Clinical management of Duchenne muscular dystrophy: the state of the art
Duchenne muscular dystrophy (DMD) is a devastating, progressive neuromuscular disorder for which there is no cure. As the dystrophin gene is located on the X chromosome, DMD occurs predominately in males. DMD is caused by a lack of functional dystrophin protein resulting from mutations in the 2.2-Mb DMD gene, whichdisrupts the reading frame. Care considerations for DMD advocate a coordinated, multidisciplinary approach to the management of DMD in order to optimize management of the primary manifestations of DMD as well as any secondary complications that may arise.
This review provides an overview of the multidisciplinary clinical management of DMD with regard to the respiratory, cardiology, orthopedic, and nutritional needs of patients with DMD. Recent advances in novel disease-modifying treatments for DMD are also discussed with specific reference to exon skipping and suppression of premature stop codons as promising genetic therapies.
The combination of multidisciplinary clinical management alongside novel gene therapiesoffers physicians a powerful armamentarium for the treatment of DMD.
KeywordsDuchenne muscular dystrophy Multidisciplinary care Exon skipping Ataluren
Diagnostic workout: why early diagnosis is crucial
Duchenne muscular dystrophy (DMD) is a lethal, progressive neuromuscular disorder caused by mutations in the dystrophin gene located on the X chromosome. DMD predominately occurs in males with a birth prevalence of 15.9–19.5 cases per 100,000 newborn males . Numerous dystrophin isoforms, expressed in muscle and non-muscle tissues, are generated by the 2.2-Mb DMD gene via unique tissue-specific promoters and alternative splicing . Intragenic deletions, duplications and point mutations, abolish production of functional dystrophin protein either through frame shifts or non-sense mutations . Lack of dystrophin protein destroys the link between the cytoskeleton and extracellular matrix, severely compromising the strength, flexibility, and stability of muscle fibers, leading to progressive muscle wasting and premature death .
No cure is available for DMD and the purpose of treatment is to control symptoms and improve quality of life . Disease severity increases with age and patients are frequently restricted to a wheelchair by a median age of 12 years and require ventilation at around 20 years; the economic burden of DMD also increases with disease progression . The use of corticosteroids, improved access to ventilation, and more specific care guidelines has increased patient longevity with wider implications for the lack of studies in older patients . Progressive cardiac or respiratory complications remain the main cause of death in DMD .
Despite the advances in diagnosis and management of DMD over the past 10 years, the average age at diagnosis is variable among countries and is still around 4–5 years of age, with a significant delay between the onset of symptoms and genetic diagnosis [6, 7, 8, 9]. Global developmental delay including cognitive and gross motor delay is a common presentation [10, 11]. A delay of 1.6 years from parental concern (mean age 2.7 years) to diagnosis (mean age 4.3 years) was identified in a retrospective review of boys diagnosed between 2003 and 2013 in England . Ideally, early diagnosis is preferable so that appropriate management of DMD can be initiated. In Italy, a lower mean age at diagnosis (i.e., 3.5 years) is due to an incidental finding of consistently elevated serum creatine kinase levels during routine assessments in children, which increased the suspicion of DMD .
There has been renewed interest in newborn screening for DMD as early initiation of treatment may become increasingly important in the future, especially if initiated before symptom onset . An assessment of creatine kinase levels on dried blood spots from newborns may aid earlier diagnosis, although false positives could be confounding. Newborn blood spot screening for DMD in Wales over a 21-year period (1990–2011) found a DMD incidence of 1:5136 (serum creatine kinase levels of ≥ 250 U/l at birth plus persistent elevation at 6–8 weeks) with DMD confirmed using genotyping/muscle biopsy studies . In addition, a two-tier system of initial screening of creatine kinase levels on dried blood spots followed by genetic analysis of the DMD gene if creatine kinase levels were ≥ 750 U/l was found to minimize false positives, suggesting that predetermined levels of creatine kinase can identify DMD in newborns .
The DMD Care Considerations Working Group published comprehensive clinical care recommendations for best practice in DMD in 2010 [16, 17] and updated in 2018 [13, 18, 19]. These advocate a coordinated, multidisciplinary approach to the management of DMD in order to optimize management of the primary manifestations of DMD as well as any secondary complications that may arise, as discussed below.
Multidisciplinary clinical management of DMD
Respiratory complications, such as respiratory muscle fatigue, mucus plugging, atelectasis, pneumonia, and respiratory failure, are a major cause of morbidity and mortality in DMD . There is a paucity of literature analyzing the cause of death in DMD. Cardiac and/or respiratory failure was identified as the main cause of death in 17 out of 21 patients (81%) over a 10-year period in a DMD population in North East England . In this retrospective case note review, only four patients (19%) died in the absence of severe cardio-respiratory failure, with cause of death identified as acute pneumonia, cardiac arrest, acute respiratory distress, or multi-organ failure.
Assessments and interventions for respiratory care determined according to disease stage (i.e., ambulatory, early non-ambulatory, and late non-ambulatory) are published in the 2018 DMD care considerations . Notably, pulmonary function thresholds have been increased (corresponding to milder levels of respiratory impairment) for the initiation of assisted coughing and ventilation interventions. Ideally, interventions for preventative measures should be promoted in order to initiate therapy in younger patients. Assessment of respiratory function using non-invasive and non-volitional techniques in patients with DMD should be considered as tools for both clinical trials and clinical monitoring from the early stages of the disorder .
Improved survival outcomes have been demonstrated following respiratory intervention. The use of inspiratory and expiratory aids has decreased hospitalization rates for respiratory complications in patients with neuromuscular disease , and the use of nocturnal ventilation, which begun in the early 1990s, has increased life expectancy in ventilated patients with DMD (14.4 years in the 1960s vs 25.3 years for patients ventilated since 1990) . Studies have also shown that continuous non-invasive ventilation has improved survival outcomes in patients with DMD  and that non-invasive mechanical ventilation plus assisted coughing and cardio-protective medication has significantly improved survival compared with patients treated with invasive ventilation (50% survival age of 39.6 vs 28.9 years; p = 0.0002) .
An evaluation of respiratory muscle function, monitoring of sleep O2 saturation and CO2, and support of inspiratory and expiratory muscle function can prevent acute respiratory failure and invasive ventilation by progressively weakening and elderly patients with neuromuscular disease, including DMD . As such, non-invasive management of respiratory muscle dysfunction can optimize quality of life and reduce expense.
While existing DMD care standards have focused mainly on the child and young adult, life expectancy of patients with DMD has increased as a result of interventions such as ventilation, cardiac treatment, and corticosteroids. However, transitioning from young to adult care and management of complications in adult life has been hindered by a lack of knowledge concerning DMD in adults, as this group of patients is new to most medical specialists . In addition, the coordination of DMD management in line with multidisciplinary best practice involving neurologists, pulmonologists, cardiologists, and rehabilitation specialists can be problematic for adult patients with DMD. Therefore, the natural history of DMD above the age of 18 years needs further consideration.
Considerable heterogeneity in motor and respiratory performances were demonstrated in a large cohort of DMD patients, in which age at ambulation loss (< 8 years, ≥ 8 to < 11 years, or ≥ 11 to < 16 years) was correlated with motor function decline, orthopedic complications, and respiratory insufficiency . This finding has implications for future design of clinical trials.
Cardiomyopathy, caused by a deficiency of dystrophin in the heart, is a major cause of morbidity and mortality in DMD . However, symptoms related to cardiomyopathy are often absent in patients with DMD due to musculoskeletal limitations . As late referral to a cardiac specialist contributes to poor clinical outcomes, early diagnosis and treatment is essential to maximize longevity and quality of life .
A multidisciplinary care team which includes a cardiologist is recommended alongside a proactive strategy for the early diagnosis and treatment of heart failure. An algorithm for cardiac monitoring, diagnosis and treatment in DMD recommends that non-invasive screening should include echocardiogram for patients < 6–7 years old; cardiovascular MRI for patients ≥ 6–7 years old; an annual cardiac assessment until the age of 10 years, including electrocardiogram and non-invasive monitoring; after 10 years of age, an annual cardiac assessment in asymptomatic patients; and, in patients with heart failure symptoms or abnormalities identified with cardiac imaging, the cardiologist should determine the frequency of assessments . Indeed, an assessment of left ventricular function found a weak correlation between echocardiography-based screening and MRI parameters in children and young adults with DMD (mean age 13.6 years, range 9.4–20.2 years), suggesting that MRI should be routinely performed at an early stage in children with DMD . For DMD patients with end-stage dilated cardiomyopathy, a left ventricular assist device as destination therapy may be suitable as palliative therapy . Due to their reduced life expectancy, DMD patients are unlikely to benefit from heart transplantation, which is at variance with milder forms of dystrophinopathies. However, nowadays with the significant increase in survival of DMD patients, heart transplantation should be reconsidered as it raises relevant ethical issues. In a systematic review of pharmacotherapy for the prevention and/or management of DMD-associated cardiomyopathy, evidence supported the use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and/or aldosterone antagonists with an improvement or preservation of left ventricular systolic function and a delay in cardiomyopathy progression . However, data was insufficient to optimize pharmacological regimens or establish optimal timing of treatment initiation.
A retrospective chart review identified good heart function as the main determinant of prolonged survival in DMD patients on mechanically assisted ventilation . In this study, prolonged survival was defined as patients with DMD who were alive and ≥ 30 years of age; early death was defined as death at < 30 years of age. In patients with prolonged survival vs early death, the mean ejection fraction was 42.2 vs 29.2% and diagnosis of dilated cardiomyopathy was 36 vs 78%, respectively (both p < 0.05). Hence, patients in the early death group had poor heart function but favorable lung function and vice versa in patients with prolonged survival. The authors hypothesized that cardiac modifier genes impact patient survival with detrimental and beneficial cardiac modifier genes associated with early death and prolonged survival, respectively. If proven correct, this may impact the design of future genetic therapies for DMD.
Considerations for the orthopedic care of DMD patients according to disease stage have been published recently . Ideally, musculoskeletal care should involve a multidisciplinary team including a physical and occupational therapist, rehabilitation physician, neurologist, orthopedic surgeon, and social worker. The ultimate aim of musculoskeletal care is to preserve motor function, reduce joint contractures, preserve a straight spine, and support bone health .
Careful management of joint contractures during the early years of disease development usually allows patients with DMD to avoid interventions such as lower limb tenotomy. Nowadays, the use of stretching and other approaches such as night splints and serial casting of ankle joints can prevent the worsening of contractures towards adulthood .
Neuromuscular scoliosis commonly occurs in patients with DMD . Although its development is believed to be related to poor mobility alongside increasing muscle weakness, the reason for its development is poorly understood . Early referral to specialist spinal centers is essential for the optimization of multidisciplinary management and long-term outcomes, with preservation of function, facilitation of daily care, and pain alleviation being the most important goals . Progression of scoliosis significantly impacts many aspects of daily life including ambulation, respiratory and cardiac complications, back and rib pain, seizure thresholds, and skin compromise . Once scoliosis has developed, surgical correction can be proposed.
Spinal surgery to treat severe scoliosis (mean preoperative scoliotic curvature of 98°, range 81°–130°) was successfully undertaken in 14 patients with DMD and poor forced vital capacity (FVC) (< 30%) following 6 weeks’ respiratory muscle training using threshold IMT . Preoperative respiratory muscle training improved FVC (21.6% on admission vs 26.2% after 6-week training), but this was not maintained over the long-term (19.8% at 2 years post-operation). This suggests that despite surgery to correct scoliosis, respiratory function will continue to decline in patients with DMD. Notably, a 7.8% annual decline in pulmonary function was identified in patients with DMD in a retrospective review of 40 patients (29 with DMD and 11 with spinal muscular atrophy) who had undergone spinal surgery from 1990 to 2006 (mean follow-up > 10 years) . In addition, a lack of significant improvement in respiratory function despite posterior spinal fusion for DMD-associated scoliosis alongside a lack of correlation between the severity of respiratory dysfunction and of scoliosis suggests that the main determinant of respiratory function decline was “intrinsic respiratory muscle weakness,” and that spinal fusion will not improve respiratory muscle weakness in patients with DMD-associated scoliosis .
Steroid treatment was identified as a promising treatment in patients with DMD in a review of studies published between 2011 and 2014 . Indeed, long-term glucocorticoid use (n = 30, mean duration 15.5 years) significantly decreased the need for spinal surgery compared with no treatment (n = 24) in a non-randomized, comparative study of boys with DMD (78 vs 8.3% did not need surgery for scoliosis; p = 5.8 × 10−7) . Patients treated with steroids also had a significantly lower death rate (3 vs 21%; p < 0.005), better pulmonary function, and were ambulatory for longer (mean of 1.5 years) than patients who were untreated. Adverse events associated with glucocorticoid use included a lower mean patient height (141 cm vs 158 cm) and higher mean weight (55 kg vs 51 kg) compared with non-treated patients; cataracts developed in 70% of treated patients. Interestingly, the fracture rate was similar between treatment groups (25–27%), which may have been due to the addition of bisphosphonates to prevent osteoporosis caused by glucocorticoid treatment .
Although corticosteroid treatment is considered the “gold standard” for DMD, adverse effects include osteoporosis and increased risk of bone fractures. High-quality evidence from randomized controlled trials is lacking to guide treatments to prevent or treat corticosteroid-induced osteoporosis and of fragility fractures in adult and pediatric patients with DMD treated with long-term corticosteroids . As part of routine monitoring of bone health in DMD, lateral spine radiography should be included alongside the initiation of glucocorticoid therapy .
Importantly, intravenous bisphosphonate used to treat low-trauma, painful vertebrate fractures in seven boys with DMD (aged 8.5–14.3 years) also improved back pain, normalized vertebral height ratios, increased density, and reshaped vertebral bodies, but was not able to prevent development of new vertebral fractures . Further studies are necessary to determine the optimal dosing regimen and benefits/risks of bisphosphonates in this patient population.
Vigilance in preventing falls is imperative in patients with DMD. In addition, the progression of fat embolization, which commonly occurs after long bone fracture, to fat embolization syndrome must be considered in patients with DMD who experience acute neurologic and respiratory symptoms following minor trauma [44, 45].
Nutritional care in patients with DMD aims to prevent obesity and malnutrition which occur at the early and late stages of DMD, respectively, as well as promote a healthy balanced diet. Guidelines for the management of nutritional, swallowing, and gastrointestinal complications in patients with DMD have been published recently . These recommend assessment by a registered dietitian nutritionist and monitoring of patient’s height and weight at every visit, with 6-monthly questions on dysphagia, constipation, gastro-esophageal reflux, and gastroparesis, alongside an annual assessment of serum concentrations of 25-hydroxyvitamin D and dietary calcium intake.
Nutritional complications associated with DMD include changes in weight, with a risk of obesity early in life due to glucocorticoid therapy and loss of ambulation, which decreases physical activity, and a transition from overnutrition to undernutrition, which tends to occur with disease progression . Interestingly, a longitudinal approach, which assessed the natural evolution of weight status in DMD, found that mild obesity in DMD patients at 13 years of age prevented underweight at later stages .
For patients with DMD, quality of life can be improved with appropriate nutritional care from a multidisciplinary team, which should include a dietician, gastroenterologist, and a swallowing therapist . The increase in life expectancy associated with modern therapies for DMD has meant that nutritional concerns and complications related to adult age must be considered. It is also important to prevent loss of lean body mass, which correlates with muscle function, in order to preserve quality of life .
Swallowing difficulties including facial weakness, reduced mastication, and poor tongue coordination may lead to undernutrition in DMD patients. A significant reduction in mandibular movements, which became more constricted with motor function loss, was identified in patients with DMD compared with gender- and age-matched healthy controls, suggesting that measurements of the active maximum mouth opening should be routinely assessed in patients with DMD . Patients with DMD may also require gastrostomy tube feeding to counteract weight loss caused by undernutrition and/or dysphagia. Gastrostomy has been shown to be well tolerated and effective in improving the nutritional status of patients with DMD in a case series of 9 patients aged 18–27 years  and in a retrospective multicenter study of 25 patients aged 11–38 years . A clinical algorithm for the management of dysphagia in DMD has also been published recently .
Constipation and other gastrointestinal complications may also occur as a result of muscle weakness. A high prevalence of constipation, which was often underdiagnosed and undertreated, was identified in a cross-sectional prospective study of 120 patients with DMD (aged 5–30 years) . The authors recommended use of the constipation section of the validated Questionnaire on Pediatric Gastrointestinal Symptoms based on Rome-III Criteria (QPGS-RIII) during routine clinical visits to diagnose functional constipation.
Significantly lower resting energy expenditure (REE) was identified in 77 patients with DMD aged 10–37 years compared with healthy controls in all age groups (p < 0.0001), and parameters strongly associated with REE included vital capacity, followed by body mass index and body weight (all p < 0.05) . Low alternative physical activity levels (i.e., energy intake divided by REE) were identified in patients in their early teens, which might relate to the occurrence of obesity in this age group. Conversely, high alternative physical activity levels were identified in patients aged ≥ 18 years, which may be due to increased inspiratory effort associated with severe respiratory failure and therefore constitute a risk factor for malnutrition in patients with advanced DMD .
Metabogenic and nutriceutical supplements may ameliorate the pathological and clinical progression of DMD via the regulation of energy and protein metabolism and the maintenance of functional muscle mass . Although efficacy data on the clinical progression of DMD with long-term supplementation strategies are lacking, early implementation of such a strategy may modify the natural history of the disorder with positive outcomes on quality of life.
Different therapeutic approaches under investigation
The development of gene therapy for DMD has been hindered by the large gene size (2.2 Mb) and volume of muscle tissue in the human body . With recent advances in novel disease-modifying treatments for DMD, successful gene therapies appear to be increasingly feasible [2, 56, 57, 58, 59]. Exon skipping to restore the reading frame and suppression of premature stop codons are promising genetic therapies.
This strategy uses antisense oligonucleotides (AONs) to induce skipping of mutant exons from premessenger RNA (mRNA) dystrophin transcripts, which restores the disrupted reading frame and produces a shortened form of the dystrophin protein . Current targets include exons 44, 45, 51, and 53 .
Eteplirsen, a phosphorodiamidate morpholino oligomer, targets the splice-donor region of exon 51 and produces a truncated, albeit in-frame, dystrophin protein that is partially functional [3, 60, 61, 62]. Eteplirsen, delivered intravenously, received accelerated approval from the US FDA on September 19, 2016 for the treatment of DMD in patients with a confirmed mutation of the dystrophin gene that is amenable to exon 51 skipping . However, repeated injections of eteplirsen are required as its effect is transient due to the target of exon skipping AONs being pre-mRNA .
Treatment with eteplirsen 30 mg/kg or 50 mg/kg (eteplirsen studies 201 and 202, NCT01396239 and NCT01540409) significantly slowed the rate of disease progression and was well tolerated in 12 patients (mean age 9.4 years) with DMD amenable to exon 51 skipping compared with 13 untreated, matched (for age, steroid use, and mutation type) historical control patients . Over a 3-year treatment period, decline in the 6-min walk distance (6MWD) was slower in eteplirsen-treated patients vs matched controls, culminating in a statistically significant difference of 151 m at 36 months (p < 0.01). The incidence of ambulation loss was lower for eteplirsen-treated patients vs matched controls at 36 months (16.7 vs 46.2%) and respiratory muscle function remained relatively stable in eteplirsen-treated patients.
An analysis of pulmonary function data from eteplirsen studies 201 and 202 showed that treatment with eteplirsen for up to 5 years may preserve respiratory muscle function in patients with DMD . In eteplirsen-treated patients, pulmonary function declined at a slower rate compared with natural history data (annual decline of 2.3 vs 4.1%, respectively, in FVC), while maximum inspiratory and expiratory pressures compared favorably between cohorts. The authors suggested that preservation of respiratory muscle may be due to eteplirsen-induced dystrophin production, which slows the decline of pulmonary function.
A 65 m (range − 335 to 83 m) average rate of decline in the 6MWD and a 24.23% (range − 4 to 78%) total average increase in percentage dystrophin-positive fibers after treatment with eteplirsen was identified in a pooled analysis of four clinical studies which assessed the safety and efficacy of eteplirsen in 38 boys (mean age 10.2 years, range 7–16) with DMD amenable to exon 51 skipping . Due to the lack of adequate statistical evidence, the authors stated that it was unclear whether the increase in 6MWD and dystrophin-positive fibers was clinically significant and that more clinical trials were needed.
Golodirsen is a phosphorodiamidate morpholino oligomer that targets exon 53 and produces an internally shortened form of the dystrophin protein. An interim analysis of data from a phase 1/2 trial (NCT02310906) confirmed that golodirsen effectively skipped exon 53, enabling the production of functional dystrophin in DMD patients with genetic mutations amenable to exon 53 skipping . Interim results from this trial, which aims to assess the safety, tolerability, and efficacy of golodirsen over a total of 144 weeks, showed that the mean percentage of normal dystrophin protein increased significantly (by 0.924%) at week 48 compared with baseline (1.019 vs 0.095%; p < 0.001).
Suppression of premature stop codons
Point mutations, which introduce a premature stop codon into the dystrophin mRNA causing the translation of a truncated, usually non-functional protein, occur in approximately 10–15% of DMD patients . Ataluren, an orally bioavailable drug, was designed to overcome premature stop codon mutations by binding to ribosomal RNA subunits and interfering with the recognition of premature stop codons; this allows the translation and production of a modified dystrophin protein . In August 2014, the European Medicines Agency granted ataluren conditional approval for the treatment of non-sense mutation DMD in ambulatory patients aged 5 years and older .
Ataluren may be clinically beneficial in a subgroup of patients with non-sense mutation DMD and a baseline 6MWD of ≥ 300 m to < 400 m . This multicenter, randomized, double-blind, placebo-controlled, phase 3 study aimed to determine the efficacy and safety of ataluren in ambulatory boys aged 7–16 years with non-sense mutation DMD confirmed by gene sequencing. Patients were randomly assigned to receive ataluren (n = 115) orally three times daily (10, 10, and 20 mg/kg of bodyweight for morning, midday, and evening doses, respectively) or placebo (n = 115). The primary endpoint was the change in 6MWD from baseline to week 48; secondary endpoints included the effect of ataluren on proximal muscle function as assessed by timed function tests (10-m run or walk, four-stair climb, four-stair descend). Endpoints were also evaluated according to pre-specified subgroups (i.e., baseline 6MWD of < 300 m, ≥ 300 m to < 400 m, and ≥ 400 m).
The primary endpoint was numerically, albeit not significantly, in favor of ataluren in the intent-to-treat population (6MWD least squares mean change − 47.7 m vs − 60.7 m for placebo), with a significant 42.9-m difference in 6MWD in the pre-specified ≥ 300- to < 400-m subgroup for ataluren-treated patients vs placebo (− 27.0 m vs − 69.9 m; p = 0.007) . The decline in physical function was less in ataluren-treated patients compared with placebo after 48 weeks as determined by the timed function tests; only the four-stair descend test was statistically significant (least squares mean change 2.78 s vs 4.75 s, respectively; p = 0.012). There were fewer non-ambulatory patients after 48-week treatment with ataluren compared with placebo in both the intent-to-treat population (8 vs 12%) and in the pre-specified ≥ 300- to < 400-m subgroup (none vs 8%). Ataluren was well tolerated with a high compliance in dosing; treatment-emergent adverse events were mostly mild to moderate in severity.
Overall, the pre-specified ≥ 300- to < 400-m subgroup showed a consistent treatment benefit with ataluren in terms of 6MWD and timed function tests, and further studies of ataluren in a targeted patient population (i.e., those with a baseline 6MWD ≥ 300 m to < 400 m) are warranted. It will also be of interest to assess whether treatment with ataluren offers long-term benefits in non-ambulatory DMD patients as well as in patients aged < 5 years. Finally, a clinical trial assessing the long-term outcomes of ataluren in patients with non-sense mutation DMD is currently underway (NCT03179631).
There is no cure for DMD. Novel genetic therapies, which restore dystrophin protein production, may preserve existing muscle function, thereby stabilizing or slowing disease progression, with promising results shown for eteplirsen and ataluren. Multidisciplinary clinical management of respiratory, cardiology, orthopedic, and nutritional needs, alongside the use of novel disease-modifying treatments, offers physicians a powerful armamentarium for the treatment of DMD. With newly gained knowledge of the optimal management and treatment of DMD, it is conceivable that further improvements in patients’ quantity and quality of life are attainable.
The authors would like to thank Melanie Gatt (PhD) for the medical writing assistance on behalf of Springer Healthcare Communications.
Medical writing assistance was funded by PTC Therapeutics, Rome, Italy.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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