Knowledge on rare diseases and orphan drugs

DMD primarily affects males with an estimated male birth prevalence of 1/3,500-1/9,300.

Onset occurs in early childhood, and affected boys may show a delay in walking (after 18 months of age) accompanied with speech and/or global developmental delay. Autism and behavioral problems, such as ADHD (attention deficit hyperactivity disorder), anxiety, obsessive compulsive disorder, are relatively common. Untreated children with DMD rarely achieve the ability to run or jump. The condition progresses rapidly and the child develops a waddling gait and a positive Gowers' sign. Climbing stairs becomes difficult and the child falls frequently. Loss of independent ambulation occurs between the ages of 6 and 13 years, the average being 9.5 years in non-steroid treated patients. Once ambulation is lost, joint contractures and scoliosis develop rapidly. Untreated patients die during late teens to early twenties from respiratory failure and or cardiomyopathy

Muscle damage is caused by the complete absence of the sarcolemmal protein dystrophin as a result of variants in the DMD gene (Xp21.2).

Diagnosis is suspected on the basis of the clinical picture, family history and laboratory findings (serum creatine kinase (CK) is 100-200 times the normal level). Genetic testing is the gold standard and involves multiplex-ligation dependent probe amplification (MLPA) for detection of deletions and duplications of exon (s) and full gene sequencing for detecting small deletions and duplications and non-sense or point mutations. Given the value of information provided by genetic analysis muscle biopsy is now recommended when genetic analysis in inconclusive. Genetic testing is therefore a critical tool in the accurate diagnosis of DMD and helps avoid missing the opportunity for personalized treatment.

Differential diagnoses include severe Becker muscular dystrophy and limb girdle muscular dystrophy.

Antenatal diagnosis is possible for families in which the diagnosis has been confirmed by molecular testing.

DMD is an X-linked recessive disease. Genetic counseling is very important: the risk of recurrence is 50% for male siblings of a proband. Female siblings have a 50% risk of being carriers and are usually asymptomatic but a small percentage manifest milder forms of the disease (symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers).

International standards of care recommend a multidisciplinary approach. Physiotherapy includes passive stretching and night time ankle-foot orthoses (AFO) to reduce tendo-Achilles contractures. Treatment with corticosteroids (prednisolone, prednisone or deflazacort) is the gold standard. Corticosteroids should be introduced early or when the child's motor skills plateau, usually around 4-5 years of age. Complications of corticosteroid therapy must be managed and include: weight management, gastric protection, monitoring and treatment of osteoporosis, ophthalmic assessment for cataracts and glaucoma. Ataluren (authorized in Europe) is the only disease-modifying drug for use in ambulatory patients older than 5 years of age and where DMD is caused by non-sense mutations. Cardiac management includes regular monitoring (echo and/or MRI) and prophylactic treatment with ACE inhibitors and/or beta inhibitors to maintain cardiac function. Respiratory management includes monitoring respiratory function, assessment for sleep hypoventilation and timely introduction of BiPAP (bilevel positive airway pressure). In older patients cough augmentation and pneumococcal and flu vaccines are recommended. Surgery may be required for correction of scoliosis.

DMD has a severe prognosis and life expectancy is significantly reduced with death occurring in the third to fifth decades, although this is improving with advancements in management and treatment.

Last update: June 2020 - Expert reviewer(s): Pr Rosaline QUINLIVAN