To learn more about Treatment and Gene Therapy for DMD and BMD, click here.

What are Dystrophinopathies: DMD, BMD, and DCM

 

Duchenne Muscular Dystrophy (DMD) and Becker Muscular Dystrophy (BMD) are genetic disorders classified as dystrophinopathies. These disorders are caused by changes in the function of the largest human gene, DMD, which codes for the dystrophin protein (13). Specific deletions in DMD cause either a reduction or complete absence of the production of the dystrophin protein leading to mild to severe muscle disorders including DMD, BMD, and DMD-associated Dilated Cardiomyopathy (DCM) (8). In DMD patients, dystrophin is virtually absent, whereas BMD patients may produce about 10 - 40% less dystrophin than healthy individuals (13). The DMD gene is housed on the X chromosome, which gives it an X-linked Recessive Inheritance Pattern. In other words, it is more frequently expressed in those assigned males at birth. Those assigned females at birth who inherit one X chromosome with an altered DMD gene may either become asymptomatic carriers or have symptoms and associated diagnoses of Expressive Carriers or “females living with dystrophinopathies.” (8).

What is Dystrophin?

Dystrophin is a cytoskeletal protein that is rod-shaped. It is critical in maintaining muscle cell structure and function (14). Dystrophin’s absence causes the onset of dystrophinopathy symptoms. This protein allows muscles to contract and relax by acting as a “shock absorber.” Because dystrophin regulates the influx of ions into muscle cells, disruption to its normal production and presence causes micro-tears in the cell membrane allowing for the free inflow of ions (10). As the calcium enters the cell, it acts as a toxin severely degenerating the muscle tissue. The damaged muscle cells die and are replaced with a combination of fat and scar tissue. Once the muscle is lost, it cannot be rebuilt. This is the driving force behind the progressive deterioration of patients’ strength and function (14).

 
 

What is: Becker Muscular Dystrophy (BMD)

BMD shows a similar pattern of muscle wasting as seen in DMD. Symptoms tend to begin more gradually and progress more slowly in BMD than in DMD, but the rate of muscle degeneration varies greatly from patient to patient. The incidence of BMD is 1 in 20,000 males and onset varies between ages 5 and 60 years. Typically, patients with BMD maintain the ability to walk at least until age 16. Some patients retain the strength to walk through adulthood (5; 3).

What Is: Duchenne Muscular Dystrophy (DMD)

DMD affects 1 out of every 5,000 babies assigned male at birth. About 20,000 children are diagnosed with DMD globally each year (4). The condition was named after the French neurologist Guillaume Duchenne who is credited as having first described DMD in 1861. Since then, DMD has been researched and studied with a great deal of attention. This is because it is a relatively common, severe, and progressive muscle-wasting disease, which allows for broader reach when raising awareness (14). The fact that there is a definitively identified, testable genetic cause allows for targeted research and treatments as compared to diseases with unknown causes, which are often treated less reliably with trial and error. 

Muscle weakness is the principal symptom of DMD and can show up with the telltale presentation of Gower’s Sign. This sign is detected when a child uses their hands to “walk them” up their thighs to help themselves to stand. Milder and more subtle symptoms can begin impacting the proximal muscles as early as age 2 or 3, only later impacting the distal limb muscles (10). An affected child may find jumping, running, and walking difficult. Beyond those mentioned, some other symptoms include falling or clumsiness associated with muscle weakness, enlarged calves, and lumbar lordosis. Due to progressive muscle weakness and scoliosis, pulmonary and cardiac muscles are eventually affected, which leads to lung and heart complications (4).

What is: DMD-Associated Dilated Cardiomyopathy (DCM)

Because DMD and BMD are inherited through an X-linked Recessive Inheritance Pattern, only those assigned male at birth are at risk for the two conditions. Those assigned females at birth who inherit one X chromosome with an altered DMD gene may either become asymptomatic carriers or have symptoms and associated diagnoses of Expressive Carriers or “females living with dystrophinopathies.” (8).

Asymptomatic carriers are those who do not have symptoms of DMD, BMD, or a DCM-related condition, but they carry the altered DMD gene and have a 50% risk of passing the gene to any biological children they may have. If any of the biological children inherit the altered X chromosome along with a Y chromosome from their other parent, they will develop DMD or BMD.

Expressive carriers of disease-causing DMD genes, also called, Females Living with Dystrophinopathies, are those who have a disease-causing alteration on one of their two copies of the DMD gene who experience symptoms of dystrophinopathies, like cardiac weakness or abnormal structure, skeletal muscle weakness, fatigue, or cognitive delays (14).

 
 

How are dystrophinopathies Diagnosed?

For most muscular dystrophies, early detection depends on precise prenatal diagnosis, genetic counseling and testing. Early in the diagnostic process, blood is drawn to detect the child’s creatine kinase (CK) levels. Damaged muscle tissue leaks the CK enzyme causing elevated levels that indicate abnormal disintegration of muscles, possibly due to muscular dystrophy or inflammation (10). High CK levels can be detected in affected newborns even before the onset of symptoms, which is why it is important to evaluate at-risk infants as soon as possible (4). Following a positive screening, diagnosis is initially based on the preliminary serum CK levels. Diagnosis is confirmed if a disease-causing change in the DMD gene is identified. Those assigned females at birth who do not show symptoms, but are identified to carry an altered DMD gene should still undergo a complete cardiac evaluation in late adolescence or sooner if symptoms occur. If the initial genetic analysis is negative, the follow-up analysis searches for small microdeletions or duplications (4). In the modern era, muscle biopsy is rarely involved, however, it can be helpful in distinguishing between different forms of muscular dystrophy and other inflammatory conditions.

Medical Management of Dystrophinopathies:

There is no cure for dystrophinopathy: management emphasizes respiratory care and treatment of cardiological complications. The muscles assisting in breathing gradually weaken, and the bronchial system must be free of secretions at all times. This can be achieved either through the use of a cough assist device or by manually assisted coughing with the help of a 24/7 caregiver (4).

Physical and occupational therapy can also help to manage symptoms and complications associated with muscular dystrophy. Physical therapy has a strong focus on facilitating mobility and strengthening large muscle groups. Occupational therapy emphasizes improving independence during specific activities and functions and can assist in recreation or daily living, like dressing or using a computer (4; 10).

Assistive tools like braces that support the ankle or foot, called orthoses, may provide support extending up over the knee. Specialty-prescribed Ankle-Foot Orthoses (AFOs) may be worn during sleep to keep the foot from pointing downward while keeping the Achilles tendon stretched (5).

During the early stages of the disease, it is recommended that patients stand for a few hours each day. This would promote circulation, healthier bones, and a straight spine. A wheelchair is needed to provide support, safety, and increased independence around the beginning of the teenage years. Unless there is an injury, such as a broken leg, the transition to wheelchair use is usually gradual, rather than a rapid shift to becoming a full-time wheelchair user (4; 5).

Summary:

Muscular dystrophies are a critical group of conditions that affect a large population worldwide. Expanding the understanding of DMD, BMD, and other forms of muscular dystrophy would improve the detection of early symptoms. It would also improve the administration of quality care and better support for health maintenance. Understanding the genetic changes responsible for DMD and BMD allows for specific and accurate genetic testing for other family members. There has been no cure for DMD or BMD yet, but careful monitoring of the clinical presentation of symptoms can help manage the condition and guide treatment choices. Treatments with corticosteroids, beta-blockers, and support from allied health professionals have advanced medical management and increased the quality of life, but the financial, physical, and emotional burdens placed on families are areas in need of more structured support. Although further research and development are required in this field to determine a cure, there is hope that novel treatment may lead to more substantial therapies in the near future.

To learn more about Treatment and Gene Therapy for DMD and BMD, click here.

 
 

There are many free testing programs available to those with a family history or symptoms of dystrophinopathies.

Clover Genetics can help you determine your risk:
contact us today!

 

Researched by: Hiya Abrol

Co-Authored by: Rachel Baer, MSc

Images: Rachel Baer, MSc

Edited and Reviewed for Accuracy by: Rachel Baer, MSc, Mark Schmertmann, MSW, LSW, and Andrew J. McCarty, MS, CGC

Published April 2023

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