Duchenne muscular dystrophy

The muscular dystrophy type Duchenne is the most common muscular hereditary disease in childhood. It occurs in a frequency of approximately 1:5000. Due to the X-linked recessive mode of inheritance almost only boys are affected. The Duchenne muscular dystrophy begins in infancy with weakness of the pelvic and thigh muscles, progresses rapidly and ends, mostly in young adulthood, always fatal once the heart and respiratory muscles is reduced. They are therefore referred to as " malignant ( = malignant) muscular dystrophy ." By optimizing therapy with home mechanical ventilation, the prognosis has improved in recent years. The Duchenne muscular dystrophy has been described by Guillaume- Benjamin Duchenne in the 19th century in Paris.

Causes

The Duchenne muscular dystrophy is a genetically determined abnormal synthesis of muscle structural protein dystrophin. It is not formed in this form of disease. In contrast, synthesized at the milder end Dystrophy Becker- Kiener dystrophin in lesser amount. The Dystrophinmangel over time leads to the destruction of muscle fibers and replacement by fat or connective tissue.

In Duchenne muscular dystrophy, a mutation in the dystrophin gene on the X chromosome ( locus Xp21.2 ) is detectable. This is in 60 to 70% is a deletion, in about 5 % to a duplication and in about 35 % to a point mutation. More than 98 % of the mutations cause this shift ( frameshift ) of the reading frame, leading to a complete loss of Dystrophinproteins. Here, the cases of de novo mutations and only 2/3 of the non- manifest disease nut ( Konduktorin ) are about 1/3 inherited.

Symptoms and course

The early childhood development course is initially normal. In 3 to 5 years old falls in affected children in a mild muscle weakness of the legs, which leads to frequent tripping and falling. In the course of the climb is only possible with the aid of a railing. Muscle weakness of the pelvic and thigh muscles causes a waddling gait ( Trendelenburg ) and a difficulty in getting up from sitting or lying down. The children climb in yourself high ( Gower's maneuver) or use walls and furniture for support. From 5 to 7 years climbing the stairs and getting up from sitting or lying down only with the help of others possible as the disease to spread to the muscles of the shoulders and arms. Between the 7th and 12th year raising the arms to the horizontal is hardly possible. Many children are already instructed in this age to a wheelchair, but can still restricted supply independently. There is usually from the age of 18 complete care.

As a result of muscle atrophy leads to painful deformities of joints and bone deformities. Characteristic of the Duchenne type are the so-called " Gnome " or " ball- calves ". They are caused by fatty deposits in the connective tissue converted lower leg muscles ( pseudohypertrophy ). Upon disassembly of the shoulder girdle muscles occurs protruding shoulder blades ( " scapulae alatae " ), also known as angel wings. Due to weakness of the respiratory muscles is expectoration, that much harder with infection of the airways and improves the life expectancy will be greatly hindered. The heart muscle is indeed most affected by the disease process, but result in increased heart rate and other changes in rhythm or impairment of myocardial contractile force rarely subjective complaints. The life expectancy of patients, depending on the course of about 40 years, but individual patients die even before the onset of puberty.

Diagnostics

The suspicion of muscular dystrophy occurs when an unusual symmetrically trained muscle weakness is observed in childhood. The medical history of particular interest to the onset of dysfunction, the progression and the occurrence of similar disturbances in the family, especially in the mother male relative. As part of the physical examination is looked after general abnormalities, such as posture, flexibility and breathing. In the neurological analysis, the function of the nerves and muscles is checked. Laboratory values ​​provide important information - the amount of creatine kinase, a muscle enzyme is often elevated in the blood. The usual additional investigations includes the electroneurography, in which the nerve is determined, and electromyography, which helps distinguish whether a primary muscle disease or a disease of the motor nerves is the cause of the weakness. As MRI and ultrasound imaging techniques are used. Here structural changes in muscles can be assessed without stress to the patient. Muscle biopsy allows the examination of the muscle at the light or electron microscope. The metabolic processes in the muscle can thus be examined carefully. The genetic diagnosis will confirm the diagnosis and make an accurate classification by type possible.

Therapy

A cure is not possible. The attempt to treat Duchenne muscular dystrophy gene therapy, failed for the time being. The reason for this was believed to be an autoimmune reaction after trying to introduce the corresponding gene in a muscle protein. Further studies with adjuvant immunomodulation were carried out in October 2010.

Effective treatment requires a collaboration of medical, physiotherapy, occupational therapy and nursing, often psychological support for patients and their relatives. The goal of all physiotherapy measures is to minimize the consequences of muscle weakness as low as possible or correct to a certain extent. By Economic Training with mild to moderate stress such as walking, swimming and boating on the ergometer is to improve the endurance and thus a reduction of weakness to achieve. Cortisone gifts and surgical solution of contractures prolong ambulation, creatine, a discrete improvement in muscle energy metabolism cause (regular therapy breaks necessary). An evolving scoliosis ( curvature of the spine ) can be straightened surgically by implanting metal rods ( Harrington rod ); thereby especially the respiratory function is improved. Since 1989 continuously adjustable telescopic rods are used. As an aid orthoses, wheelchair, shower chair, bath lifts, Raised toilet seats and wheelchair ramps are used. Since the self- breathing continues to decrease due to the increasing weakness of the respiratory muscles, mechanical ventilation may be necessary between the average ages of 18 and 20 years. This is mainly non-invasively via a nasal or nasal - oral mask. Carrying out a tracheotomy is initially usually not necessary and is typically only late, if the patient is also the day dependent on the ventilator is performed. From a general Tracheotomierung it is now largely moved away. Of particular note is the Abhustschwäche. Through physiotherapy techniques or apparatus measures also help support is possible. An accompanying the muscular fatigue may - in addition to adequate rest periods - are positively affected by vitamin infusions and oxygen treatments. Another approach is based on fully read the defective gene, despite the mutation. This should be possible, for example, with the aid of ataluren. Once the disease spreads to the respiratory muscles, regular pulmonary function tests must be made. In recent years, good progress in the possibility of home mechanical ventilation were made. When creating a training program, the heart conductivity must be checked. Sometimes the use of a cardiac pacemaker may be required.

In a Canadian non-randomized comparative clinical study of 54 boys who were 8.7 years old at baseline in average and 30 of them received daily 0.9 mg / kg deflazacort and 24 no treatment were an after an average of 15.2 years boy with therapy (3 %) and five boys died without therapy ( 21%). Significantly more boys without therapy had developed a severe scoliosis and had been operated on it ( six ( 20 %) and twenty-two ( 92%) boys with or without cortisone therapy). During therapy, lung function was significantly better, the children ran independently longer and could go up on average one and a half years longer without assistance stairs. However, twenty-one boys ( 70 %) developed a cataract cortisone ( and no child without therapy), but it does only two children were operated on cataract. The size was 17 cm less cortisone on average, the weight average 4 kg higher.

A careful genetic counseling of parents is part of the therapy. If the mother Konduktorin, as brothers of affected children have a 50 % chance of also developing, sisters are the same 50 % chance of asymptomatic wearers ( female carriers ) of the defective gene.