Duchenne muscular dystrophy (DMD)

Duchenne muscular dystrophy (DMD) is a rare, genetic neuromuscular disorder that is caused by mutations in the dystrophin gene.¹ The disease is characterized by progressive decline in muscle function, leading to loss of ambulation and respiratory and cardiac failure.¹

DMD is included under a spectrum of dystrophinopathies, which encompass incurable muscle diseases arising from mutations in the dystrophin gene. The severity of symptoms ranges from mild (such as asymptomatic hyperCKemia) to severe and progressive (Becker muscular dystrophy [BMD] and DMD).^2–5

What is dystrophin?

Dystrophin provides stability and structure to the muscle fiber and membrane during contraction.⁶ It is expressed in skeletal and cardiac muscle and localizes to the cytoplasmic face of the muscle cell plasma membrane, or sarcolemma.^7–10 As part of the dystroglycan complex, dystrophin ensures connection of the intracellular contractile machinery to the extracellular matrix of myocytes, which provides mechanical support to skeletal or cardiac plasma membranes during contractions.^6,10

DMD is caused by mutations in the dystrophin gene that result in an absent or defective dystrophin protein.^1,2

The dystrophin gene is one of the longest human genes known and contains 79 exons.¹¹

Overall, more than 7000 mutations, including deletions, duplications, and small mutations, have been identified in the dystrophin gene, many of which are clinically relevant.^11,12

DMD is an X-linked recessive disorder that primarily affects males^13,14
Mutations in the dystrophin gene follow an X-linked recessive inheritance pattern. Where the mutation is inherited, each son will have a 50% chance of inheriting the defective gene from his mother.⁹ Although daughters may also inherit the defective gene with equal probability, the presence of a normal dystrophin gene inherited paternally is compensatory, typically resulting in asymptomatic or milder forms of the disease in females.^13,15

Several different mutation types can prevent the creation of a full-length, functional dystrophin protein¹⁶
The most frequent mutations observed in the dystrophin gene are:^11,16

1. Deletions (~68%) of ≥1 exon
2. Duplications (~11%) of ≥1 exon
3. Small mutations (~20%) usually involving ≤3 base pairs, such as:
   • small deletions or insertions, splice site mutations, and nonsense mutations
4. Other rare types of mutation, such as intronic mutations and missense mutations, which comprise the remaining <1%

The more severe phenotypes of DMD may typically be associated with mutations that disrupt the open reading frame, resulting in truncated, nonfunctional protein. The more variable phenotype of Becker muscular dystrophy (BMD), a milder form of inherited, progressive muscle wasting (vs DMD), is associated, in most cases, with in-frame deletions that result in an abnormal, smaller, but still functional, dystrophin protein.^4,15,16 The reading frame hypothesis holds for just over 90% of cases, however, exceptions exist.¹⁵ These involve patients with BMD carrying frame-shift deletions or duplications or DMD with in-frame deletions/duplications.¹⁵

Dysfunctional or absent dystrophin leads to muscle degeneration and fibrosis^17,18
As a result of absent or dysfunctional dystrophin, the connection between the actin cytoskeleton and connective tissue is lost and muscle fibers are easily damaged during contraction, leading to chronic muscle damage, inflammation and eventually replacement of muscle fibers by fat and fibrotic tissue and thus loss of muscle function.¹⁷

Loss of muscle tissue begins in infancy and is irreversible^13,19
The absence of dystrophin in DMD results in ongoing muscle damage and replacement of muscle fibers by scar tissue and fat.^18,19

• By the age of 5, prominent muscle weakness becomes evident with a 50–60% drop in strength²¹
• By age 6, only 60% of predicted muscle mass is retained, decreasing to just 20% at age 16²²

DMD occurs in 1 in every 3600 to 6000 live male births with no family history in ~30% of cases, whereas only 10% of female carriers show any disease manifestation.^13,23–25

Although phenotypes for affected girls are usually much milder than in boys, in rare cases of chromosomal rearrangement or skewed X inactivation the disease severity can be similar to that seen in affected boys.¹³

In the US, the estimated prevalence of Duchenne and Becker muscular dystrophy was 1.38 per 10 000 male individuals in 2010 according to the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) Data and Statistics.^26,27 The prevalence of DMD was three times higher than the prevalence of BMD.²⁶

Challenge in recognizing the signs and symptoms of DMD may result in diagnostic delay.^28,29

A challenge to initial diagnosis is spontaneous mutation of the DMD gene. This occurs in approximately one third of cases in which spontaneous mutations occur with no family history of DMD.³⁰

In patients with DMD:

• Average delay in diagnosis (from first symptoms) ranges from 1.3 to ~2.5 years^23,31
• Average age at diagnosis is between 4.3 and 4.11 years^29,31

Diagnostic delay in DMD may occur for several reasons. Firstly, heterogeneity of presentation may slow recognition by healthcare professionals. Additionally, parental factors may play a part in widening the diagnostic timeframe, owing to hesitance in searching for a diagnosis due to conflicting feelings, as revealed during interviews.³²

Recognizing suggestive signs and symptoms
DMD can be suspected in early childhood with delayed motor milestones, including delays in sitting and standing independently. The first symptoms of DMD identified by parents are typically general motor delays which include: clumsiness and frequent falling, gait problems including toe-walking, flat-footedness and delay in walking. Additional symptoms that may raise suspicion of DMD include learning and speech problems.^1,2

The Gowers’ sign, a maneuver used to rise from a supine position in which a child uses their upper arms, pushing on their legs to compensate for weak pelvic muscles, is also a common early sign of the disease that can be detected.^33,34

Earlier identification of motor delays allows for timely referral for developmental interventions as well as diagnostic evaluations and treatment planning.³⁵

Other signs and symptoms of DMD:

• Elevated serum creatine kinase (CK) or transaminases^1,36–38
• Cognitive delay^1,25
• Calf hypertrophy^1,25
• Abnormal gait^1,23

Elevated CK levels reflect muscle damage and are a sign of certain neuromuscular disorders.^39–41 A CK test should be ordered if:

• Positive family history with suspicion of abnormal muscle function^1,28
• Developmental delay, such as difficulty rising to stand or not walking well by 16–18 months^1,28
• Unexplained increases in transaminases^1,28

Genetic testing can confirm DMD
Genetic diagnosis is required to confirm DMD and to identify the specific mutation causing the disease.¹ It is the only method for determining a patient’s specific mutation type.^1,16

• An understanding of the specific DMD-causing mutation is important because it may help identify medical management options and potential to enroll into clinical trials¹⁶
• Carrier testing may help reduce the transmission of DMD and improve outcomes for women at risk^1,43

The natural history of DMD follows a relentless, progressive course during which patients lose functional ability over time.¹

Interventions that potentially modify the natural history of DMD may be of greater benefit in the less damaged muscles of younger children.^9,29,31

Loss of ambulation is a key predictor of disease progression¹⁹
Loss of ambulation is a key predictor of disease progression, including severe respiratory insufficiency and death due to respiratory failure.¹⁹ Loss of ambulation at a younger age is associated with earlier and more severe respiratory failure.¹⁹

The management of DMD involves many healthcare professionals, and coordination among them is crucial to maximizing therapeutic benefit¹
The DMD Care Considerations Guidelines suggest that upon confirmed diagnosis, a neuromuscular specialist should coordinate care across specialties and interventions.¹ Along with improved patient survival, subspecialties caring for DMD patients have shifted to more anticipatory strategies to achieve prevention, earlier diagnosis, and better treatment of predictable and potentially modifiable disease complications.¹

According to recommendations published by the DMD Care Considerations Working Group, patients, caregivers, and providers should engage in yearly discussion of long-term treatment goals and make use of resources that allow for proactive planning for unique health-related issues in DMD.⁴⁵

Multiple adaptations to daily living are required as a result of DMD, and environmental accessibility becomes a concern when patients experience loss of function in lower limbs, upper limbs, and respiration^45,46
Adaptations to daily living are required beginning at the earliest stages of DMD, which include:^1,45

• Changes in diet to help prevent obesity and malnutrition
• Submaximal aerobic activities and stretching to help reduce the risk of contracture and deformity, and minimization of falls to prevent fractures

Transition of care is needed to help patients navigate from adolescence to adult life
Considerations during the transition from pediatric to adult healthcare should include home accessibility and assistive technology, education and vocational planning, and independent transportation to maintain activities of adulthood.⁴⁵

The 2018 DMD Care Considerations Working Group recommends monitoring psychosocial issues and referral to a psychologist and/or speech-language pathologist when appropriate for:⁴⁵

• Intellectual disability
• Attention-deficit hyperactivity disorder
• Autism spectrum disorder

Patients with DMD are at increased risk of anxiety and depression, especially during points of major care transition:⁴⁵

• At each visit to the neuromuscular clinic, mental health and quality of life need to be assessed, and, at minimum, each clinic should have a plan to address suicidality. Psychopharmacological interventions should be evaluated for the treatment of moderate-to-severe symptoms, or for milder symptoms when nonpharmacological interventions are ineffective