, they are the muscles that develop around the hips (quadriceps, ileopsoas, buttocks etc.) and at the shoulders (deltoid, pectoral, subscapular, etc.).
The first muscular deficits appear in the lower limbs. Only at a later time do they arise even on the higher ones.
Epidemiology
The incidence of Duchenne muscular dystrophy is about one in every 3, 500 newborns. In Italy, about 20, 000 people are affected.
There are several forms of dystrophy, but DMD is the most common.
It mainly affects the male sex. However, the disease also occurs in some women. The reason for this will be explained in the chapter on causes.
Causes
The cause of Duchenne muscular dystrophy is a genetic mutation affecting the sex chromosome X. In this chromosome, the dystrophin gene, an essential muscle protein, resides. The genetic mutation determines the complete absence of dystrophin in muscle tissue.
DYSTROPHINE
Dystrophin is a protein contained in the cells that make up the muscle fiber . It performs various functions, in particular:
- It combines the membrane of the muscle fiber, the sarcolemma, with the cell membrane and the extracellular matrix.
- It regulates the movements of the calcium ion inside the cell (NB: calcium is responsible for muscle contraction).
In the absence of dystrophin, therefore, these processes fail and the muscle cell undergoes a lethal oxidative stress .
PATHOGENESIS AND PATHOLOGICAL ANATOMY
Figure: dystrophin inside the muscle . From the site: actionduchenne.org
What exactly happens inside the muscular cell ( myocyte ) without dystrophin?
The control of calcium is lost and, to pay the consequences of this, are the mitochondria . Cell membranes, on the other hand, become fragile and break more easily. These events lead to the death ( necrosis ) of the muscle cell.
Moreover, the cellular repair and replacement mechanism is not fast enough, consequently a progressive deterioration of the situation is observed.
All this leads to the loss of muscle fibers, observed in the patient's hyposthenia, and the replacement of myocytes with connective tissue ( fibrosis ) and fat cells . The patient, in this state, shows some swollen muscles: the connective and adipose tissue are responsible. This is called pseudohypertrophy .
GENETICS
Why does Duchenne muscular dystrophy mainly affect the male sex?
The woman has two X chromosomes. If only one of the two chromosomes is mutated and does not produce dystrophin, the other X chromosome intervenes, the one still healthy, which compensates for the deficiencies of the first.
Instead, man has only one X chromosome in his cells. If this chromosome is mutated, there is no alternative source of dystrophin from which to draw. Therefore, this fundamental protein is completely absent and muscle disorders occur.
In fact, even some women with only one mutated X chromosome experience disorders similar to those of humans. The precise reason is currently under study.
INHERITANCE AND TRANSMISSION
Duchenne muscular dystrophy belongs to the category of genetic diseases, whose inheritance is linked to the X chromosome.
The woman, with a mutated X chromosome, is called a healthy carrier of the disease. This means that he can have a normal life and have children after joining a healthy man. However, children can inherit the mutated X chromosome and:
- If they are male, they have a 50% chance of being born either sick or healthy.
- If they are females, they have a 50% chance of being born or healthy or healthy carriers.
Figure: the union between a healthy carrier of Duchenne muscular dystrophy and a healthy male. Children have a 50% chance of inheriting the mutated X chromosome. A female can be healthy or a healthy carrier; a male can be healthy or sick. From the site: fsrmm.ch
NB: only the union between a female carrier and a healthy man is considered, as a sick man with DMD is not in a position to have a normal life.
Is the mother always healthy?
Thanks to modern genetic tests, we have seen that about half of the parents of DMD patients do not have any chromosomal abnormalities.
So when does the X chromosome change in children?
The hypothesis is that a spontaneous mutation occurs in the maternal oocyte or during embryonic development of the fetus.
Symptoms
To learn more: Duchenne Dystrophy Symptoms
Duchenne muscular dystrophy causes weakening ( hyposthenia ) and atrophy of the voluntary muscles, which depart from the trunk and allow movements of the lower and upper limbs.
The appearance of the first symptoms occurs between the 2nd and 4th year of life. After that, the state of health progressively worsens.
At the beginning, the patient has difficulty walking and running. Later, he also struggles to move his arms and neck. Between the ages of 10 and 20, hyposthenia progresses and affects almost all of the muscles, including involuntary-smooth ones.
Finally, even if they are less frequent, cognitive / behavioral deficits may arise.
MOTOR PROBLEMS
The characteristic motor manifestations are:
- Delay of the first steps (NB: it can also occur in healthy children)
- Difficulty walking, running, jumping and climbing, for hyposthenia of lower limb muscles
- The walk is rocking, similar to that of a goose. It is called "anserina" or "tilting" gait
- Hypostenia of the muscles of the upper limbs and neck
- Difficulty getting up from the ground. The patient "climbs" on himself, propping up his upper limbs and knees ( sign of Gower )
- Enlarged calves due to pseudohypertrophy
- Scoliosis and lumbar hyperlordosis, for hyposthenia of the hip flexor muscles
- Contractures due to prolonged immobility
Faced with these symptoms, the patient is confined to a wheelchair. The use of the wheelchair can begin as early as puberty.
COGNITIVE DISORDERS
Patients with DMD suffer in some cases from cognitive and behavioral deficits. The most common are dyslexia and attention deficit hyperactivity disorder ( ADHD ).
COMPLICATIONS
From the age of 8-10, the symptomatic picture of DMD patients begins to get complicated.
Hyposthenia affects all the muscles of the body, including involuntary-smooth ones. The respiratory muscles are weakened, those of the myocardium (the heart muscle), chewers, etc. The effects of these complications are dramatic: the patient breathes with difficulty and cannot feed.
Slowly, therefore, the motor abilities are progressively reduced and the forced immobility, which results from it, determines osteoporosis and various articular disorders. At the age of 20, patients are already severely debilitated and "physically" fragile.
The following table summarizes the main complications of Duchenne muscular dystrophy:
| Complications | Short description |
| Respiratory disorders | The respiratory muscles weaken. The patient has "shortness of breath" and is struggling to cough. Difficult cough predisposes to lung infections, as germs are no longer excreted. |
| Cardiac disorders | Cardiomyopathy, due to weak myocardium. The consequences are:
|
| Osteoporosis | The bones become weak, due to forced immobility and therapeutic treatment based on steroids |
| Digestive disorders |
|
| Joint disorders | Hyposthenia and immobility determine a tendon contraction. The tendon reflexes, in particular the achilleus, are lacking |
Diagnosis
A first diagnosis of Duchenne muscular dystrophy can be based on the observation of the aforementioned characteristic signs: in fact, the patient's "anserine" gait and how the latter rises from the ground (Gower's sign) are signs of hypostenia at the level of lower limbs.
There are also several laboratory tests, the outcome of which is to be considered very reliable.
They consist of:
- Blood tests
- Muscle biopsy
- Electromyography
- Genetic tests
BLOOD TESTS
An enzyme, creatine kinase (CK) is contained in the blood. Patients with DMD appear to have very high doses of creatine kinase, 10 to 100 times more than normal. Conversely, unaltered enzyme levels exclude Duchenne muscular dystrophy. Therefore, it is a reliable test, although it must be specified that any muscular dystrophy, not only that of Duchenne, causes an increase in creatine kinase.
MUSCULAR BIOPSY
Muscle biopsy is the next step in the creatine kinase test. In fact, the analysis of a sample of muscle tissue allows us to know the cells that make it up, the state of the muscle fibers and the levels of dystrophin. The section of a piece of muscle is performed under local anesthesia.
What characteristics must the biopsy have, to confirm the diagnosis of DMD?
- Complete absence of dystrophin (low levels characterize other forms of muscular dystrophy).
- Presence of fibro-adipose tissue, instead of muscular tissue (sign of pseudohypertrophy).
- Degenerated muscle fibers.
ELECTROMYOGRAPHY
Electromyography is used to evaluate action potentials, which trigger muscle contraction. The principle, on which this instrumental examination is based, is somewhat complicated. Suffice it to say that surface electrodes are used, which measure the capacity of the respiratory muscles.
GENETIC TESTS
Genetic tests show possible mutations of the genetic material (DNA), which makes up the chromosomes. They can be performed on a patient's blood sample, or before birth on a sample of amniotic fluid.
In the first case, a simple and quick withdrawal is performed.
In the second case, the advantage of a pre-natal diagnosis is countered by a danger to the health of the fetus linked to the procedure.
Treatment
Unfortunately, there is no specific therapy for Duchenne muscular dystrophy.
The treatment, to date, consists only in the control of the described symptoms, in order to improve the life of patients with DMD. Currently, some therapeutic approaches based on molecular biology techniques are being tested.
Control the symptoms of Duchennes muscular dystrophy means:
- Promote the patient's motor activity and slow down muscle weakness, also using:
- Physiotherapy and orthopedic equipment
- Steroid drugs
- Treat the effects of respiratory, cardiac, digestive and osteo-articular complications in a timely manner
THE ACTIVITY ? MOTORIA AND REHABILITATION
Both are fundamental, if one wants to slow down the atrophy and the weakening of the muscles.
Encouraging the patient to move, as far as possible, serves to maintain muscle tone and prevent some complications. In fact, physical exercise preserves from osteoporosis, constipation and scoliosis.
Constant physiotherapy, postural education and the use of special braces preserve, at least in part, joint, tendon and muscle mobility.
DRUGS
Patients with DMD take oral steroids (or corticosteroids ) to maintain muscle mass and strength. This treatment begins at the age of 5-8 years. Without this assumption, the muscles would encounter, very quickly, degeneration. The most commonly used steroids are prednisolone and deflazacort .
NB: one of the side effects of steroids is overweight . However, patients with DMD progressively lose muscle tone, therefore they are usually very "thin".
TREATMENT OF COMPLICATIONS AND PREVENTION
Respiratory and cardiac complications are the most dramatic consequences of Duchenne muscular dystrophy, as they seriously endanger the patient's life. Therefore, therapeutic and preventive countermeasures have been developed. These remedies consist of vaccinations, which protect against viral respiratory tract infections, drugs and portable breathing apparatus .
For the osteo-articular complications, the benefits of motor activity have already been mentioned. To these are added the treatments based on vitamin supplements and surgery.
Finally, digestive disorders can also require minor surgery and the use of certain drugs that facilitate digestion.
The following table shows the treatment and preventive measures of the most frequent complications.
| Complication | Treatment | Prevention |
| Respiratory disorders | Vaccines:
| Periodic checks:
|
| Cardiac disorders | Drugs for the treatment of cardiomyopathy:
| Periodic checks:
|
| Digestive disorders | drugs:
| High fiber diet |
| Osteoporosis | To make bones "stronger":
| Incentive motor activity |
| Joint disorders | Surgery:
| Incentive motor activity |
Prognosis
Duchenne muscular dystrophy significantly affects the length and quality of life of patients. Around 10 years old, you already need the wheelchair; at 20, respiratory and cardiac complications are more than advanced and often lead to death. The prognosis, therefore, is never positive.
However, advances in the field of medicine and physiotherapy have prolonged the life expectancy of patients. Today, the average life expectancy for an individual with DMD is 27-30 years. However, there are exceptions. Some patients, in fact, reach 40-50 years. This depends on several factors, such as: the severity of DMD (different from patient to patient), family care and timely treatment of complications.
Research
Understanding the mechanisms that cause disease is of great help in testing new therapies. Several research groups around the world (including Italy) are studying Duchenne muscular dystrophy in detail, to develop more effective therapeutic approaches than the current ones.
At the moment (March 2014), promising results come from:
- Research concerning the improvement of steroid therapy . The most effective steroid type and dose to maintain muscle tone and strength is being evaluated.
- A gene therapy, called " exon skipping ". This is a particular molecular biology technique capable of restoring dystrophin protein synthesis. Experimentation has reached the human phase.
- A cell therapy based on the use of stem cells . Experimentation is at the animal stage.
- Pharmacological Trials . Several drugs are being evaluated, the best known is PTC124 . Experiments are in the animal phase.
It is necessary to wait a few more years to know the effective effectiveness of these therapies. The goal of the researchers is to replace current treatments, which only alleviate symptoms, with a specific cure for Duchenne muscular dystrophy.
