Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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Duchenne muscular dystrophy (DMD) is a genetic neuromuscular disorder that affects 1 in 5000 males. The author outlines the clinical presentation and advances in the molecular pathogenesis and treatment of Duchenne muscular dystrophy. Proactive management with corticosteroids and early recognition of cardiac and respiratory pathophysiology has had a significant impact on improving the outcome of patients with Duchenne muscular dystrophy. Additionally, new exon-skipping treatments are showing promise in patients with certain DMD gene mutations and gene therapy preliminary results are very encouraging.
• Duchenne muscular dystrophy is a multisystem progressive genetic disease that primarily causes skeletal and cardiac muscle degeneration.
• Dystrophin, a subsarcolemmal protein, is responsible for the severe pathology of muscle cells, and most therapeutic efforts are directed to provide this protein for the muscle tissue.
• Survival is currently prolonged with corticosteroid use, ventilatory support, and multidisciplinary care.
Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy and one of the most common lethal genetic diseases. Studies published between 1850 and 1890 defined the course of the disorder in boys (82; 35; 41). The biochemical and genetic basis of Duchenne muscular dystrophy was elucidated in 1986 and 1987 in a series of studies that is considered a major early triumph of human molecular genetics (84; 50; 51; 66). Becker muscular dystrophy (BMD) refers to a milder phenotype that is allelic to the same gene that causes Duchenne muscular dystrophy.
• Duchenne muscular dystrophy is a multisystem X-linked recessive disease characterized by progressive weakness of skeletal muscle identified in early childhood.
• Parents of boys with Duchenne muscular dystrophy note initial symptoms at a mean age of 2.5 years; however, a definite diagnosis is typically not made until about 5 years of age, which indicates a significant delay in diagnosis.
• 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.
• The rate of deterioration is variable, and disease severity does appear related to genetic mutation; however, all children show a decline in motor function, with a loss of ambulation and an eventual need for respiratory assistance.
• Corticosteroids have been shown to improve muscle strength, pulmonary function, timed motor function, and delay loss of ambulation.
Presentation. Parents of boys with Duchenne muscular dystrophy note initial symptoms 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 is typically not made until about 5 years of age, which indicates a 2.5-year delay from identification of symptoms (24). Non-Caucasian and high poverty patients have been associated with older diagnosis. Additionally, specific genetic mutation subtypes may have later age of symptom onset and, thus, later diagnosis (30). In a family with a previously affected boy, the parents might suspect involvement of a second child much earlier. In recent years, cognitive changes within the first year of life have been identified, indicating onset of symptoms is earlier (26). There is likely a relationship between neurodevelopment and Duchenne muscular dystrophy mutation, with a percentage of Duchenne muscular dystrophy patients found to have speech delay (39%), learning difficulties (28%), inattentive-overactive behavior disorder (8%), and oppositional-defiant (5%) behavior disorder (107). Intellectual disability in these children is thought to be nonprogressive; however, severity of cognitive disability may vary depending on DMD gene mutation (32; 93).
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 (65; 11). 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 Duchenne muscular dystrophy patients typically require noninvasive/invasive ventilation for survival by age 18 (37). 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 (105).
Corticosteroids have been shown to improve muscle strength, pulmonary function, timed motor function, and delayed cardiomyopathy onset and loss of ambulation (up to 3 years in some patients) (10; 40; 44). Nonambulatory patients receiving corticosteroids have improved percent-predicted forced vital capacity and upper extremity strength (27).
Duchenne muscular dystrophy is a lethal condition; however, survival has improved with advancements in medical care and implementation of multidisciplinary standards of care (37). Most early textbooks state that the majority of Duchenne muscular dystrophy patients die by 20 years of age from respiratory insufficiency. Today, with multidisciplinary care and assisted ventilation, their lifespan can be doubled to up to 40 years (62). In patients utilizing assisted ventilation, cardiac dysfunction has become the major comorbidity (58).
• Duchenne muscular dystrophy is caused by loss-of-function mutations of an extremely large gene, the Duchenne muscular dystrophy gene (DMD gene), located on the X-chromosome (Xp21).
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 (66; 95). Several mRNA and protein isoforms vary in size and tissue distribution (03). Deletions affecting 1 or more exons are present in 68% to 78% of boys with Duchenne muscular dystrophy; duplications are present in 11% (31; 16). The remaining boys have point mutations, small insertions, or small deletions. In all mutations, the protein product of the gene, dystrophin, is absent or markedly deficient (50; 51; 17).
Dystrophin is localized to the plasma membrane of all myogenic cells, some classes of neurons, and in small amounts in other cell types (52).
Deficiencies of other isoforms produced in liver tissue and other nonexcitable tissues do not seem to cause pathology (03). 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 (91; 34). 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 (33; 106).
Dystrophin may play an important functional role in addition to its more evident structural role, though this is not completely understood. Some hypotheses include:
• Dystrophin mediates the subsarcolemmal localization of neuronal nitric oxide synthetase, which is necessary for muscle relaxation. The absence of dystrophin causes a redistribution of neuronal nitric oxide synthetase in the cytosol of muscle cells and can cause oxidative damage to the cell. Although the absence of neuronal nitric oxide synthetase in and of itself does not cause dystrophic features, several lines of evidence suggest that free radical mediated injury and oxidative stress may lead to muscle necrosis (48; 92).
• Calcium is increased in dystrophic muscle fibers, leading to excessive influx of calcium into the cells through membrane gaps leading to cell demise, perhaps through the activation of proteases (55). The increase of intracellular calcium is thought to be caused by “stretch activated channels” (05). Altered homeostasis of calcium may be related to a defect in the ryanodine receptor shown in mdx mice (09).
• Cellular apoptosis may be the earliest event in dystrophic muscle (98). Experiments in mdx mice have shown that apoptosis can be seen long before dystrophic changes and before muscle necrosis becomes evident. A puzzling fact has been that the mdx mice become weak only after exercise despite the total lack of dystrophin, and apoptosis was observed in normal muscle and muscle of mdx mice both before and after exercise (06). Thus, it is postulated that apoptosis is a normal mechanism of muscle remodeling, somehow leading to dystrophic changes in the absence of dystrophin.
• Duchenne muscular dystrophy affects approximately 1 in 5000 male births worldwide (77).
• Ten percent of isolated cases of “idiopathic hyper-CKemic myopathy” in females are isolated cases of dystrophinopathy.
Genetic counseling and prenatal diagnosis have begun to lower the incidence 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 (85). 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 (83; 49). 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 (90).
• Duchenne muscular dystrophy is an inherited condition, and currently, the full clinical course cannot be prevented.
• The disease’s high spontaneous mutation rate makes genetic counseling challenging.
• Neonatal screening for Duchenne muscular dystrophy is being piloted in some states and countries.
Duchenne muscular dystrophy disease 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 (19).
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, is under pilot in the United States and being implemented in Eastern China (59; 60). Identifying affected boys at birth will allow for earlier treatment with corticosteroids and initiation of potential new genetic treatments before the appearance of muscle fibrosis. Genetic counseling can also be provided to unsuspecting parents (77; 101).
Becker muscular dystrophy. In the milder Becker muscular dystrophy, serum creatine kinase levels can approach those of Duchenne muscular dystrophy, however they are frequently lower.
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 1 of the 4 sarcoglycan genes (36). Thus, any patient presenting as Duchenne dystrophy but having negative Duchenne muscular dystrophy gene testing and normal dystrophin levels on muscle biopsy should be tested for sarcoglycanopathy.
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.
Other mild elevation in serum creatine kinase due to other causes. Unusual muscle activity (exercise), metabolic myopathies, viral infection, and muscle damage of any kind can also cause elevated serum creatine kinase. However, the degree of elevation rarely approaches that of Duchenne muscular dystrophy.
• Serum creatine kinase levels in Duchenne patients are always elevated between 5000 and 150,000 IU/L (normal is less than 200 IU/L).
• Identification of dystrophin gene mutation is essential to identify mutation specific therapies currently in clinical trials and also avoids the previous diagnostic gold standard of muscle biopsy (02; 12).
• Additionally, early identification of female carriers and prenatal diagnosis should be offered to family members for pregnancy considerations and clinical evaluation; 49% of female Duchenne muscular dystrophy carriers have been identified to have cardiac fibrosis (69).
Many different molecular diagnostic technologies are available to evaluate for various DMD gene mutations. Unless family history has identified a specific prior mutation, 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 (31; 16). If quantitative assays cannot completely characterize the mutation, sequencing of the coding DMD regions can evaluate for deletion endpoints, point mutations, and other small alterations (12; 67). Recommendations and algorithms for molecular testing have been updated by the Duchenne Muscular Dystrophy Care Consideration Working Group (67).
In patients testing negative for a DMD gene mutation, it is important to test the status of the dystrophin protein in a muscle biopsy (57). 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 (51). Levels of 12% to 18% usually indicate a milder phenotype such as Becker muscular dystrophy (51). It is important to note that all Duchenne dystrophy biopsies also show secondary deficiencies of many other proteins, such as sarcoglycans and dystroglycans (51).
• A comprehensive care guide detailing care throughout the 5 stages of Duchenne muscular dystrophy, from diagnosis to the late nonambulatory phase, may be reviewed in The Lancet Neurology (13). Despite published multidisciplinary guidelines, implementation of these care recommendations remains variable (08).
• Glucocorticoids are recommended for the treatment of all Duchenne muscular dystrophy boys, both ambulatory and nonambulatory.
Glucocorticoid treatment. Glucocorticoids are recommended for the treatment of all DMD boys, both ambulatory and non-ambulatory (72).They improve muscle strength and pulmonary function, as well as reduce the need for scoliosis surgery and delay onset of cardiomyopathy (86; 40). 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; 86; 40; 72). Deflazacort (EMFLAZA) approved by the FDA in 2017 (the first FDA approved medication for Duchenne muscular dystrophy) has shown likely equal effectiveness in improving muscle strength and may delay the time to loss of ambulation when compared to prednisone (22; 40; 44; 73; 74; 71).
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) (63). 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 (100; 28; 89). Corticosteroids are currently recommended for ages 5 years and older. There remain unanswered questions regarding corticosteroids in infants, including what dose should be given and will early treatment lead to longer benefit (29).
Despite clear guidelines that steroids should be offered to patients with Duchenne muscular dystrophy, they are inconsistently or never prescribed (43; 45). 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 (115; 18). Minimizing glucocorticoid-induced weight gain is important to maintain mobility and to reduce sleep-disordered breathing (115). Deflazacort may be associated with fewer side effects, particularly weight gain and osteoporosis (40; 44). Weekend prednisone dosing has also been considered by specialists to have potentially fewer side effects (94). A head-to-head trial comparing daily prednisone 0.75 mg/kg/day, intermittent prednisone (10 days on/10 days off), and deflazacort 0.9 mg/kg/day to determine the relative effectiveness and adverse event profile over 3 years is ongoing (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 (68). 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 Duchenne muscular dystrophy patients on glucocorticoids (68; 14; 113). 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 (114; 14; 113). Duration of treatment, beyond when adult height is obtained, is not well studied (113).
Joint contractures can compromise comfort and mobility. Detailed rehabilitation guidelines throughout all stages of Duchenne muscular dystrophy may be reviewed in the journal Pediatrics (23). 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 (20; 23). Achilles tendon contractures generally begin to limit mobility by the end of the first decade, and surgical tendon lengthening can be done, but should be considered in patients with significant ankle contraction and good proximal upper extremity strength (99; 14). 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. Early scoliosis surgery may delay the respiratory and cardiac complications associated with Duchenne muscular dystrophy (110). Patients should be visually screened for scoliosis with every clinical exam. Spine radiograph can be considered in obese patients where visualization may be more difficult (14). In patients with identified scoliosis, radiographic following should be done every 6 to 12 months. (14). 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, but on corticosteroids, have a less predictable course so monitoring for progression is more reasonable (64; 14).
Pulmonary management. Proactive respiratory care has an important role in the management of Duchenne muscular dystrophy patients, improving survival and quality of life (103; 37; 70; 111). As muscle weakness ensues, patients are at risk for several respiratory complications, including ineffective cough, pulmonary infections, obstructive sleep apnea, and respiratory failure (102). Other known complications of Duchenne muscular dystrophy, including cardiac, gastrointestinal, and orthopedic changes, likely also contribute to respiratory decline (14). Detailed guidelines for respiratory management in ambulatory and nonambulatory Duchenne muscular dystrophy patients are available for review (14; 102). 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 (14). 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 (14). 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 (14). Sleep studies should be completed yearly in patients with symptoms of sleep-disordered breathing (14). 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 3 times, tracheostomy should be considered (14).
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 (14). 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) (54; 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 (88; 38); however, further studies are being conducted to assess benefit of treatment in young, asymptomatic patients (age < 10) (75; 14). There was no substantial difference in the improvement of cardiac function in Duchenne muscular dystrophy patients treated with lisinopril (an ACE inhibitor) or losartan (an angiotensin receptor blocker) (07). 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 (75; 56).
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 Duchenne muscular dystrophy patients live well into their 30s, transition of care into adulthood, as well as psychosocial issues associated with chronic illness, become important management considerations (Saito et al 2017; 15; 108).
Emerging treatments. Considerable research efforts are underway to develop novel therapeutics for Duchenne muscular dystrophy; many are based on knowledge of the molecular defect. This has led to encouraging new genetic-based treatments in clinical trials.
Exon skipping. The use of antisense oligonucleotides to restore the Duchenne muscular dystrophy reading frame and produce functional dystrophin is becoming a promising treatment of patients with particular deletions. A 3-year study of 12 patients who received an intravenous infusion of eteplirsen, a morpholino compound targeting exon 51, showed a slower rate of decline in ambulation assessed by the 6-minute walk test compared to untreated matched historical controls (79; 78). Studies have also suggested that long-term treatment with eteplirsen slows disease progression in ambulatory and nonambulatory boys (04; 61). Eteplirsen is now approved for use by the FDA under the accelerated approval pathway for patients who have mutations amenable to exon 51 skipping (about 13%); however, the results of a confirmatory phase 3 clinical trial are pending (78). Golodirsen (Vyondys) and Viltolarson (Viltepso) for 53 skippable mutations have also been approved by the FDA with accelerated approval (01). In a phase 2 randomized clinical trial, Viltolarsen (Viltepso) was safe and effective after 25 weeks, with a significant increase in dystrophin production and clinical improvement of timed function tests compared to controls (25).
Stop codon suppression. An oral delivery of ataluren, which promotes nonsense read through, has been shown to be well tolerated and associated with slowed disease progression, including delayed loss of ambulation (39; 21; 81). Ataluren has been conditionally approved by the European Medicines Agency, and FDA approval will be revisited in 2020 (87).
Gene therapy. Gene replacement strategies have the ability to treat all Duchenne muscular dystrophy mutations. Systemic delivery of “naked” DNA has been achieved and has paved the way for long-awaited clinical trials (116; 117). The first gene therapy clinical trial utilized adeno-associated virus vectors in 6 Duchenne muscular dystrophy boys. Transgene expression was undetectable, but a T-cell specific immune response to mini-dystrophin was detected (76). Systemic delivery of microdystrophin with the MHCK7 promotor resulted in 60% gene expression in mouse skeletal muscle and 100% in cardiac muscle, with reduced fibrosis (97). Overall, these vectors still need to be improved with regards to methods for gene delivery, immunological responses, and persistence of gene expression before they can be expected to show functional success in Duchenne muscular dystrophy patients (96; 112; 47). Microdystrophin gene therapy clinical trials are underway. A phase I/II trial to assess the safety of rAAVrh74.MHCK7.micro-dystrophin in children with Duchenne muscular dystrophy is following 4 patients who received a single dose of rAAVrh74.MHCK7.mico-dystrophin through peripheral limb vein. The study found robust dystrophin expression as measured by Western blot and immunohistochemistry after 90 days with positive functional improvement, and significant decrease in creatine kinase levels maintained after 1 year, without serious adverse events (80). A phase I/II trial to assess safety/tolerability of SGT-001 in adolescents with Duchenne muscular dystrophy at the University of Florida is also active (NCT03368742).
Another potential therapy, currently in clinical trial, includes vamorolone, which is an anti-inflammatory steroid that aims to slow progression of Duchenne muscular dystrophy without the side effects of corticosteroids (53; 104).
In female carriers either manifesting Duchenne muscular dystrophy or not, there is no reported increased risk during pregnancy to either the mother or child.
Patients are at increased risk of malignant hyperthermia during exposure to halothane anesthesia.
Consensus guidelines for the care of Duchenne muscular dystrophy patients 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, but the risks/benefits of receiving these infusions during a pandemic should be discussed with the patient’s neurologist. It is recommended that angiotensin-converting enzyme inhibitors and/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 (109).
Michele Gatheridge MD
Dr. Gatheridge of the University of Rochester Medical Center has no relevant financial relationships to disclose.See Profile
Emma Ciafaloni MD FAAN
Dr. Ciafaloni of the University of Rochester received personal compensation for serving on advisory boards and/or as a consultant for Alexion, Avexis, Biogen, PTC Therapeutics, Ra Pharma, Sarepta, Strongbridge Biopharma PLC, and Wave; and for serving on a speaker’s bureau for Biogen. Dr Ciafaloni also received research and/or grant support from Orphazyme, Santhera, and Sarepta.See Profile
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