Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is the most common pediatric neuromuscular disorder, affecting roughly 1:4,000 live male births globally. Approximately 18,000 boys are currently affected in the United States and 188,000 in the rest of the world. The combination of the disease’s prevalence, seriousness, unpredictable occurrence, cross-cultural presentation, and the combined emotional and financial expense of the clinical sequelae make DMD a significant public health concern.

DMD is an X-linked developmental disorder that causes progressive muscular weakness usually leading to death by young adulthood. The disorder is caused by a mutation in the dystrophin gene, located in humans on the X chromosome (Xp21). The dystrophin gene codes for the protein (dystrophin) that provides structural stability to the dystroglycan complex on muscle cell membranes. The lack of dystrophin reduces membrane stability resulting in alterations to a series of complex signaling pathways (calcium signaling, oxidative stress, etc.) that ultimately lead to chronic cycles of myofiber degeneration and regeneration, progressive histological fibrosis, muscle wasting and weakness, and an early death.

In DMD, the course of the physical impairment is progressive. Early motor developmental milestones tend to be delayed, and by age four or five, falling and/or trouble climbing stairs becomes increasingly apparent. As muscles continue to weaken, the boys begin to walk stiffly with lumbar lordosis to compensate for weakening leg muscles, and they require increased physical support. Mean age to the initial use of a wheelchair is 10 years with a range of 7 to 13 years (McDonald et al., 1995), although daily glucocorticoids have extended the ambulatory period by 2-3 years. Death generally occurs by early adulthood, mostly due to respiratory or cardiac failure resulting from extreme muscle weakness, unless patients are ventilated. Patients with ventilator support can survive many decades, but require assistance with all activities of daily life.

There is currently no ability to replace dystrophin in DMD patients’ muscle. Clinical management typically involves a combination of medical, surgical, and rehabilitative approaches, with about 50% of patients prescribed daily glucocorticoids. The goals of treatment are to slow disease progression, control secondary conditions and to improve the quality of life of the patients and families living with the disease (McDonald et al., 1999).

Vamorolone has received Orphan Drug Designation in the US and in Europe and is being developed for chronic treatment of boys with Duchenne muscular dystrophy. If successful, vamorolone may allow boys to achieve several years of prolonged ambulation without the toxicity associated with current treatment. Thus, more boys may receive treatment and they may be treated earlier and for longer periods of time.

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