DMD is a progressive disorder of skeletal muscles that results in loss of ambulation by age 13 years. It primarily affects boys. Muscle weakness is the first symptom and progresses to cardiac and respiratory involvement.

DMD is a rare disease that can be difficult to study. Inability to obtain individual phenotype data (IPD) can result in immortal time bias in studies.

Symptoms

Symptoms of DMD include muscle weakness and wasting (loss of muscle bulk). The most severe form of MD, Duchenne muscular dystrophy, is caused by a change (mutation) in the gene that gives instructions for making a protein called dystrophin. This protein helps maintain the structure of muscles.

Weakness in DMD progresses rapidly and affects the muscles of the legs and pelvis, arms, back and neck. Children with DMD develop a waddling gait, have difficulty walking and may need to use a wheelchair by their teenage years. They may also have problems with heart and breathing.

DMD is inherited in a pattern known as X-linked recessive inheritance. This means only boys are affected, but females can be carriers and may have milder symptoms than boys. For this reason, it is important for females to be offered testing from mid to late adolescence. They can then start to plan ahead for the future and consider their options.

Diagnosis

The first sign of DMD is muscle weakness, usually starting around age 2. It starts in the proximal muscles (those closest to the body) and progresses downward. Eventually, it can cause a waddling gait and lumbar lordosis (an inward curve of the spine). Children with DMD may also have trouble jumping and running.

Doctors diagnose DMD by examining your child and doing blood tests. One of these tests checks the levels of creatine kinase, an enzyme that muscles release when they become damaged. A high CK level is a sign that your child has DMD.

Other tests can include a sample of muscle tissue to look for changes caused by the mutated gene or an electromyogram to check how well your child’s nerves are working. Your doctor may also recommend that your child have a heart test, called an echocardiogram, to see how the heart muscle is working.

Girls and women who carry the mutated gene for DMD are at risk for developing heart problems as they get older. They should have a heart checkup every 2 years until age 10, then once a year.

Treatment

There is no cure for DMD, but treatments can slow progression and improve quality of life. Treatment options include corticosteroids, which have been shown in clinical trials to decrease the rate of muscle weakness; physical therapy to strengthen muscles and prevent contractures; medications to help with heart disease, such as ACE inhibitors and beta-blockers; surgery to treat scoliosis; and breathing assistance, such as BiPAP or a tracheostomy.

The first exon-skipping pharmacologic treatment for DMD, eteplirsen (Exondys 51), was approved by the FDA in 2016. It is designed to partially resolve mutations that cause DMD and result in at least some functional dystrophin protein.

DMD most commonly affects boys because the gene for dystrophin is on the X chromosome. Girls have two X chromosomes from their mothers and one from their fathers. Boys with DMD are at higher risk of developing a scoliosis or having to have a tracheostomy as they get older. The good news is that new research is providing hope and increasing the number of effective therapies.

Prevention

A multidisciplinary approach involving medical, surgical and rehabilitative interventions can significantly alter the natural course of DMD and improve QOL and longevity131. Recently, it has been found that genetic variants that modify the phenotype by influencing immune or fibrotic processes slow down disease progression. For example, R16-containing dystrophins restore sarcolemmal nNOS and ameliorate muscle pathology in symptomatic DMD mouse models, while depletion of the serine/threonine protein phosphatase sarcolipin reduces muscle weakness and fibrosis92.

In DMD, infiltration of inflammatory cells contributes to the pathology. Pro-inflammatory M1 macrophages induce lysis of degenerated muscles while anti-inflammatory M2 macrophages promote regeneration and prevent fibrosis formation. CD4+ helper T cells produce inflammatory cytokines and CD8+ cytotoxic T cells kill damaged muscle cells.

Visceral smooth muscle involvement leads to constipation, bowel obstruction and gastroesophageal reflux disease (GERD). Pharmacological treatment includes osmotic laxatives or lactulose and histamine 2 receptor antagonists or proton pump inhibitors for gastric acid suppression137. Progressive dilated cardiomyopathy is another late manifestation of DMD and may lead to heart failure, conduction abnormalities, ventricular arrhythmia or sudden death9,136.