Duchenne Muscular Dystrophy: Understanding Pathophysiology and Disease Burden

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ABSTRACT

Duchenne muscular dystrophy (DMD) is a rare neuromuscular disease that continues to result in progressive loss of ambulation, respiratory failure, cardiomyopathy, and early mortality. This disease imposes a substantial and rising economic burden on patients, caregivers, and the health care system, with total spending estimated at many times that of unaffected individuals and costs increasing further as patients transition from ambulatory to nonambulatory disease stages.

Diagnosis is frequently delayed by several years and the recent addition of DMD to the Recommended Uniform Screening Panel for newborn screening is expected to shift diagnosis increasingly into the presymptomatic period, raising new questions about when disease-modifying therapy should begin. Fragmented coverage across pharmacy and medical benefits and the logistical demands of lifelong multidisciplinary care compound the challenges families face in accessing and coordinating appropriate treatment.

As additional medications such as exon-skipping therapies advance through clinical development, the number of DMD therapies available through accelerated pathways is likely to grow, along with the volume of additional evidence that must be tracked and incorporated into coverage policy over time. Managed care professionals must balance evolving labeling and clinical data, particularly given the irreversible nature of muscle loss in DMD.

Introduction

Duchenne muscular dystrophy (DMD) is a progressive, X-linked neuromuscular disorder caused by pathogenic variants in the DMD gene, typically resulting in absent or markedly reduced functional dystrophin.¹ Affecting approximately 1 in 3500 to 5000 live male births worldwide, DMD is the most prevalent inherited muscular disease of childhood.² Although advances in multidisciplinary care and supportive therapies have improved survival and quality of life, DMD remains a lethal disease, phenotypically characterized by skeletal muscle degeneration, progressive respiratory and cardiac dysfunction, loss of ambulation, and premature mortality.² As treatment options have evolved from adjunctive care to precision medicine, understanding the molecular basis of DMD has become increasingly important for managed care professionals responsible for formulary development, utilization management, and coverage decisions.

Pathophysiology, Genetics, and Natural History

The DMD gene, located on the X chromosome, is the largest known human gene, spanning 79 exons and 2.2 Mb.³ The gene encodes dystrophin, a large cytoskeletal protein that serves as an essential structural and signaling component within skeletal, cardiac, and smooth muscle cells.^3,4 The primary role of dystrophin is to function as a mechanical stabilizer by preserving sarcolemmal integrity during muscle contraction.⁵ When dystrophin is absent or deficient, muscle fibers become highly susceptible to contraction-induced injury.⁵ Repeated contraction-induced damage initiates a continuous cycle of myofiber degeneration and attempted regeneration, worsened by chronic inflammation, oxidative stress, and progressive remodeling of muscle tissue.⁵ Over time, healthy contractile muscle is progressively replaced by adipose and fibrotic tissue, resulting in irreversible loss of muscle function.⁵ Importantly, dystrophin is expressed in tissues beyond skeletal muscle, including respiratory, cardiac, and gastrointestinal smooth muscle.⁵

Because of its large size, the DMD gene is susceptible to numerous mutations and genomic rearrangements that produce varying effects on dystrophin isoforms, including reduced expression, altered protein size, or complete loss of functional dystrophin.⁴ Dystrophinopathies encompass a spectrum of disease severity, with Becker muscular dystrophy (BMD) representing a generally milder phenotype than DMD. In BMD, pathogenic DMD variants typically permit production of partially functional dystrophin, resulting in later onset and slower progression of muscle weakness, although substantial clinical variability exists. More than 4000 pathogenic DMD variants have been identified, with the most common alterations consisting of large exon deletions, exon duplications, and smaller sequence variants such as point mutations.⁶ Pathogenic variants causing DMD typically disrupt the reading frame, resulting in premature termination and absent or markedly reduced functional dystrophin.⁶ The resulting absence or near-absence of dystrophin leads to the severe phenotype characteristic of DMD.⁶

Pathogenic variants are not distributed uniformly throughout the DMD gene but instead cluster within several mutational “hot spots.”⁶ The first encompasses exons 2 through 20 and accounts for approximately 15% of exon deletions and nearly half of exon duplications, with deletions involving exons 3 through 7 occurring most frequently.⁶ The second hot spot spans exons 45 through 55 and accounts for roughly 70% of exon deletions.⁶ This region is particularly relevant to current clinical practice because many FDA-approved exon-skipping therapies target mutations affecting these exons.⁶ As a result, comprehensive molecular genetic testing is essential, not only to establish the diagnosis, but also to identify what mutation-specific treatments patients may be eligible for.

Clinical Presentation

Although DMD is present at birth, classical clinical manifestations typically become more obvious as children experience delayed gross motor milestones.⁷ Importantly, DMD is phenotypically heterogeneous, with substantial variability in the onset and rate of disease progression among affected individuals. Parents commonly report delayed gross motor milestones, difficulty running or climbing stairs, frequent falls, toe walking, or difficulty rising from the floor using the characteristic Gower sign.⁷ Calf pseudohypertrophy resulting from fatty infiltration of muscle tissue is another typical early clinical finding.⁷

Early symptoms, including poor head control, delayed independent sitting, crawling, standing, and walking, are often subtle and not uncommonly attributed to developmental variation, contributing to delays in diagnosis.⁷ In a recent parent-reported study, infants with DMD demonstrated measurable delays as early as 2 to 3 months of age across multiple developmental domains, including gross and fine motor skills, adaptive behavior, personal and social development, and communication.⁷ These findings indicate that the earliest manifestations of DMD can be detectable long before diagnosis is typically established.

The average age at confirmed diagnosis is approximately 4 to 5 years, representing a delay of up to 2 years from symptom onset.⁷ Notably, this interval has changed little over the past 2 decades despite sustained efforts by public health agencies and patient advocacy organizations to improve disease recognition and facilitate earlier diagnosis.⁷ This persistent gap is particularly concerning given the progressive and irreversible nature of muscle degeneration, as treatment delays may result in permanent loss of muscle tissue before disease-modifying therapies can be initiated.⁷

DMD follows a predictable but heterogeneous pattern of functional decline.⁸ Although the timing and rate of progression vary among individuals, progressive and irreversible muscle loss begins years before overt functional deterioration becomes clinically evident.⁸

During early childhood, most patients remain ambulatory but exhibit progressive proximal muscle weakness and declining motor performance.⁸ In this phase, cognitive abnormalities may become apparent.⁸ Intellectual disabilities were reported in more than one-third of patients living with DMD, and 11.7%, 3.1%, and 20% exhibited attention-deficit/hyperactivity disorder, autism spectrum disorder, and moderate to severe reading problems, respectively.⁹

Motor development improves or remains relatively stable during early childhood before reaching a plateau and subsequently declining, although the timing of this transition varies among individuals.⁸ Thereafter, progressive muscle weakness results in the gradual loss of acquired motor abilities.⁸ Historically, loss of ambulation commonly occurred during the early teenage years; however, the timing is variable and has shifted with contemporary corticosteroid use, multidisciplinary care, and disease-modifying therapies.⁹ As lower extremity function deteriorates, upper extremity weakness becomes increasingly disabling, further limiting independence.⁸ Progressive scoliosis frequently develops following wheelchair dependence and may further compromise respiratory function.⁹

Cardiac and pulmonary complications become increasingly prominent during adolescence and adulthood.⁹ Progressive cardiomyopathy and respiratory muscle weakness contribute to increasing cardiac and respiratory morbidity, with some individuals ultimately requiring noninvasive or invasive ventilatory support.⁹ Despite improvements in respiratory and cardiac management, cardiac or respiratory failure remain leading causes of mortality in DMD.⁹

Notably, disease progression reflects cumulative structural loss of muscle tissue, as seen in TABLE 1.^7-9 Genotype, genetic modifiers, corticosteroid exposure, supportive care, and disease-modifying therapies can influence individual functional trajectories. Accordingly, age-based descriptions of disease progression represent population-level patterns rather than fixed milestones for an individual patient. As functional muscle is progressively replaced by fibrofatty tissue, regenerative capacity becomes increasingly limited and established muscle loss is largely irreversible.⁵ This biologic principle has profound implications for treatment timing, supporting intervention before substantial irreversible muscle loss has occurred.

Diagnosis

Prompt testing is recommended for patients with suspected DMD, beginning with determination of serum creatine kinase (CK) levels.⁸ If DMD is strongly suspected based on clinical presentation and elevated CK levels, next-generation sequencing techniques are used. If initial multiplex ligation-dependent probe amplification (MLPA) results for deletion/duplication analysis are negative, sequencing of the DMD gene should be performed to identify smaller sequence variants, including nonsense, frameshift, splice-site, and other pathogenic variants. Precise molecular characterization establishes the diagnosis, informs prognosis, identifies carrier status among family members, enables targeted carrier testing and reproductive counseling for at-risk family members, and determines eligibility for mutation-specific therapies.⁸ For exon-skipping therapies, eligibility depends on whether skipping a specific exon is predicted to restore the dystrophin reading frame for the individual pathogenic variant, rather than simply on the presence or absence of a particular exon.

Recognition of the importance of early detection reached a significant milestone on December 16, 2025, when the US Department of Health and Human Services (HHS) accepted the recommendation to add DMD to the Recommended Uniform Screening Panel (RUSP) for newborn screening.¹⁰ The RUSP identifies conditions that HHS recommends states include in their universal newborn screening programs; however, states ultimately determine which conditions are included and the timing of implementation.¹⁰ As of September 2026, newborn screening has been implemented in Massachusetts, Minnesota, and Ohio, with other states pending implementation.¹¹ The expansion of newborn screening is therefore expected to shift DMD diagnosis increasingly into the presymptomatic period, creating new clinical and coverage considerations regarding when to initiate disease-modifying therapy in children who have not yet developed measurable functional impairment.

Earlier diagnosis offers important advantages. It enables earlier engagement with multidisciplinary care, anticipatory cardiac and pulmonary surveillance, rehabilitation interventions, and timely consideration of corticosteroid and disease-modifying therapies when clinically appropriate.⁸ Early identification and molecular characterization also establish eligibility for genotype-specific therapies and clinical trials.³ In addition, earlier diagnosis can shorten the diagnostic odyssey for patients and families and facilitate genetic counseling and testing of at-risk family members.

Disease Burden

Historically, DMD was associated with markedly reduced survival, with respiratory failure representing a major cause of early mortality.¹² Advances in respiratory support, cardioprotective management, corticosteroid therapy, and coordinated multidisciplinary care have substantially improved survival, and many individuals with DMD now live into their fourth decade of life and beyond.¹²

The burden of DMD extends far beyond physical disability. Progressive loss of independence can affect multiple dimensions of health-related quality of life (HRQOL), including psychological well-being, social participation, relationships, school and work, and the ability to perform activities of daily living (ADLs).¹³ A systematic review of 45 studies identified a broad range of physical, psychological, social, and well-being domains relevant to individuals with DMD, highlighting the multidimensional impact of the disease on HRQOL.¹³ As mobility declines, patients experience increasing difficulty performing ADLs; participating in school, work, and recreational activities; and maintaining social relationships.¹³ Progressive dependence on mobility aids and caregivers can further limit independence and contribute to reduced participation in activities.¹³ Importantly, physical disability and HRQOL are not synonymous; individuals with DMD may report better quality of life than would be inferred from functional impairment alone.

The review also demonstrated that DMD imposes a substantial burden on caregivers and the broader family.¹³ Greater caregiver burden is consistently associated with worsening patient functional status and the amount of time devoted to daily caregiving.¹³ Caregivers frequently report symptoms of depression, anxiety, sleep disturbance, emotional distress, and reduced participation in work, leisure activities, and social relationships.¹³ Financial strain is common, with many families reporting financial difficulties related to the costs of care.¹³ Caregiver and family costs may include direct medical and nonmedical expenses, home modifications and assistive equipment, travel related to medical care, and indirect costs associated with reduced employment, absenteeism, or impaired work productivity. Caregiver burden may also increase during major disease transitions, including loss of ambulation, while uncertainty regarding treatment access and future care can contribute additional stress.¹³ Importantly, DMD affects the wider family, with parents reporting adverse effects on family functioning and sibling well-being.¹³ Collectively, these findings underscore that the burden of DMD extends well beyond the patient and should be considered when evaluating the overall clinical and societal impact of the disease.

The burden of treatment adverse effects should also be noted. Corticosteroids are the cornerstone of DMD management because they prolong ambulation, preserve pulmonary function, and slow the progression of muscle degradation.² However, these benefits must be balanced against the substantial toxicity profile associated with chronic corticosteroid exposure.² The adverse effects of chronic corticosteroid exposure are well documented; complications include growth suppression, weight gain, Cushingoid features, osteoporosis and fractures, behavioral and mood disturbances, hypertension, glucose intolerance, cataracts, adrenal suppression, and increased susceptibility to infection.¹⁴ Recognizing these risks, the Duchenne Muscular Dystrophy Care Considerations recommend proactive surveillance, mitigation, and management of corticosteroid-related toxicities.^15-17 Patients on corticosteroids require ongoing multidisciplinary monitoring, including assessment of growth, weight, blood pressure, pubertal development, adrenal function, glucose metabolism, ocular complications, behavioral health, and bone health.¹⁴ Bone-health surveillance includes assessment for vertebral and long-bone fractures and evaluation of bone mineral density when clinically appropriate, rather than reliance on DEXA alone. These surveillance and management needs add to the overall treatment burden for individuals with DMD and their families and require coordination across multiple disciplines.

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