DUCHENNE MUSCULAR DYSTROPHY: EXPLORING CAUSES, SYMPTOMS, AND RECENT BREAKTHROUGH RESEARCH

Medically Reviewed by Dr. Sony Sherpa (MBBS) - October 01, 2024

Duchenne Muscular Dystrophy (DMD) is a rare recessive genetic neuromuscular disease that causes the slow degeneration of muscle fibers and progressive limb weakness. The condition results from genetic mutations in the DMD gene, which prevents the production of dystrophin, a vital protein required to keep muscle cell membranes intact. DMD is the most severe form of disease within the spectrum of inherited muscular dystrophies, all of which arise due to dystrophin gene mutations.

It is usually diagnosed in children early on, between the ages of 2 and 7, due to obvious signs of pelvic muscle weakness that prevent optimal movement. As the disease progresses, muscle atrophy affects both the lower and upper limbs and eventually requires wheelchair assistance. Cardiomyopathy and respiratory issues are common in the late stages, often resulting in heart or respiratory failure.

Duchenne Muscular Dystrophy prevalence is low despite the fact that it is one of the most common inherited neuromuscular conditions. It occurs in 6 out of every 100,000 births.^[1] It is known to mostly affect males, with 1 in every 3500-5000 born diagnosed with DMD.

In this article, we will cover the causes, risk factors and symptoms of DMD and other types of dystrophy, as well as DMD diagnosis and treatment options. While there is no cure for this disease, recent scientific breakthroughs suggest that a cure might be possible in the future. A few of these are also discussed below.

Causes and Risk Factors

The cause of DMD is a mutation in the DMD gene, which is a gene that codes for dystrophin and is located on chromosome X (or Xp21). ^[2]

Dystrophin is a protein that helps keep muscle cells intact and stable by connecting muscle filaments inside muscle cells to the cell wall.^[3] This reinforces the muscle’s structure and ability to contract. It also helps to transmit the force generated by contracting muscle to the tendon and bone. Without dystrophin, both muscle and bone become more vulnerable to damage and degeneration.

Dystrophin, Connective Tissue and Muscle Stability. Dystrophin is found to be more concentrated at the origin and insertion of muscles, which are the points at which the muscle connects to tendons or ligaments. The insertion of a muscle moves when the muscle contracts, while the origin of a muscle remains stable. This helps the muscle to remain contracted as required. The lack of dystrophin disrupts the connection between muscles and tendons, causing the muscle to be looser during contraction. To compensate for the effects of DMD, children with the condition tend to use the origin and insertion of their muscles for better stability when attempting to stand up or sit down (Gowers’ sign).

Calcium, Dystrophin and Muscle Wasting. Dystrophin also directly regulates calcium levels in muscle cells. The movement of calcium in and out of muscle cells is vital for muscle contraction and relaxation. Healthy dystrophin helps prevent the abnormal opening of a calcium channel called the ryanodine receptor (RyR). When the DMD protein is absent, it can cause this channel to leak calcium, resulting in higher levels of muscle weakness, injury, oxidative stress and inflammation. Through the course of DMD, the muscle tissue exhausts its ability to repair itself in response to usual wear and tear, leading to scar tissue buildup. Muscle fibers eventually get replaced with connective tissue and fat, which reinforces muscle weakness.

How is Duchenne Muscular Dystrophy Inherited?

DMD is a recessive X-linked disorder, which means that the DMD gene mutation is passed down from the mother, who carries a faulty copy on one of her X chromosomes. Males are more often affected as they carry only one X chromosome, while females carry two.

Female carriers who become pregnant may not necessarily give birth to a child with DMD. The risk is shared jointly, meaning there is a 25% chance for a boy to be born with or without DMD or for a girl to be born a carrier or not. Daughters of males with DMD will be carriers due to inheriting the faulty X chromosome, while sons will be completely unaffected due to receiving the functional Y chromosome.

Roughly 2.5-20% of female carriers are susceptible to milder muscle weakness, often limited to the arms, legs and back. Scientists theorize that this is due to the silencing of the healthy X chromosome and the expression of the diseased one. These women would also be less tolerant to exercise and suffer from respiratory issues due to having weaker heart muscle and a higher heart disease risk. Without treatment, these issues can lead to early heart failure or similar life-threatening consequences.

Up to 30% of DMD cases are the result of spontaneous genetic mutations that occur during pregnancy, irrespective of the parents’ genetic makeup.

Risk Factors for DMD and Complications

Aside from parental genetics, there are several other factors that can increase the risk of acquiring DMD or variations as well as promote worse outcomes for those with the condition. These include:

• Gender: As explained, males are at a much higher risk of contracting DMD due to only possessing one X chromosome.
• Fertility Problems, Toxins and Prior Miscarriage: Those with fertility issues, who have suffered from previous miscarriage, and/or who are exposed to toxins during pregnancy are at an increased risk of inducing spontaneous DMD or another genetic disorder in the developing fetus. Some types of miscarriages leave behind residual genetic material that increases the risk of future miscarriage or spontaneous genetic mutations in the embryo.
• Low BMI: Having less muscle tissue naturally contributes to increased muscle weakness, quicker disease progression and symptom severity. Metabolic issues or a lack of nutrition classically contribute to a low BMI.
• Reduced Mobility: Patients who engage in less physical activity are less likely to fall and contract injuries^[4]. Careful exercise is encouraged with an emphasis on safety.
• Cardiac or Respiratory Problems: The strength of the heart and lung muscles is critical for those with DMD as it allows them to lead longer lives. If born with other inherent weaknesses in these areas, the disease may progress a lot more rapidly.

Types of DMD

Duchenne muscular dystrophy is the severest, most frequently observed type of dystrophinopathy. Yet, there are other types of dystrophy that can occur due to other DMD gene mutations. These include:

Becker Muscular Dystrophy

Becker MD^[5] is a well-characterized milder form of DMD where some dystrophin is still produced, yet the levels are low, or the protein is dysfunctional. This type of DMD usually displays milder symptoms with a slower rate of progression and typically only begins during late childhood or teen years. As Becker MD can be caused by a wider variety of mutations in the dystrophin gene, symptoms and severity can vary. Some people with Becker DMD have a normal lifespan, while others may develop serious complications such as cardiomyopathy or respiratory failure at early ages.

Intermediate Forms of Muscular Dystrophy

Intermediate forms are rare types of muscular dystrophies that have clinical features intersecting DMD and Becker DMD. As with Becker MD, intermediate forms are also caused by dystrophin gene mutations, leading to low amounts of normal dystrophin or higher amounts of faulty protein. Intermediate forms can begin anywhere between early childhood, as seen in DMD, through to the teen years, as seen in Becker MD. The symptoms vary in their severity and presentation depending on the mutations present, yet are generally thought to reside somewhere between DMD and Becker MD.

DMD Symptoms

The hallmark of DMD is progressive muscle weakness. The weakness often begins in the hips and upper legs before progressing through to the upper torso, shoulders and arms, and then to the rest of the body.

DMD in Infancy. The child’s development often appears to be normal during infancy. There may be signs of delayed motor development, yet these are not usual until symptoms of muscle weakness first appear. Infants may also present with slightly more relaxed muscles and poor control of head movements.

Early Stage Disease

Symptoms first become obvious by 2-3 years of age. The child might find it difficult to walk normally without assistance. It is common for these children to walk on their toes, have an abnormal posture, struggle to run or climb stairs, and frequently lose balance and fall.

Gowers’ sign is considered a prime symptom of DMD. Named after neurologist Sir William Richard Gowers in 1879, it refers to patterns of movement observed in those with DMD who try to compensate for their muscle weakness^[6]. Common signs of Gowers’ maneuver include:

• Applying mild pressure to or climbing up the thighs with one’s hands for support when shifting from sitting to standing positions.
• Flexing the torso to get to a comfortable position.
• A wide-based or waddling-style gait.
• A greatly curved lower spine that causes the hips to angle forward, the shoulders to lean back excessively, and the posterior to stick out.
• Walking on the toes to avoid applying pressure on the leg muscles.

Enlarged calf muscles and sometimes those of the tongue and forearms appear in early stages. This is usually the result of excessive scar tissue that forms inside the muscle, also known as a type of pseudohypertrophy. Some DMD patients may have learning disabilities and intellectual impairments, with 20-30% of patients having an IQ lower than 70. Most can go to school without needing special assistance.

Mid Stage Disease

As the disease progresses, muscle weakness affects the lower legs, forearms, neck, abdominal muscles, and those inside the body. Without physiotherapy, children with DMD may need leg braces by 8-9 years of age. A wheelchair is usually relied on from age 10-12. Facial muscle weakness is sometimes present, and the child may have abnormal joint stiffness. Due to compromised muscle contraction and force transmission to the bone, the bones of those with DMD are often weak with a lower bone density and prone to fracture.

Late Stage Disease

DMD-associated cardiomyopathy affects all patients by their twenties yet can develop in their teen years. This often presents as heart enlargement or Dilated Cardiomyopathy and is accompanied by arrhythmias and other signs of heart disease, such as exercise intolerance and shortness of breath. Other symptoms that may occur during later disease stages include incontinence and weakness of the throat, leading to respiratory issues or difficulty swallowing.

How is DMD Diagnosed?

Parents often suspect the child has a problem between the ages of 2 and 7. A doctor will take note of muscle weakness and other symptoms before asking detailed questions about the child in order to better understand their medical history. A physical examination can help to assess the child’s reflexes, evaluate posture, and check their gait for any abnormalities such as Gowers’ sign.^[7]

Once a muscular disorder is suspected, the doctor may send for several tests, including:

• Blood tests. Blood tests are used to check for muscle damage. Children with DMD tend to have creatine kinase levels 10-20 times the normal range.
• Muscle Biopsy. A muscle biopsy is a type of exam in which a sample is removed and assessed under a microscope. It can show the extent of muscle scarring and degeneration.
• Genetic Testing. Various techniques are used to check for dystrophin, which is less than 5% in patients with DMD. Those with other forms may reveal low to normal levels, yet genetic mutations will be present.
• Electrocardiogram and Endocardiogram. An ECG may be used to check for arrhythmias and cardiomyopathy.

DMD Treatment

Treatment options for DMD are currently aimed at facilitating the best quality of life possible. Mainstay options include corticosteroids, physical and occupational therapy, gene therapy and surgery.

Corticosteroids

Children over the age of 4 can start corticosteroid therapy. Corticosteroids inhibit the immune response and block inflammation, which results in delaying muscle degradation in those with DMD. It also tends to improve poor posture, breathing, and progression of cardiomyopathy in these patients. Common steroids used include prednisone or deflazacort, which has a milder side effects profile.

Gene Therapies

There are several different approved gene therapies for the treatment of Duchenne muscular dystrophy (DMD). They all work by targeting the genetic defect that causes DMD to restore the production of dystrophin. Here is a brief summary of what each one does:

• Ataluren is a small molecule that allows the ribosome to read through premature stop codons (nonsense mutations) in the dystrophin gene and produce a functional protein. A nonsense mutation occurs when a mutation in the DMD gene gives rise to a stop codon instead of a sequence that produces the protein. Ataluren is approved in the European Union, US, UK and Brazil for people with DMD aged 5 years and older who have a nonsense mutation. This accounts for about 10-15% of DMD cases.^[8]
• Eteplirsen is an antisense oligonucleotide (ASO) that binds to a specific exon or region of the dystrophin gene and causes it to be skipped during messenger RNA production (splicing). Targeted exon skipping results in a shorter yet functional dystrophin protein. Eteplirsen targets exon 51 of the DMD gene and is approved for use in the US to treat roughly 13% of cases that are amenable to exon 51 skipping.
• Golodirsen and Viltolarsen are other ASOs that target exon 53 of the dystrophin gene. Golodirsen is approved for use in the United States and Vitolarsen is approved in the US, EU and Japan for roughly 8% of people with DMD who have a mutation amenable to exon 53 skipping.
• Elevidys (SRP-9001) is a gene therapy that delivers a micro-dystrophin gene using AAVrh74, an adenovirus vector. This means that a short version of the dystrophin gene is embedded inside this virus, which passes through into muscle tissue and allows for the production of a functional protein. So far, the therapy is approved for use in the US for boys aged 4-5 years with DMD.^[9]

These drugs are not curative, yet they may slow down the progression of the disease and improve the quality of life of people with DMD. Gene therapies are costly and may pose side effects. Those interested ought to consult a genetic counselor to assess their eligibility.

Supportive Therapies

Those with DMD benefit from a team of multiple professionals who can help them adjust and learn vital skills required for living with DMD. Often, these therapies dramatically improve the child’s quality of life, and the skills remain into young adulthood.

Supportive therapies include:

• Occupational Therapy helps children with DMD to adjust to living with DMD and to perform daily activities with more ease and independence. It can start as soon as the child shows signs of muscle weakness, and it can continue throughout their life, depending on their needs and goals. 
• Physical Therapy or gentle exercise is recommended to help delay joint stiffness (contractures). Since those with DMD are prone to overexertion, and exercise can promote excessive muscle degeneration, it is best to consult with a physiotherapist. Physical therapy is likely to involve stretches, range-of-motion exercises and low-intensity cardio, deep breathing exercises, and light weightlifting.
• Speech Therapy might be required to help those with throat muscle degradation to speak, eat and swallow better. It may also be necessary for children with learning disabilities or speech impediments.

Nutrition

Caregivers need to be aware that patients are at risk for obesity and ought to consume a healthy, nutrient-dense diet that promotes optimal metabolism. Calcium, vitamin D3 and vitamin K2 supplements are advisable to prevent or delay osteoporosis.

Physical Assistive Devices

Most children require a wheelchair by the time they reach 12 years of age and may rely on leg braces by 8-9 years. If children have reduced pulmonary function, they may need to rely on a wheelchair from an even younger age.

Orthopedic Surgery

Orthopedic surgery can help patients with DMD to correct or prevent deformities of the bones and joints, such as contractures, scoliosis, or fractures. It can improve the mobility, posture, and function of the patients, as well as reduce pain and complications. This is usually only recommended during the later stages of the disease course or if physiotherapy doesn’t help.

Respiratory Support

If respiratory problems start to develop due to cardiomyopathy and throat muscle weakness, a respirator may be required during the later stages. Some with DMD benefit from a cough-assisting device. In the early stages, breathing exercises and techniques may help to keep the diaphragm strong and to ensure proper breathing, especially if in a wheelchair.

Prognosis and Outlook

The prognosis and outlook for those with DMD are often poor. DMD causes progressive muscle weakness and wasting, leading to disability and early death. Most people with DMD succumb to heart or lung problems in their 20s or 30s.

Early diagnosis, treatment, care and supportive therapies can all help enhance the lives of patients with DMD. With advances in medical care and research, some people with DMD may live longer and better lives. Those applying for clinical trials or making use of current therapy tend to be mobile for longer with better posture and physical aptitude.

Current Research and Future Developments

Gene therapy is currently at the forefront of Duchenne muscular dystrophy treatment. Most currently approved therapies work with the genetic mutations that cause DMD by skipping over faulty parts of the gene that prevent a functional protein from being produced.^[10] While these therapies have improved measures of muscle weakness and have prolonged the time till a wheelchair is needed, they are not curative and are only capable of treating a fraction of those with DMD.

Recent research has been focusing on a definitive cure that aims to get muscle to produce functional dystrophin^[11]. Elevidys was one of the first treatments approved to achieve this goal, using a viral vector to deliver functional transcription units of the dystrophin gene to muscle, resulting in functional dystrophin production. While approved for boys aged 4-5, this therapy is still undergoing phase III clinical trials and isn’t proving as effective as researchers had hoped. Several similar therapies are being developed and refined, with promise for a curative option.

CAP-1002. CAP-1002 is a cutting-edge treatment currently in development that is designed to tackle cardiomyopathy induced by DMD. This therapy comprises specialized cardiac stem cells engineered to secrete micro-dystrophin in heart tissue alongside repair factors, resulting in improved heart function and repair. Studies reveal that this therapy also targets dystrophin deficits in skeletal muscle and is capable of enhancing its regeneration as well.^[12] CAP-1002 is currently recruiting for a phase III clinical^[13].

Conclusion

DMD is a recessive x-linked genetic condition in which the muscle becomes weak and progressively degenerates due to dystrophin loss. It mainly affects males who start to experience symptoms as early as 2 years of age. As the disease progresses, children are often wheelchair-bound by the age of 12 and usually succumb to heart muscle weakness, cardiomyopathy and respiratory issues in their twenties.

Treatment options involve steroids to slow down muscle degeneration, supportive therapies to help patients adjust to living with the disease, and gene therapy. Current gene therapy options show promising results, although they can only treat specific gene mutations and delay disease progression by a couple of years. Recent advances in Duchenne muscular dystrophy treatment aim to provide full relief from the condition by providing the body with a functional copy of the dystrophin gene, allowing cells to produce dystrophin.

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