Background

Duchenne muscular dystrophy which is genetic disorder characterized by progressive muscle degeneration and weakness. It is one of the common and severe forms of muscular dystrophy, predominantly affecting males. DMD is generally caused by mutations in the gene that encodes for the protein dystrophin, which is essential for maintaining the structure and stability of muscle fibers.

It is an X-linked recessive disorder means the mutated gene is on the X chromosome. Female individuals have two X chromosomes and male individuals have one X and another Y chromosome. Therefore, DMD primarily affects males because they have only one copy of the gene, and if that copy is mutated, they develop the disorder.

Females can be carriers of the DMD gene mutation but typically do not show symptoms. The dystrophin gene on the X chromosome at the Xp21 locus is the most significant in the human genome, consisting of 79 exons. Mutations in this gene result in absent or dysfunctional dystrophin protein production.

Dystrophin is a critical protein that plays a crucial role in stabilizing the muscle cell membrane. Without dystrophin, muscle fibers become fragile and prone to damage during muscle contraction and relaxation. The progressive degeneration of muscle fibers in DMD leads to muscle weakness, difficulty in motor functions, and loss of ambulation in early adolescence.

The disorder affects various muscles, including the limbs, trunk, and respiratory system. Symptoms usually become evident in early childhood, with delayed motor milestones such as difficulty walking, frequent falls, and inconvenience getting up from the floor. Calves often appear enlarged due to the infiltration of fat and connective tissue.

As the disease progresses, individuals with DMD may develop complications such as scoliosis (curvature of the spine), respiratory difficulties, cardiac dysfunction, and muscle contractures. Historically, DMD significantly impacted life expectancy, with most individuals not surviving beyond their late teens or early twenties due to respiratory or cardiac complications.

There is presently no known cure for DMD (Duchenne muscular dystrophy), but various treatments and interventions aim to manage symptoms, slow disease progression, and improve quality of life. These include corticosteroid medications, physical therapy, orthopedic interventions, respiratory support, and cardiac management.

Research efforts continue to explore potential therapies, including gene therapy, exon skipping, and other emerging approaches aimed at restoring or compensating for the lack of dystrophin protein. These advancements hold promise for future treatments and potential cures for DMD.

Epidemiology

Since Duchenne muscular dystrophy is an inherited disorder with X-linked recessive fashion, Male individuals are more commonly impacted compared to the females.

The approximate occurrence rate is 1 in 3600 male individuals live-born infants. Several investigations have approximated the frequency of Duchenne muscular dystrophy as 2 per 10,000 individuals in the American States. It stands as the one of most prevalent and grievous congenital myopathies.

Anatomy

Pathophysiology

The Duchenne muscular dystrophy (DMD) pathophysiology involves a cascade of events resulting from the absence or dysfunction of the dystrophin protein.

• Absence of dystrophin: Dystrophin is a large protein located at the inner surface of muscle fibers, where it connects the cytoskeleton to the extracellular matrix. It performs a crucial function in maintaining the structural integrity of muscle cells during contraction and relaxation. In DMD, mutations in the dystrophin gene lead to either the absence or a non-functional form of dystrophin.
• Disruption of the dystrophin-associated protein complex (DAPC): Dystrophin interacts with various proteins, including sarcoglycans, dystroglycans, and syntrophins, forming the DAPC. This complex provides stability to the muscle cell membrane during muscle contractions. The DAPC is disrupted without dystrophin, making muscle fibers more susceptible to damage.
• Membrane fragility and muscle fiber damage: The absence of dystrophin and the disruption of the DAPC result in increased vulnerability of muscle fibers to mechanical stress. During muscle contraction, the sarcolemma (cell membrane of muscle fibers) experiences excessive stress, leading to microtears and damage. Over time, repeated cycles of damage and repair contribute to the progressive degeneration of muscle fibers.
• Inflammation and immune response: The muscle fiber damage triggers an inflammatory response characterized by infiltrating immune cells, like macrophages and T cells, into the damaged muscle tissue. These immune cells generally release pro-inflammatory cytokines and chemokines, further promoting muscle fiber degeneration and impairing muscle regeneration.
• Muscle fiber regeneration and fibrosis: In response to muscle fiber damage, satellite cells (muscle stem cells) are activated and attempt to repair the damaged fibers. However, in DMD, the regenerative capacity is overwhelmed by ongoing degeneration, leading to inadequate muscle repair. Instead, fibrotic tissue, consisting of collagen and other extracellular matrix proteins, accumulates in the muscle, further impairing muscle function.
• Progressive muscle weakness and atrophy: The continuous cycle of muscle fiber degeneration, inflammation, and inadequate repair leads to progressive muscle weakness and atrophy. Initially, the lower limbs are primarily affected, resulting in difficulties with walking and motor functions. As the disease progresses, weakness spreads to other muscle groups, including those involved in breathing and cardiac function.
• Secondary complications: Progressive muscle weakness and loss of function in DMD can lead to various complications. These may include contractures (muscle tightness and joint deformities), scoliosis (curvature of the spine), respiratory insufficiency (due to weakened respiratory muscles), cardiomyopathy (heart muscle weakness), and other associated medical conditions.

Etiology

The primary etiology of Duchenne muscular dystrophy (DMD) is a genetic mutation in the dystrophin gene located on the X chromosome.

• Genetic inheritance: DMD is an X-linked recessive disorder, meaning it is caused by mutations in the dystrophin gene located on the X chromosome. Female individuals have two X chromosomes and male individuals have one X and another Y chromosome. Since DMD is recessive, females typically do not develop the disorder but can be carriers if they have one mutated copy of the dystrophin gene. Males, however, are more commonly affected since they have one X chromosome, and if it carries the mutation, they will develop DMD.
• Dystrophin gene mutation: The dystrophin gene is the largest in the human genome, consisting of 79 exons. Mutations in this gene disrupt the production or function of the dystrophin protein. The most common mutation in DMD is large-scale gene deletions, where one or more exons are missing. Other mutations include duplications, insertions, and point mutations (single nucleotide changes).
• Absence or dysfunctional dystrophin protein: Dystrophin is a crucial protein in maintaining muscle cells’ structural integrity. It connects the cytoskeleton of muscle fibers to the extracellular matrix. In DMD, the dystrophin gene mutations lead to the dystrophin protein’s absence or dysfunction. Without functional dystrophin, muscle fibers become fragile and prone to damage during muscle contractions.
• Spontaneous mutations: In some cases, DMD can occur due to spontaneous mutations in the dystrophin gene. These mutations are not inherited from either parent but arise as new changes in the affected individual’s genetic material. Spontaneous mutations account for a small percentage of DMD cases.
• Genetic carrier status: Females who carry one mutated copy of the dystrophin gene are called carriers. Carriers typically do not show symptoms of DMD because they have a second standard copy of the gene on their other X chromosome. However, carriers have a 50% chance of passing the mutated gene to their children, possibly having a child with DMD.
• Genetic testing: It is used to confirm the diagnosis of DMD and identify specific mutations in the dystrophin gene. This testing can also determine female carrier status and provide information for genetic counseling and family planning.

Genetics

Prognostic Factors

Prognostic factors in Duchenne muscular dystrophy (DMD) can help predict the course and outcome of the disease. These factors can vary among individuals, but here are some commonly recognized prognostic factors in DMD:

• Age at diagnosis: The age at which DMD is diagnosed can impact disease progression and prognosis. Early diagnosis allows for early intervention and management, which can help slow disease progression and improve outcomes.
• Genetic mutation: The specific mutation in the dystrophin gene can influence disease severity and progression. Different mutations can result in variations in the amount and functionality of the dystrophin protein, leading to differences in muscle degeneration and functional decline.
• Ambulation status: The ability to walk independently, referred to as ambulation status, is an important prognostic factor in DMD. Typically, individuals with DMD lose the ability to walk between the ages of 7 and 13. Those who lose ambulation earlier tend to have a more rapid disease progression and may experience more severe complications.
• Rate of disease progression: The disease progresses rate can vary among individuals with DMD. Some individuals may experience a slower decline in muscle function and have a milder course. In contrast, others may have a more rapid progression with early loss of ambulation and increased complications.
• Cardiac involvement: Cardiomyopathy, or heart muscle weakness, is a common complication of DMD. The extent and severity of cardiac involvement can significantly impact prognosis. Regular cardiac monitoring and management are essential to address complications and improve outcomes.
• Respiratory function: Progressive weakness of the respiratory muscles can lead to respiratory insufficiency and the need for ventilatory support. The decline in respiratory function and the timing of respiratory complications can affect prognosis and overall survival.
• Corticosteroid treatment: Corticosteroid medications, such as prednisone and deflazacort, are commonly prescribed in DMD. Early initiation and long-term use of corticosteroids have been shown to slow disease progression, preserve muscle function, and improve outcomes. Adherence to corticosteroid treatment and the response to therapy can influence prognosis.
• Supportive care and interventions: Access to comprehensive multidisciplinary care, including physical therapy, orthopedic interventions, respiratory support, and cardiac management, can significantly impact prognosis. Timely interventions and management of complications contribute to improved quality of life and potentially prolong survival.

Clinical History

Clinical history

Duchenne muscular dystrophy (DMD) clinical presentation typically manifests in early childhood and progresses over time. Here is a breakdown of the clinical presentation based on age group, associated comorbidities or activity, and acuity of presentation:

Age group:

• Early childhood: Symptoms of DMD often become apparent between the ages of 2-5 years. Boys may exhibit delayed motor milestones, such as delayed walking or difficulty running and climbing stairs. They may also display a waddling gait or walk on their toes. Gowers’ sign, characterized by using hands and arms to “climb up” their own body to stand from a sitting or lying position, is commonly observed.

Physical Examination

Physical examination

During a physical examination of a patient suspected of having Duchenne muscular dystrophy (DMD), a healthcare provider may look for various signs and perform specific assessments to evaluate muscle strength, motor function, and other associated features. Here are some critical components of a physical examination for DMD:

General appearance and growth assessment: The healthcare provider may observe the patient’s overall appearance, including body habitus, facial features, and growth parameters. Children with DMD may exhibit a characteristic appearance, such as a waddling gait, enlarged calf muscles (pseudohypertrophy), and difficulties with motor tasks.

Motor function assessment: The healthcare provider may assess the patient’s motor function, including muscle strength, coordination, and range of motion. They may ask the patient to perform specific movements, such as walking, running, hopping, and climbing stairs, to evaluate gross motor skills.

Gowers’ sign: The provider may assess for Gowers’ sign, a characteristic maneuver observed in DMD. This involves observing how the patient rises from supine (lying down) to standing. Patients with DMD often use their hands and arms to climb up their bodies, pushing against their legs due to weak proximal muscles.

Muscle strength evaluation: The healthcare provider may perform manual muscle testing to examine the strength of various muscle groups. They typically use the Medical Research Council (MRC) scale, ranging from 0 (no muscle contraction) to 5 (normal muscle strength). Muscle strength is commonly assessed in the lower limbs (hip flexors, knee extensors, ankle dorsiflexors) and upper limbs (shoulder abductors, elbow flexors, hand grip).

Joint range of motion and contractures: The provider may assess the range of motion of major joints, looking for any limitations or contractures (restricted movement due to muscle tightness). Commonly evaluated joints include the hips, knees, elbows, and ankles.

Cardiac evaluation: Given the cardiac involvement seen in DMD, a cardiac examination may assess heart sounds, detect any murmurs or abnormal rhythms, and evaluate signs of cardiomyopathy (e.g., heart enlargement).

Respiratory assessment: Since respiratory muscle weakness is a hallmark of DMD, the provider may assess respiratory function by monitoring the patient’s breathing pattern, respiratory rate, and signs of respiratory distress. Pulmonary function tests (P.F.T) may also be conducted to evaluate lung function.

Scoliosis evaluation: Scoliosis, a curvature of the spine, commonly occurs in DMD. The provider may assess the patient’s spinal alignment by evaluating the back for any asymmetry or abnormal curvature.

Age group

Associated comorbidity

Associated comorbidity or activity:

Muscle weakness and fatigue: Boys with DMD may experience progressive muscle weakness, particularly in the lower limbs. This weakness can lead to difficulties with activities requiring muscle strength, such as running, jumping, and climbing. Fatigue may also be evident after minimal exertion or physical activity.

Enlarged calves: Many boys with DMD have enlarged calf muscles, often due to fat and connective tissue infiltration. This is known as pseudohypertrophy and is a characteristic feature of the condition.

Cardiac involvement: DMD can cause cardiomyopathy, leading to muscle weakness. Symptoms of cardiac involvement may include shortness of breath, fatigue, palpitations, and chest pain.

Respiratory difficulties: Progressive weakness of the respiratory muscles can lead to respiratory insufficiency. Boys with DMD may exhibit respiratory difficulties such as frequent respiratory infections, difficulty breathing, diminished respiratory function, and bad cough.

Skeletal abnormalities: As DMD progresses, boys may develop skeletal abnormalities, including scoliosis (curvature of the spine), joint contractures (muscle tightening and limited joint movement), and decreased bone density.

Associated activity

Acuity of presentation

The acuity of presentation:

Gradual progression: The clinical presentation of DMD usually exhibits a gradual progression, with symptoms worsening over time. The initial signs, such as delayed motor milestones, may be subtle, and the rate of progression can vary among individuals.

Differential Diagnoses

Differential Diagnosis

When evaluating a patient with suspected Duchenne muscular dystrophy (DMD), healthcare providers consider several differential diagnoses to rule out conditions that might present with similar symptoms. Here are some critical differential diagnoses to consider:

• Becker muscular dystrophy (BMD): BMD is a milder form of muscular dystrophy which is caused by mutations in the same dystrophin gene as DMD. While DMD typically presents in early childhood and progresses rapidly, BMD often has a later onset, typically in adolescence or adulthood, and progresses more slowly. Muscle weakness and complications are generally less severe in BMD compared to DMD.
• Spinal muscular atrophy (SMA): SMA is an autosomal recessive neuromuscular disorder characterized by progressive muscle weakness and atrophy. It is caused by survival motor neuron (SMN1) gene mutations. SMA can have similar features to DMD, but it typically lacks the characteristic pseudohypertrophy seen in DMD. SMA is associated with specific patterns of weakness, such as proximal muscle weakness and preserved strength in the face and extraocular muscles.
• Limb-girdle muscular dystrophy (LGMD): LGMD refers to a group of genetic muscular dystrophies that primarily affect the muscles around the shoulders and hips (limb-girdle region). The age of onset, progression, and pattern of muscle involvement can vary depending on the specific subtype of LGMD. LGMD can sometimes be distinguished from DMD by a milder course, later onset, and more variable involvement of other muscle groups.
• Myotonic dystrophy (DM): Myotonic dystrophy is a multisystem disorder characterized by myotonia (prolonged muscle contractions) and muscle weakness. It is caused by mutations in the DMPK gene (DM1) or the CNBP gene (DM2). While DMD primarily affects skeletal muscle, myotonic dystrophy involves multiple organ systems and can present with various symptoms, including muscle stiffness, weakness, cardiac abnormalities, and cognitive impairment.
• Congenital muscular dystrophy (CMD): CMDs are a group of genetic disorders that cause the muscle weakness and hypotonia from birth or early infancy. They are typically associated with abnormalities in muscle structure and function. Different subtypes of CMD have specific clinical features and genetic mutations. These conditions may present distinct patterns of muscle weakness, joint contractures, and associated organ involvement.
• Metabolic myopathies: Certain metabolic disorders, such as mitochondrial myopathies or glycogen storage diseases, can present with muscle weakness and fatigue. These conditions are often associated with specific metabolic abnormalities, including abnormal energy production or storage. Differentiating metabolic myopathies from DMD may require specialized metabolic testing, including enzyme assays, genetic testing, or muscle biopsy.

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

Treating Duchenne muscular dystrophy (DMD) involves a multidisciplinary approach to managing symptoms, preserving muscle function, and improving quality of life. Here are the different components of DMD treatment based on the given categories:

Modification of environment:

• Physical therapy and exercise: Regular physical therapy, including stretching and strengthening exercises, can help maintain muscle function, improve mobility, and prevent contractures. Physical therapists can provide individualized exercise programs based on the patient’s abilities and needs.
• Assistive devices: Depending on the stage of the disease, assistive devices such as braces, orthotics, wheelchairs, or mobility aids may be recommended to support mobility and independence.
• Environmental adaptations: Modifying the home environment, such as installing ramps, grab bars, and adaptive equipment, can help optimize accessibility and safety for individuals with DMD.

Administration of a pharmaceutical agent:

• Corticosteroids: Corticosteroids have been shown to slow disease progression, preserve muscle strength, and improve motor function. They are typically initiated early in the disease course and used long-term under medical supervision.
• Emerging therapies: Several novel therapeutic approaches are being investigated in clinical trials for DMD. These include exon-skipping drugs, gene therapy, and other targeted treatments for the underlying genetic defect.

Intervention with a procedure:

• Cardiac management: Regular cardiac monitoring, including echocardiograms and electrocardiograms, is vital to detect and manage DMD-related cardiac complications. Cardiac medications, such as angiotensin-converting enzyme inhibitors or beta-blockers, may be prescribed to manage cardiomyopathy and support cardiac function.
• Respiratory support: Individuals with DMD may require interventions to support breathing as respiratory muscles weaken. This can include non-invasive ventilation, such as continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP), to assist with breathing during sleep or respiratory insufficiency. In advanced stages, invasive ventilation via tracheostomy may be necessary.

The phase of management:

• Early-stage management: In the early stages of DMD, the focus is on maintaining mobility, preventing contractures, and optimizing physical function through physical therapy, exercise, and corticosteroid treatment.
• Intermediate stage management: As the disease progresses and mobility declines, assistive devices, environmental modifications, and respiratory support may be required. Regular monitoring of cardiac and respiratory function becomes crucial.
• Advanced stage management: In the advanced stages of DMD, interventions such as ventilatory support, feeding assistance, and comprehensive palliative care may be needed to address the complex medical and supportive care needs of the individual.

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

Medication

Future Trends

Media Gallary

References

Duchenne Muscular Dystrophy – StatPearls – NCBI Bookshelf (nih.gov)