AON-Mediated Exon Skipping for Duchenne Muscular Dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a genetic, X-chromosome recessive, severe and progressive muscle wasting disorder, affecting around 1 in 3500 newborn boys. The onset of the disease is in early childhood and, nowadays, most children are diagnosed before the age of 5. The first signs of muscular weakness become apparent around the age of 2 or 3 years. In most patients the age at which the child starts to walk is delayed (retarded motor development). The children have less endurance and difficulties with running and climbing stairs (Moser, 1984). Gower’s sign is a reflection of the weakness of the muscles of the lower extremities (knee and hip extensors): the child helps himself to get upright from sitting position by using his upper extremities: first by rising to stand on his arms and knees, and then “walking” his hands up his legs to stand upright (Gowers, 1895). Muscle wasting is often symmetrical, however not all muscles are affected to the same extent. A prominent feature of the disease is enlargement of the calve muscle, caused by replacement of muscle fibres by connective and adipose tissue. Furthermore, the pelvic girdle, trunk and abdomen are severely affected and to a lesser extent the shoulder girdle and proximal muscles of the upper extremities. Progressive weakness and contractures of the leg muscles lead to wheelchair-dependency around the age of 10. Thereafter the muscle contractions increase rapidly leading to spinal deformities and scoliosis, often with an asymmetric distribution pattern. Involvement of the intercostal muscles and distortion of the thorax lead to respiratory failure and patients often require assisted ventilation in the mid to late teens. Thereafter dilated cardiomyopathy becomes apparent and most patients die before the age of 30. Another common feature is mental retardation (IQ less than 70) in around 20-30% of the patients (Emery, 2002).