Clinical manifestations

Presentation and course

Presentation. Parents of boys with Duchenne muscular dystrophy note initial symptoms (typically difficulty walking/motor delay) at a mean age of 2.5 years, prompting evaluation by a primary care provider around 3.6 years of age; however, a definite diagnosis of Duchenne muscular dystrophy is typically not made until about 5 years of age, indicating a 2.5-year delay from identification of symptoms (112). Non-Caucasian and high poverty patients have been associated with later diagnosis. Additionally, specific genetic mutation subtypes may have later age of symptom onset and, thus, later diagnosis (26). In a family with a previously affected boy, the parents might suspect involvement of a second child earlier. Cognitive changes within the first year of life have been identified, indicating onset of symptoms is earlier (22). Early screening with serum creatine kinase in any boy who presents with developmental delay and specific motor test abnormality (ie, walking delay greater than 18 months) may help with earlier diagnosis (86).

Patients with Duchenne muscular dystrophy typically present to their pediatrician with proximal muscle weakness, elevated serum levels of creatine kinase, or, rarely, malignant hyperthermia after exposure to halothane anesthesia.

(1) Proximal muscle weakness. The most frequent presenting symptom is abnormal gait, delayed walking (3 to 6 months later than normal), frequent falling, difficulties getting up from the floor or climbing a stair, inability to jump or hop, and toe walking.

The abnormal gait is best characterized as a “waddle” and is due to early weakness of the glutei muscles (hip extensor and shock absorbers) when taking a step. Duchenne muscular dystrophy children bring their center of gravity to the other leg, repeating the same action with the next step, resulting in the typical waddle. The weakness of the hip extensors also leads to the forward tilt of the pelvis with compensatory lordosis, and frequently, to toe walking. The lordosis disappears in the sitting position. The tendency to walk on the toes precedes any contracture of the Achilles tendon and is due to a combination of weakness of the anterior tibialis muscle and an attempt to balance the center of gravity in the upright position.

The difficulty in getting up from the floor worsens with time. Normal children can do this in less than a second, usually jumping up from a prone to sitting and standing position. Children with Duchenne muscular dystrophy, like other children with proximal muscle weakness, take more than 2 seconds to perform this maneuver. Watching and timing this maneuver is useful in diagnosing and following the degree of muscle weakness. As the weakness progresses, children have to turn 45, then 90, and then 180 degrees to get up from a supine position on the floor. With mild weakness, patients may need to first place a hand on the knee to push themselves up. Eventually, the Duchenne boy goes to the full Gowers maneuver: he turns from supine to prone, then gets on his knees and elbows, extends knees and arms, moves the arms close to the trunk, and “marches up himself” with both hands on the legs until obtaining an upright position.

Enlargement of the muscles due to fat/fibrosis (pseudohypertrophy), especially of the calves, is an early and characteristic feature of Duchenne muscular dystrophy; this enlargement may become more prominent while the child is ambulating.

Although weakness of the arms is not a presenting symptom, mild proximal weakness might be found on early examination.

(2) Elevated serum levels of creatine kinase. Presymptomatic elevation of serum creatine kinase in children is a frequent presentation of Duchenne muscular dystrophy. Striking elevation of serum creatine kinase is present from birth (typically 100 to 200 times normal; normal is less than 200 IU/L). Along with elevated creatine kinase, transaminases (ALT and AST) are also elevated, which may mislead physicians to look for liver diseases.

(3) Malignant hyperthermia after exposure to halothane anesthesia. Malignant hyperthermia is a rare presentation of Duchenne muscular dystrophy. Patients undergoing surgery with halothane anesthesia can experience a malignant hyperthermic episode, with an increase in serum creatine kinase levels due to acute muscle necrosis. In a small number of young boys experiencing a malignant hyperthermic episode, serum creatine kinase levels remain dramatically elevated months after the episode. These patients should be investigated for muscular dystrophy.

Clinical course. The rate of deterioration is variable and disease severity does appear related to genetic mutation; however, on quantitative assessment, all children show a downward trend (63; 06). The age of loss of ambulation varies between 7 and 13 years; however, any period of immobilization markedly accelerates this deterioration. Ambulation, physical therapy, and stretching exercises can minimize Achilles tendon contracture. However, once nonambulatory, patients tend to rapidly develop fixed skeletal deformities, progressive scoliosis, symptomatic respiratory weakness, and cardiac dysfunction. Untreated patients with Duchenne muscular dystrophy typically require noninvasive/invasive ventilation for survival by age 18 (35). Common cardiac findings are left ventricular dilation and depressed left ventricle ejection fraction. The exact mechanism of this is unclear but may be related to myocardial fibrosis (109).

Corticosteroids have been shown to improve muscle strength, pulmonary function, timed motor function, and delay cardiomyopathy onset and loss of ambulation (up to 3 years in some patients) (05; 38; 41). Nonambulatory patients receiving corticosteroids have improved percent-predicted forced vital capacity and upper extremity strength (23).

There is likely a relationship between neurodevelopment and Duchenne muscular dystrophy mutation, with a percentage of patients with Duchenne muscular dystrophy found to have speech delay (39%), learning difficulties (28%), inattentive-overactive behavior disorder (8%), and oppositional-defiant (5%) behavior disorder (111). Intellectual disability in these children is thought to be nonprogressive; however, severity of cognitive disability may vary depending on DMD gene mutation (29; 99).

Prognosis and complications

Duchenne muscular dystrophy is a lethal condition; however, survival has improved with advancements in medical care and implementation of multidisciplinary standards of care (35). Most early textbooks state that the majority of patients with Duchenne muscular dystrophy die by 20 years of age from respiratory insufficiency. Today, with multidisciplinary care and assisted ventilation, their lifespan can be doubled with an estimated life expectancy in ventilated patients of 29.9 years (66; 15). In patients utilizing assisted ventilation, cardiac dysfunction has become the major comorbidity (56). It remains unclear what the impact of new exon skipping and gene therapy treatments will have on survival.

Biological basis

Etiology and pathogenesis

Duchenne muscular dystrophy is caused by mutations in the Duchenne muscular dystrophy gene (DMD gene) located on the X-chromosome (Xp21). Inheritance is X-linked recessive pattern. DMD gene occupies 2.5 million base pairs of DNA and is about 10 times larger than the next largest gene identified to date. The gene contains 79 exons of coding sequence, which together form the 14,000-base pair mRNA molecule (64; 100). Several mRNA and protein isoforms vary in size and tissue distribution (01). Deletions affecting one or more exons are present in 68% to 78% of boys with Duchenne muscular dystrophy; duplications are present in 11% (28; 12). The remaining boys have point mutations, small insertions, or small deletions. Deleted exons appear to be focused in mutation hotspots clustered in the region from exon 43-55 (60% to 65% of patients). In all mutations, the protein product of the gene, dystrophin, is absent or markedly deficient (48; 49; 13).

Dystrophin is localized to the plasma membrane of all myogenic cells, some classes of neurons, and in small amounts in other cell types (50).

Deficiencies of other isoforms produced in liver tissue and other nonexcitable tissues do not seem to cause pathology (01). Dystrophin deficiency at the plasma membrane of muscle fibers disrupts the membrane cytoskeleton and leads to secondary loss of other components of the cytoskeleton, resulting in membrane instability and transient abnormal membrane flux (97; 31). The membrane leakage occurs from birth and causes the histopathologic features of active myopathy, yet muscle dysfunction is typically not detected until delayed walking. The chronic myopathy leads to fibrosis of muscle and, eventually, failure of regeneration. Abnormalities in dystrophin isoforms also play a role in brain abnormalities and cognitive disabilities (30; 110).

Dystrophin may play an important functional role in addition to its more evident structural role, though this is not completely understood.

Epidemiology

Genetic counseling and prenatal diagnosis have begun to lower the incidence of Duchenne muscular dystrophy in countries where molecular diagnostic techniques are available; however, a high incidence of Duchenne muscular dystrophy is maintained through the dystrophin gene's high spontaneous mutation rate. About one third of cases with no family history are due to new mutations in single eggs. Thus, even if genetic counseling were effectively implemented for all relatives of patients with Duchenne muscular dystrophy and if prenatal diagnosis were fully utilized, the disease incidence would decrease to no lower than about 1 in 10,000 (90). This is in marked contrast to other genetic diseases such as Tay-Sachs, in which carrier detection and counseling have virtually eliminated it from specific high-risk populations.

Ten percent of isolated cases of “idiopathic hyper-CKemic myopathy” in females are isolated cases of dystrophinopathy (88; 47). These patients are heterozygous carriers of dystrophinopathy who have skewed lyonization of their X chromosomes and express dystrophin deficiency to a variable extent with variable clinical manifestations (96). Female carriers of dystrophinopathy should have surveillance for cardiomyopathy and should consider psychosocial support for caretaker burden as well as the psychosocial effects from the risk of cardiomyopathy (101).

Prevention

Duchenne muscular dystrophy is most often transmitted to male offspring by asymptomatic female carriers, as is typical of X-linked recessive conditions. Once a boy with Duchenne muscular dystrophy is identified, it is imperative to obtain molecular diagnosis for consideration of future mutation specific therapies. Genetic counseling should be offered to his immediate family members; mother's future sons may be at risk for Duchenne muscular dystrophy, and sisters of the proband may be carriers of the gene (16).

Genetic counseling of Duchenne families is complicated due to the high spontaneous mutation rate. For example, the mother of an isolated case of Duchenne muscular dystrophy has only a 66% chance of being a carrier, even though the mutation was carried in her egg to her affected son. Moreover, even if molecular diagnostics show that the mother is not a carrier of her affected son's mutation, there is still a recurrence risk because her ovaries may carry the mutation, even though her other tissues do not (gonadal mosaicism). Serum creatine kinase levels can be used as a first step to evaluate carrier status. A creatine kinase level above the upper limit of normal usually indicates a carrier; however, normal levels do not exclude carrier risk because only 70% of carriers will show elevated serum creatine kinase. Serum creatine kinase determinations in female carriers will normalize with advancing age, so measurements should be taken as soon as the affected boy is identified. Serum creatine kinase measurements are notoriously variable and can be affected by exercise and other activities not related to the disease.

Neonatal screening for Duchenne muscular dystrophy, based on elevated creatine kinase, has been piloted in the United States and is being implemented in other countries (57; 58). Identifying affected boys at birth can allow for earlier treatment with corticosteroids and initiation of new genetic treatments before the appearance of muscle fibrosis. Genetic counseling can also be provided to unsuspecting parents (81; 104).

Differential diagnosis

Confusing conditions

Sarcoglycanopathy. Rare cases of Duchenne-like muscular dystrophy that appear to have an autosomal recessive inheritance pattern have been reported, and about 20% to 40% of such patients have been found to have mutations of one of the four sarcoglycan genes (34).

Other childhood onset types of LGMD. Typical symptoms include proximal muscle weakness with varying age of onset and progression.

Becker and intermediate dystrophinopathies. In the milder Becker muscular dystrophy, serum creatine kinase levels can approach those of Duchenne muscular dystrophy; however, they are frequently lower.

X-linked vacuolar myopathy with excessive autophagy (XMEA). X-linked vacuolar myopathy with excessive autophagy is typically characterized by slow progression of proximal muscle weakness, which does not alter longevity. Muscle biopsy reveals excessive autophagic activity and exocytosis of the phagocytosed material. Onset is typically in childhood, though it can be variable.

Acquired inflammatory myopathies, dermatomyositis, polymyositis, viral myositis. Creatine kinase (CK) elevation may be similar to Duchenne muscular dystrophy; however, weakness typically progresses over weeks to months. Muscle pain and skin rash may also be present.

Late onset Pompe myopathy. An inherited autosomal recessive progressive metabolic myopathy that presents in the first year of life to adulthood. Muscle weakness is typically proximal and is commonly associated with respiratory insufficiency.

Associated or underlying disorders

Malignant hyperthermia. Malignant hyperthermia following use of halothane anesthesia does not necessarily indicate Duchenne muscular dystrophy. In patients having malignant hyperthermia as the primary disorder, serum creatine kinase levels will return to less than 10 times the upper limit of normal within 2 weeks after the episode. The small number of young boys whose serum creatine kinase values remain elevated months after a malignant hyperthermic episode should be investigated for Duchenne muscular dystrophy.

Diagnostic workup

In patients suspect to have Duchenne muscular dystrophy, a serum CK is an initial good screening marker. Serum creatine kinase levels in patients with Duchenne muscular dystrophy are always elevated between 5000 and 150,000 IU/L (normal is less than 200 IU/L). If the patients CK is elevated, genetic testing for Duchenne muscular dystrophy should be considered. Many different molecular diagnostic technologies are available to evaluate for various DMD gene mutations. Unless family history has identified a specific prior mutation, suspected patients should be evaluated initially for gene deletion/duplications. Large deletions (68% to 78% of patients) or large duplications (11%) can be assessed by PCR, multiplex ligation-dependent probe amplification, and chromosome microarray techniques (28; 12). Multiplex ligation-dependent probe amplification is currently the most widely applied technology due to convenience, high sensitivity, and cost (65; 37). Next generation sequencing, although advancing in ability to identify copy number variants, still has some limitations such as in identifying female carriers and duplications in males (37). If quantitative assays cannot completely characterize the mutation, sequencing of the coding Duchenne muscular dystrophy regions can evaluate for deletion endpoints, point mutations, and other small alterations (07; 67). Recommendations and algorithms for molecular testing have been updated by the Duchenne Muscular Dystrophy Care Consideration Working Group (67) and European Molecular Genetics Quality Network (37).

In patients testing negative for a DMD gene mutation, it is important to test the status of the dystrophin protein in a muscle biopsy (55). This is rarely done in patients with a confirmed genetic diagnosis. Absent dystrophin levels or levels less than 3% of normal are generally considered diagnostic of Duchenne muscular dystrophy (49). Levels of 12% to 18% usually indicate a milder phenotype such as Becker muscular dystrophy (49). It is important to note that all Duchenne dystrophy biopsies also show secondary deficiencies of many other proteins, such as sarcoglycans and dystroglycans (49).

Management

Glucocorticoid treatment. Glucocorticoids are recommended for the treatment of all DMD boys, both ambulatory and non-ambulatory (74).They improve muscle strength and pulmonary function, as well as reduce the need for scoliosis surgery and delay onset of cardiomyopathy (91; 38). When administered early in the disease process, prednisone 0.75 mg/kg/day, recommended by the current practice parameter set by the Academy of Neurology, has been shown to prolong ambulation for as long as 3 years (42; 91; 38; 74). Deflazacort (EMFLAZA), approved by the FDA in 2017 (ages 5 and older), has shown likely equal or superior effectiveness in improving muscle strength and delayed time to loss of ambulation when compared to prednisone (38; 41; 75; 78; 73; 76). In October 2023, vamorolone (AGAMREE), a novel dissociative steroid was approved by the FDA for use in ages 2 years and older. In long-term clinical trials, vamorolone was shown to maintain muscle strength in patients with Duchenne muscular dystrophy aged 4 to 7 for up to 2 years with stable height percentiles compared to patients treated with corticosteroids who demonstrated growth delay (44; 70). Continuing studies to evaluate vamorolone long term and its cost effectiveness will be helpful to determine optimal steroid treatment.

Long-term glucocorticoid use and glucocorticoid use for nonambulatory patients should also be considered. A study from MD STARnet showed that patients receiving long-term corticosteroid treatment (3.1 to 10.2 years) had prolonged ambulation by 2 years compared to untreated patients, and 1.2 years compared to the short-term treated group (0.25 to 3 years) (60). Glucocorticoids in nonambulatory patients have been shown to slow the decline of upper limb weakness, improve percent predicted forced vital capacity, and slow the decline of left ventricular ejection fraction, delaying the onset of cardiomyopathy (103; 24; 95). There remain unanswered questions regarding corticosteroids in infants, including what dose should be given and will early treatment lead to longer benefit (25).

Despite clear guidelines that steroids should be offered to patients with Duchenne muscular dystrophy, they are inconsistently or never prescribed (40; 43). Some patients start steroids but stop using them due to significant side effects; however, these side effects can be managed. Guidelines for treatment of endocrine complications due to prolonged glucocorticoid use, including obesity, obesity-related complications, and adrenal insufficiency are available (120; 14). Minimizing glucocorticoid-induced weight gain is important to maintain mobility and to reduce sleep-disordered breathing (120). Deflazacort may be associated with fewer side effects, less weight gain, and behavioral issues, whereas cataracts and bone health may appear worse compared to prednisone (08). Deflazacort is being explored for specific types of Duchenne muscular dystrophy mutations, in comparison to prednisone (107). Intermittent prednisone (10 days on/10 days off) over short term (6 months) has been shown to be noninferior to daily regiment with similar individual side effects (62; 45).

Bone health. Osteoporosis, resulting in low trauma vertebral and long bone fractures, is a complication in Duchenne muscular dystrophy due to the underlying myopathic process and glucocorticoid treatment. Vertebral fractures often are asymptomatic and can lead to chronic low back pain and spine deformity. Femur fractures can lead to early loss of ambulation and fat embolism syndrome (69). It is recommended to monitor for vertebral fractures with routine spinal radiographs at diagnosis and every 1 to 3 years, with more frequent monitoring in patients with Duchenne muscular dystrophy on glucocorticoids (69; 10; 117). For patients on glucocorticoids, the addition of growth hormone and testosterone may prolong time to next vertebral fracture (68). In addition, serum 25-hydroxyvitamin D, serum calcium, spinal bone mineral density, and DEXA scan should be checked yearly, with other serum bone health markers checked at baseline and periodically thereafter. Intravenous bisphosphonates to maintain vertebral height, based on studies in osteogenesis imperfecta, are recommended for treatment of patients diagnosed with osteoporosis, defined as a child at risk for osteoporosis who sustains a long bone or vertebral fracture (118; 10; 117). Duration of treatment, beyond when adult height is obtained, is not well studied (117).

Joint contractures can compromise comfort and mobility. Detailed rehabilitation guidelines throughout all stages of Duchenne muscular dystrophy may be reviewed in the journal Pediatrics (19). Early in the disease, contracture of the ankles often leads to toe walking. Physical and occupational therapy assessments should be completed every 4 to 6 months, with frequent stretching of the involved tendons 4 to 6 days per week, and ankle-foot orthoses at night. Knee-ankle-foot orthoses can be considered for prevention of contracture in the late ambulatory or early nonambulatory stages (17; 19). Achilles tendon contractures generally begin to limit mobility by the end of the first decade, and surgical tendon lengthening can be considered in patients with significant ankle contraction and good proximal upper extremity strength (102; 10). Mobility should be encouraged as soon as possible after surgery.

Scoliosis is often seen during the first decade of life as the patient attempts to compensate for imbalance due to proximal leg weakness and becomes a primary concern when the patient uses a wheelchair. Wheelchair design and fitting are important for prevention or slowing of scoliosis. Scoliosis surgery has been shown to improve FVC for approximately 2 years postoperatively compared to nonsurgical treatment, delaying respiratory decline and thus extending survival in patients with Duchenne muscular dystrophy scoliosis (121). Patients should be visually screened for scoliosis with every clinical exam. Spinal radiographs can be considered in obese patients where visualization may be more difficult (10). In patients with identified scoliosis, radiographs should be done every 6 to 12 months (10). A curve of more than 20 degrees in patients not treated by corticosteroids should trigger evaluation by a spinal surgeon due to fear of progression. In contrast, patients with spinal curvature on corticosteroids have a less predictable course so monitoring for progression is more reasonable (61; 10).

Pulmonary management. Proactive respiratory care has an important role in the management of patients with Duchenne muscular dystrophy, improving survival and quality of life (108; 35; 72; 115). As muscle weakness ensues, patients are at risk for several respiratory complications, including ineffective cough, pulmonary infections, obstructive sleep apnea, and respiratory failure (106). Other known complications of Duchenne muscular dystrophy, including cardiac, gastrointestinal, and orthopedic changes, likely also contribute to respiratory decline (10). Detailed guidelines for respiratory management in ambulatory and nonambulatory patients with Duchenne muscular dystrophy are available for review (10; 106). It is recommended that ambulatory boys, starting around age 5 or 6, have a measured forced vital capacity (FVC) annually to follow trajectory and accurately monitor for forced vital capacity decline in the absence of symptomatic dyspnea (10). Nonambulatory Duchenne muscular dystrophy boys should have pulmonary function testing twice a year, to include seated forced vital capacity, maximum inspiratory and expiratory pressures, peak cough flow, and blood oxygen saturation by pulse oximetry (10). Cough assist can be utilized when forced vital capacity is less than 50% predicted, cough peak flow is less than 270 liters per minute, or if cough becomes weak. Noninvasive ventilation (daytime and nocturnal) should be discussed when forced vital capacity is less than 50%, or in patients with abnormal sleep studies (10). Sleep studies should be completed yearly in patients with symptoms of sleep-disordered breathing (10). There is no clear evidence to favor 24-hour noninvasive ventilation versus tracheostomy in patients requiring assisted ventilation; however, in patients unable to use noninvasive respiratory assistance or in patients at risk for aspiration or who fail extubation three times, tracheostomy should be considered (10).

Cardiac management. Dilated cardiomyopathy due to dystrophin deficiency develops with variable severity after 6 years of age, thus it is recommended that patients have an annual screening cardiac assessment with electrocardiogram, as well as noninvasive imaging (echocardiogram or cardiac MRI). In patients who are symptomatic, imaging can be done more frequently based on cardiologist recommendation (10). Cardiac MRI measurement of “serial circumferential strain” appears to be more sensitive and reliable then “ejection fraction” calculation by echocardiogram, making MRI possibly a more useful tool for detection of early cardiomyopathy; however, this can be a difficult procedure for younger patients (6 to 7 years of age) (51; 46). Angiotensin-converting enzyme (ACE) inhibitor or beta-receptor blocker/diuretic should be used to prevent progression of cardiomyopathy. Treatment should be initiated by the first sign of cardiac decline (94; 36); however, further studies are being conducted to assess benefit of treatment in young, asymptomatic patients (younger than 10 years of age) (80; 10). There was no substantial difference in the improvement of cardiac function in patients with Duchenne muscular dystrophy treated with lisinopril (an ACE inhibitor) or losartan (an angiotensin receptor blocker) (03). In the late nonambulatory patients, it is important to monitor cardiac function and clinical manifestations of heart failure, and to optimize pulmonary function, with consideration of early initiation of noninvasive nocturnal ventilation, which has been shown to improve survival, though there may not be an effect on left ventricular dysfunction (80; 54).

Multidisciplinary and long-term care. Management of a patient with Duchenne muscular dystrophy requires a multidisciplinary team approach, including multiple medical specialists outlined above, multidisciplinary rehabilitation teams (physical and occupational therapists, speech language pathologists, orthotists), psychologists, nutritionists, and social workers. As patients with Duchenne muscular dystrophy live well into their 30s, transition of care into adulthood, as well as psychosocial issues associated with chronic illness, become important management considerations (11; 113).

Genetic treatments. Considerable research efforts are underway to develop novel therapeutics for Duchenne muscular dystrophy based on knowledge of the molecular defect. This has led to encouraging new FDA-approved treatments.

Exon skipping. The use of antisense oligonucleotides to restore the Duchenne muscular dystrophy reading frame and produce functional dystrophin is a promising treatment of patients with particular deletions. There are currently four FDA-approved (under accelerated approval) exon skipping therapies targeting exon 51, 53, and 45 (Table 1). Eteplirsen is approved for use in patients who have mutations amenable to exon 51 skipping (about 13%). A phase 3 clinical trial showed treatment (96 weeks) with eteplirsen slows disease progression measured by the 6 meter walk test, and annual change in FVC percentage predicted, with a favorable safety profile (82; 02; 59; 79; 53). Golodirsen (Vyondys) and viltolarsen (Viltepso) target 53 skippable mutations. Long-term phase 1/2 data for golodirsen have shown favorable safety data and suggestion of functional benefit to be further explored in future studies (105). In a phase 2 clinical trial over 4 years, viltolarsen (Viltepso) treated patients showed stabilization of motor function over the first two years of treatment and then significant slowing of disease progression in the following two years compared to controls. There were mild to moderate adverse events, without drug discontinuation (21). Finally, casimersen for exon 45 skipping has shown increased dystrophin production in patients and is proceeding with phase 3 data (116). Other exon skipping molecules in phase II clinical trials include SRP-5051 from Serepta (vesleteplirsen), WVE-N531 (WAVE Life Sciences), and AAOC 1044 (Avidity Biosciences). AAOC 1044 skips exon 44, which received FDA fast track designation based on promising early clinical trial results (119). Multiple other emerging treatments are in phase 1 trials.

Table 1. FDA-Approved Exon Skipping Therapies

Gene therapy. Gene replacement strategies have the ability to treat the majority of Duchenne muscular dystrophy mutations. Systemic delivery of “naked” DNA has been achieved and has paved the way for long-awaited clinical trials (123; 124). There are multiple gene therapy trials utilizing various methods for delivery of dystrophin in clinical trials. ELEVIDYS is currently FDA approved, under accelerated approval, for use in select patients (Table 2).

ELEVIDYS. ELEVIDYS (SRP-9001) is currently FDA approved, under accelerated approval, for ambulatory 4- and 5-year-old boys with Duchenne muscular dystrophy and a confirmed mutation in the DMD gene (52). In phase II trials of 4- to 8-year-old Duchenne muscular dystrophy patients, ELEVIDYS produced robust dystrophin expression with positive functional improvement, up to 2 years without serious adverse events (83; 84). Results from the pivotal phase 3 EMBARK study were presented by Serepta in October 2023, revealing improvement in secondary endpoints of time to rise and 10-meter walk; however, the primary endpoint of improvement in North Star Ambulatory Assessment was not statistically significant. Full results are awaiting publication. A phase 1 study (ENDEAVOR) using commercial grade delandistrogene moxeparvovec is currently enrolling (NCT04626674). At 1 year, patients demonstrated stabilized or improved North Star Ambulatory Assessment total scores (122). ELEVIDYS is contraindicated in patients with any deletion in exon 8 or 9 due to risk of an immune-mediated myositis reaction.

CIFFREO. A phase 3 trial with Pfizer’s PF-06939936 using AAV9 to carry minidystrophin in ambulatory patients is ongoing (NCT03362502). Data from previous phase 1/1b trials have not been formally published.

IGNITE DMD. A phase I/II trial to assess safety/tolerability of solid biosciences SGT-001 in adolescents with Duchenne muscular dystrophy is ongoing. Data have shown sustained expression of functional dystrophin in patients up to 2 years. Patients receiving the 2E14 vg/kg dose have also maintained motor function compared to natural history controls during this time period (32). The INSPIRE DUCHENNE clinical trial using SGT-003, a microdystrophin transgene with a novel capsid, was just announced. This will be a phase I/II trial to evaluate the safety/tolerability of SGT-003 in 4 to 5 year olds (NCT06138639).

AFFINITY DUCHENNE. A phase I/II trial with RGX-202 utilizes microdystrophin and AAV8 (NCT05693142).

Table 2. FDA-Approved Gene Replacement Therapies

Stop codon suppression. An oral delivery of ataluren, (Translarna), which promotes nonsense read through, has been shown to be well tolerated and associated with slowed disease progression, including respiratory decline and delayed loss of ambulation up to 2.2 years (18; 85; 77). Ataluren has been conditionally approved by the European Medicines Agency and is being investigated in the United States (92).

Gene editing utilizing CRISPR (clustered regularly interspaced short palindromic repeats). Gene editing for Duchenne muscular dystrophy is aimed at restoring the gene reading frame and producing some functional dystrophin. There has been promise using the CRISPR/Cas9 system to target mutated exons and perform a variety of mechanisms to knock-in/edit/skip such mutations, producing functional dystrophin in the mdx mice and dog. Most studies focus on the exon region of 45-55 or 21-23. Challenges with delivery, off-target mutagenesis, and evaluation of long-term effects exist. Additionally, there is a limitation to the length of the template and, thus, it is unlikely this method can be used for large DMD deletion mutations. Further development is needed prior to clinical trial (20).

Special considerations

Pregnancy

In female carriers either manifesting Duchenne muscular dystrophy or not, there is no reported increased risk during pregnancy to either the mother or child.

Anesthesia

Patients are at increased risk of malignant hyperthermia during exposure to halothane anesthesia.

COVID-19

Consensus guidelines for the care of patients with Duchenne muscular dystrophy during the COVID-19 pandemic have been published. Recommendations include continuing current corticosteroid regiments with potential dose adjustments should they become ill to prevent adrenal insufficiency and consideration of stress dose steroids in the setting of acute illness or hospitalization. Exon-skipping agents are encouraged to be continued. The risks and benefits of receiving these infusions during a pandemic should be discussed with the patient’s neurologist. It is recommended that angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prophylaxis or treatment of cardiomyopathy should be continued. Those with chronic respiratory insufficiency should be treated in collaboration with pulmonary and/or anesthesiology specialists and should not receive supplemental oxygen without ventilatory support. Finally, hydroxychloroquine has uncertain benefit and may cause skeletal or cardiac muscle damage and thus should not be prescribed for this patient population (114).

Based on a small study of children with neuromuscular conditions and documented SARS-CoV-2 infection (n=29 with five Duchenne muscular dystrophy/bone mineral density subjects), 89% of patients were asymptomatic or had mild symptoms to include mild upper respiratory symptoms and fever. Ten percent of patients had moderate symptoms to include mild respiratory distress without respiratory decline (93). In a separate review of seven adults Duchenne muscular dystrophy and SARS-CoV-2, there were no patients who developed moderate to severe symptoms, and all patients with mild symptoms recovered without complication or hospitalization (98). These results indicate there may be a protective role of young age, which may outweigh neuromuscular risk factors to include reduced respiratory capacity. These findings may also may support that the SARS CoV-2 variants, known at the time of this publication, may not be more life threatening for this population than other respiratory viruses.