Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD), rare X-linked form of muscular dystrophy that affects about 1 in 3,500 to 5,000 male births and is characterized by progressive muscle weakness, with symptoms beginning in early childhood. A neuromuscular disorder, Duchenne muscular dystrophy is caused by the absence of dystrophin, a critical muscle protein. The protein’s absence leads to weakened cell membranes in skeletal, heart, and diaphragm muscles and overall muscle degradation over time. Wheelchair use is often required by the time people with DMD reach their teenage years, and many die in their 20s. Advances in medical science have extended life expectancy into the 30s and beyond in some cases.

Causes

DMD is caused by mutations in the DMD gene located on the X chromosome, which leads to the production of little or no dystrophin protein in muscle cells.

Dystrophin protects the muscle cell membrane during contraction. It also binds together actin filaments on the inside of the cell with components of the dystrophin-associated glycoprotein complex (DGC) on the cell membrane’s exterior. Without dystrophin, weakened muscle cells break down over time.

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Because the DMD gene is on the X chromosome, the son of a mother carrying the mutation has a 50 percent chance of inheriting DMD, and a daughter has a 50 percent chance of becoming a carrier. Female carriers may exhibit cardiomyopathy and muscle fatigue. Approximately 30 percent of DMD cases are caused by a spontaneous genetic mutation, with no family history of the disease. The DMD gene is one of the largest genes in the human genome, making it difficult to treat with typical gene replacement therapies.

Becker muscular dystrophy is a milder form of DMD, in which symptoms sometimes do not present until later in life.

Symptoms and diagnosis

DMD symptoms begin early in life as children begin to walk and engage in greater physical activity. Typically, this is about two and a half years old. Most children are not diagnosed until they are four or five because of a general lack of awareness of the disease.

The hallmark physical signs of DMD are enlarged calves caused by the breakdown of muscles. Many children also demonstrate a movement called Gowers sign, in which they need to walk their hands up their legs to be able to stand. Children with DMD often waddle when they walk and fall frequently.

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DMD is often initially diagnosed with a creatine kinase (CK) test. The presence of this enzyme in the bloodstream indicates damage to muscle tissues. Genetic testing is then done to confirm the diagnosis and determine the location and type of gene mutation.

Prognosis

Early in life children with DMD have challenges keeping up with peers, experience falls, and have difficulty climbing stairs. As teenagers most individuals transition to using a manual or electric wheelchair or scooter, as falls become more prevalent and walking becomes difficult.

Before 1970 the median life expectancy for individuals with DMD was 18. Individuals born after 1990 have a median life expectancy of 28 years. More awareness about the disease, better medical care, and new disease-modifying treatments have led to increased life expectancy. With early intervention and proper medical management, some individuals live into their 40s.

Treatment

A standardized treatment model has gained more adoption since the mid-2010s. Typically, glucocorticoid steroids are started early to combat inflammation associated with muscle breakdown. Although this treatment has helped individuals maintain the ability to walk for a longer period of time and can improve heart function, there are a number of side effects, including osteoporosis, mood swings, appetite changes, delayed puberty, water retention, and suppression of the immune system.

Consistent stretching, physical therapy, and use of orthotics can help individuals maintain greater range of motion and avoid muscle contractures, in which muscles become short and tight.

Electric wheelchairs can allow individuals to maintain their independence when they have an increased fall risk or are unable to walk. Adaptive technology offers ways to overcome muscle weakness that spreads to the upper body. Certain drive controls require only the minor movement of the fingertips, eyes, and head.

Breathing can become compromised as diaphragm muscles weaken. A BiPAP (bilevel positive airway pressure) machine is typically prescribed for use at night. As weakening progresses, BiPAP support is required during the day.

A number of therapies approved by the U.S. Food and Drug Administration (FDA) aim to alter the progression of the disease. The first gene therapy for DMD, Elevidys (delandistrogene moxeparvovec-rokl), was approved in 2023. Pharmaceutical companies are pursuing approval for other gene therapy approaches.

For patients with specific gene mutations, four approved “exon-skipping” drugs have shown promise. They are Amondys 45 (casimersen), Exondys 51 (eteplirsen), Viltepso (viltolarsen), and Vyondys 53 (golodirsen), with the numbers referring to the specific exons that are “skipped.” The drugs cause the cell to “skip” over the mutated portion of the dystrophin gene with the goal of producing a functional dystrophin protein.

Additionally, new glucocorticoid steroid, anti-fibrotic, and anti-inflammatory treatments are available to address secondary symptoms.

Research

Today a number of biotech companies are pushing to innovate on existing FDA-approved therapies. However, there are risks associated with these new treatments as companies run clinical trials to test safety and effectiveness. Multiple deaths have been reported while individuals were receiving experimental gene editing and gene therapy treatments.

One gene therapy involves inserting the complete DMD gene into a single adeno-associated virus (AAV) capsid. An AAV is a non-disease-causing virus that helps deliver gene therapies into the cell; however, it can hold only a small amount of genetic material. To compensate, all current AAV gene therapy treatments deliver a small “micro-dystrophin” protein approximately one-third the size of full-length dystrophin. That means that some important features of natural dystrophin are not included in the cell delivery package.

Other approaches in the drug development pipeline include the gene-editing tool CRISPR, new exon-skipping approaches that target muscles more effectively, stem cell therapy, small-molecule approaches to improve heart function and muscle regeneration, and more.