Duchenne Muscular Dystrophy (DMD)

Overview

Plain-Language Overview

Duchenne Muscular Dystrophy (DMD) is a genetic disorder that causes progressive muscle weakness and loss of muscle mass. It primarily affects boys and usually begins in early childhood. The condition is caused by a mutation in the gene responsible for producing dystrophin, a protein essential for muscle strength and stability. As the disease progresses, individuals may have difficulty walking, and eventually, the muscles used for breathing and the heart can be affected. Although there is currently no cure, treatments focus on managing symptoms and improving quality of life.

Clinical Definition

Duchenne Muscular Dystrophy (DMD) is an X-linked recessive neuromuscular disorder characterized by mutations in the DMD gene encoding the protein dystrophin, which is critical for maintaining the structural integrity of muscle cell membranes. The absence or severe deficiency of dystrophin leads to progressive muscle fiber degeneration and replacement by fibrofatty tissue. Clinically, DMD presents in early childhood with delayed motor milestones, proximal muscle weakness, and calf pseudohypertrophy. Patients typically lose ambulation by the early teenage years. Cardiac involvement, including dilated cardiomyopathy, and respiratory failure are common complications. Diagnosis is supported by elevated serum creatine kinase levels, genetic testing, and muscle biopsy showing dystrophin deficiency. The disease course is progressive and fatal, with most patients succumbing to respiratory or cardiac failure in the third decade of life. Management is multidisciplinary, focusing on corticosteroid therapy, respiratory support, and cardiac care.

Inciting Event

There is no specific inciting event; the disease is caused by genetic mutations present from birth.

Latency Period

none

Diagnostic Delay

Early symptoms such as motor delay and mild weakness may be mistaken for normal variation or other conditions, delaying diagnosis.
Lack of awareness about the disease among caregivers and some clinicians can contribute to delayed recognition.
Initial symptoms may be subtle, leading to delayed referral for genetic testing or muscle biopsy.

Clinical Presentation

Signs & Symptoms

Progressive proximal muscle weakness beginning in early childhood.
Delayed motor milestones such as walking.
Frequent falls due to muscle weakness.
Enlarged calf muscles (pseudohypertrophy).
Respiratory difficulties from diaphragm weakness.

History of Present Illness

Progressive muscle weakness beginning in the proximal lower limbs, often noticed as difficulty running or climbing stairs.
Frequent falls and difficulty rising from the floor, often described as using the Gowers' maneuver.
Enlarged calf muscles due to pseudohypertrophy.
Delayed motor milestones such as walking independently.

Past Medical History

History of delayed motor development or early muscle weakness.
Possible recurrent respiratory infections due to weakened respiratory muscles in advanced disease.
No prior illnesses directly cause DMD but comorbidities may affect disease progression.

Family History

Positive family history of X-linked muscular dystrophy or known DMD mutations.
Affected male relatives with similar symptoms or early loss of ambulation.
Carrier females may have mild symptoms or be asymptomatic.

Physical Exam Findings

Presence of Gowers' sign indicating proximal muscle weakness.
Pseudohypertrophy of the calf muscles due to fat and connective tissue replacement.
Waddling gait caused by hip girdle muscle weakness.
Decreased deep tendon reflexes in affected muscles.

Diagnostic Workup

Diagnostic Criteria

The diagnosis of Duchenne Muscular Dystrophy (DMD) is established by identifying a pathogenic mutation in the DMD gene through genetic testing, accompanied by clinical features such as progressive proximal muscle weakness and elevated serum creatine kinase levels. Muscle biopsy demonstrating absent or markedly reduced dystrophin protein supports the diagnosis when genetic testing is inconclusive. Early onset of symptoms, typically before age 5, and characteristic findings such as calf pseudohypertrophy and loss of ambulation by early adolescence further confirm the diagnosis.

Pathophysiology

Key Mechanisms

Duchenne Muscular Dystrophy results from mutations in the DMD gene leading to absence of the dystrophin protein, which destabilizes the muscle cell membrane.
Lack of dystrophin causes increased susceptibility to muscle fiber damage during contraction, leading to progressive muscle degeneration and replacement by fibrofatty tissue.
The absence of dystrophin disrupts the dystrophin-glycoprotein complex, impairing sarcolemma integrity and calcium homeostasis.

Involvement	Details
Organs	Heart is commonly involved in DMD, with cardiomyopathy causing heart failure.
Organs	Lungs are affected due to respiratory muscle weakness leading to respiratory insufficiency.
Tissues	Skeletal muscle tissue undergoes progressive fibrosis and fatty replacement in DMD.
Tissues	Cardiac muscle tissue is affected leading to dilated cardiomyopathy in advanced disease.
Cells	Skeletal muscle fibers are the primary cells affected in DMD, undergoing degeneration due to dystrophin deficiency.
Cells	Satellite cells are muscle stem cells involved in muscle regeneration but become exhausted in DMD.
Chemical Mediators	Creatine kinase is elevated in serum as a marker of muscle damage in DMD.
Chemical Mediators	Inflammatory cytokines such as TNF-alpha contribute to muscle inflammation and degeneration.

Treatment

Pharmacological Treatments

Corticosteroids
- Mechanism: Reduce inflammation and slow muscle degeneration by modulating immune response and stabilizing muscle cell membranes
- Side effects: Weight gain, osteoporosis, hypertension, glucose intolerance
Exon-skipping agents (e.g., eteplirsen)
- Mechanism: Promote skipping of mutated dystrophin gene exons to restore partially functional dystrophin protein production
- Side effects: Injection site reactions, potential kidney toxicity

Non-pharmacological Treatments

Physical therapy maintains muscle strength and prevents contractures.
Use of assistive devices improves mobility and independence.
Respiratory support such as non-invasive ventilation helps manage respiratory failure.
Cardiac monitoring and management prevent complications from cardiomyopathy.

Prevention

Pharmacological Prevention

Corticosteroids (e.g., prednisone, deflazacort) to slow muscle degeneration.
ACE inhibitors and beta-blockers to manage and delay cardiomyopathy progression.

Non-pharmacological Prevention

Regular physical therapy to maintain muscle strength and prevent contractures.
Use of assistive devices such as braces and wheelchairs to support mobility.
Respiratory support including non-invasive ventilation as disease progresses.
Cardiac monitoring with regular echocardiograms and MRI.

Outcome & Complications

Complications

Respiratory failure from progressive respiratory muscle weakness.
Cardiac failure due to dilated cardiomyopathy.
Contractures and joint deformities from muscle fibrosis.
Obesity related to decreased mobility.

Short-term Sequelae	Long-term Sequelae
Increased fatigue and muscle weakness limiting daily activities. Frequent falls and difficulty with ambulation. Early signs of respiratory insufficiency such as dyspnea on exertion.	Progressive loss of ambulation typically by early adolescence. Chronic respiratory failure requiring ventilatory support. End-stage cardiomyopathy leading to heart failure. Severe contractures and skeletal deformities.

Differential Diagnoses

Duchenne Muscular Dystrophy (DMD) versus Becker Muscular Dystrophy (BMD)

Duchenne Muscular Dystrophy (DMD)	Becker Muscular Dystrophy (BMD)
Onset in early childhood (before age 5) with rapid progression.	Onset typically in adolescence or early adulthood with slower progression.
Muscle biopsy shows absence of dystrophin protein.	Muscle biopsy shows partially functional dystrophin with reduced quantity.
Serum creatine kinase (CK) levels are markedly elevated, often 10-100 times normal.	Serum creatine kinase (CK) levels are elevated but generally lower than in DMD.

Duchenne Muscular Dystrophy (DMD) versus Polymyositis

Duchenne Muscular Dystrophy (DMD)	Polymyositis
Onset in early childhood with progressive muscle weakness and calf pseudohypertrophy.	Elevated serum CK with inflammatory markers and presence of autoantibodies.
Muscle biopsy shows absence of dystrophin without inflammatory infiltrates.	Muscle biopsy shows inflammatory infiltrates with muscle fiber necrosis.
No systemic inflammatory markers or autoantibodies present.	Symmetric proximal muscle weakness develops over weeks to months in adults.

Duchenne Muscular Dystrophy (DMD) versus Spinal Muscular Atrophy (SMA)

Duchenne Muscular Dystrophy (DMD)	Spinal Muscular Atrophy (SMA)
Muscle weakness is primarily proximal with pseudohypertrophy of calves.	Lower motor neuron signs predominate with muscle atrophy and fasciculations.
Absent or severely reduced dystrophin on muscle biopsy.	Normal dystrophin levels on muscle biopsy.
No SMN1 gene mutation; diagnosis confirmed by dystrophin gene analysis.	Genetic testing reveals SMN1 gene deletion or mutation.