Mutations in the DMD gene result in Duchenne or Becker muscular dystrophy due to absent or altered expression of the dystrophin protein. The more severe Duchenne muscular dystrophy typically presents around ages 2 to 5 with gait disturbance, and historically has led to the loss of ambulation by age 12. It is important for the practicing pediatrician, however, to be aware of other presenting signs, such as delayed motor or cognitive milestones, or elevated serum transaminases. Becker muscular dystrophy is milder, often presenting after age 5, with ambulation frequently preserved past 20 years and sometimes into late decades.
Key points
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Duchenne and Becker muscular dystrophy (DMD and BMD) are X-linked disorders that occur because of mutations in the DMD gene, encoding the dystrophin protein, which provides an important part of the protein complex that provides a link between the cytoskeleton the extracellular matrix.
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In most cases, DMD occurs because of mutations that result in the production of no dystrophin, and BMD occurs because of mutations that result in the production of partially functional dystrophin; this concept is being used for novel potential therapies directed at DMD.
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DMD typically presents at ages 2 to 5 years with gait abnormalities or motor performance that falls behind peers, but clinicians must be aware it may present with delayed motor milestones, early cognitive impairment, or elevated serum transaminases, any of which should lead to testing serum creatine kinase.
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Treatment with systemic corticosteroids (prednisone and deflazacort) is the only therapy that has definitively been shown to alter the course of DMD; careful monitoring and counseling are required to minimize side effects.
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Promising potential therapies, such as exon skipping or nonsense suppression, are directed toward specific mutations or mutation classes; definitive mutation analysis of the DMD gene from genomic DNA is widely available and detects approximately 95% of mutations.
Introduction
Duchenne and Becker muscular dystrophy (DMD and BMD) are related disorders that occur because of mutations in the DMD gene, encoding the dystrophin protein. DMD is more severe, and more common, with newborn screening studies showing an incidence ranging from 1:3802 to 1:6291 live male births (rather than the 1:3500 that is commonly cited), and BMD is about one-third as common. Because the gene is X-linked, the diseases affect only boys (except in those rare cases explained by unusual genetic mechanisms such as balanced chromosomal translocations).
The dystrophin protein consists of an N-terminal actin-binding domain, a long central rod domain consisting of 24 spectrin-like repeats, and a C-terminal dystroglycan-binding domain. Within the central rod domain is a second actin-binding domain as well as a binding site for neuronal nitric oxide synthase; additional proteins, including dystrobrevin and syntrophin, bind dystrophin distal to the dystroglycan-binding domain. These partners suggest a role for dystrophin in signaling, but it is clear that dystrophin plays a critical role as a structural linker between the cytoskeletal F-actin and β-dystroglycan, one of the proteins of the membrane-bound dystroglycan-associated glycoprotein complex. Another of these proteins, α-dystroglycan, is located externally, where it binds with the extracellular matrix. The deformational forces generated by muscle contraction are significant, and in the absence of dystrophin, which is typically the case with DMD, the muscle membrane is damaged. This damage leads to elevations of creatine kinase (CK) in the serum and to calcium influx within the muscle fiber, leading in turn to activation of calcium-dependent proteases. Cycles of muscle fiber necrosis, degeneration, and regeneration follow, with increasing endomysial fibrosis and fatty replacement of muscle over time, and loss of muscle contractile function. In BMD, a partially functional dystrophin is typically produced, leading to an attenuated clinical course and attenuated muscle pathologic abnormality.
At the level of gene mutations, the difference between an absent or a partially functional dystrophin (and hence DMD or BMD) is explained by the concept of the “reading frame rule.” Mutations that ablate the open reading frame (or “out-of-frame” mutations) lead to translation termination and DMD. In contrast, those that maintain an open reading frame (or “in-frame” mutations) lead to BMD, via translation of an internally truncated protein that still has domains critical to binding F-actin and β-dystroglycan. This reading frame rule is generally accurate, being 90% specific in DMD cases, and it is important for the pediatrician ordering and interpreting genetic tests to be familiar with it, but as discussed later exceptions to the rule occur. Nevertheless, restoration of an open reading frame is a key goal of new molecular therapies now in clinical trials.
Introduction
Duchenne and Becker muscular dystrophy (DMD and BMD) are related disorders that occur because of mutations in the DMD gene, encoding the dystrophin protein. DMD is more severe, and more common, with newborn screening studies showing an incidence ranging from 1:3802 to 1:6291 live male births (rather than the 1:3500 that is commonly cited), and BMD is about one-third as common. Because the gene is X-linked, the diseases affect only boys (except in those rare cases explained by unusual genetic mechanisms such as balanced chromosomal translocations).
The dystrophin protein consists of an N-terminal actin-binding domain, a long central rod domain consisting of 24 spectrin-like repeats, and a C-terminal dystroglycan-binding domain. Within the central rod domain is a second actin-binding domain as well as a binding site for neuronal nitric oxide synthase; additional proteins, including dystrobrevin and syntrophin, bind dystrophin distal to the dystroglycan-binding domain. These partners suggest a role for dystrophin in signaling, but it is clear that dystrophin plays a critical role as a structural linker between the cytoskeletal F-actin and β-dystroglycan, one of the proteins of the membrane-bound dystroglycan-associated glycoprotein complex. Another of these proteins, α-dystroglycan, is located externally, where it binds with the extracellular matrix. The deformational forces generated by muscle contraction are significant, and in the absence of dystrophin, which is typically the case with DMD, the muscle membrane is damaged. This damage leads to elevations of creatine kinase (CK) in the serum and to calcium influx within the muscle fiber, leading in turn to activation of calcium-dependent proteases. Cycles of muscle fiber necrosis, degeneration, and regeneration follow, with increasing endomysial fibrosis and fatty replacement of muscle over time, and loss of muscle contractile function. In BMD, a partially functional dystrophin is typically produced, leading to an attenuated clinical course and attenuated muscle pathologic abnormality.
At the level of gene mutations, the difference between an absent or a partially functional dystrophin (and hence DMD or BMD) is explained by the concept of the “reading frame rule.” Mutations that ablate the open reading frame (or “out-of-frame” mutations) lead to translation termination and DMD. In contrast, those that maintain an open reading frame (or “in-frame” mutations) lead to BMD, via translation of an internally truncated protein that still has domains critical to binding F-actin and β-dystroglycan. This reading frame rule is generally accurate, being 90% specific in DMD cases, and it is important for the pediatrician ordering and interpreting genetic tests to be familiar with it, but as discussed later exceptions to the rule occur. Nevertheless, restoration of an open reading frame is a key goal of new molecular therapies now in clinical trials.
Clinical features
Duchenne Muscular Dystrophy
Typically, parents of boys with DMD seek attention when their boys are between ages 2 and 5 years old. They frequently describe altered gait, often with toe walking that leads to a referral to a physical therapist or orthopedic surgeon even before a serum CK is tested. Parents frequently describe a diagnostic odyssey, with diagnosis taking more than a year from presentation, but serum CK elevations that are typically 50 to 100 times the normal levels lead quickly to a diagnosis of muscular dystrophy. Gait acquisition and other motor skills may be delayed in comparison with their peers, and the American Academy of Pediatrics recommends testing of serum CK for all cases of motor delay. Language development may similarly be delayed; cognition is affected, and the intelligence quotient (IQ) is diminished by one standard deviation with improvements in verbal IQ with age. On examination, proximal weakness is evident even at an early age and can be demonstrated by difficulty in climbing stairs ( [CR] ), hopping on either foot, or arising from the floor, which is usually performed with the use of the classic Gower maneuver ( [CR] ). Calf enlargement is usually seen—the classic “pseudohypertrophy” of Duchenne, although true muscle hypertrophy is present—as is tight heel cords and lordosis, both of which may be quite mild at presentation.
Boys with DMD typically improve in strength through the sixth or seventh year, followed by a measurable plateau in function for up to 2 years before a decline leading to wheelchair dependence. In historical studies from the presteroid treatment era, the loss of independent ambulation reliably occurred before the age of 12 years. Once in a wheelchair, forced vital capacity begins to decline, leading to ventilatory insufficiency, particularly at night. Scoliosis also is frequent and may require surgical correction. The incidence of cardiomyopathy increases with age and arguably has a greater clinical impact now that improvements in noninvasive ventilatory care are improving life expectancy. In the absence of ventilatory intervention, death typically occurs late in the second or early in the third decade.
Becker Muscular Dystrophy
BMD is much more clinically heterogeneous. Half of affected boys demonstrate muscle weakness by age 10, typically in a limb-girdle pattern, but many without muscle weakness at that age recall myalgias with exertion and calf hypertrophy. BMD is defined by loss of ambulation by the age of 15 or greater, but most patients with childhood onset of weakness typically lose ambulation in the third or fourth decade. Others, however, have much milder symptoms, including onset of limb-girdle weakness beginning only in mid or late adulthood ; isolated quadriceps weakness ; adult or childhood cramp-myalgia syndromes or exercise-induced myoglobinuria ; or (very rarely) asymptomatic hyperCKemia. Cognition is usually normal, although isolated cognitive impairment has been reported. Cardiomyopathy is common, although the age at onset may vary depending on the structure of the residual dystrophin protein.
Serum chemistries
The serum CK level is almost always the first diagnostic test performed once the diagnosis of DMD or BMD is suspected. It is always elevated, frequently 50 to 100 times normal in DMD, and lower in BMD, where it peaks around 10 to 15 years of age. It is elevated at birth, leading to its use as a tool for newborn screening ; both CK level and DNA mutational analysis can be performed from Guthrie card blood spots. Extremely elevated serum CK levels are sometimes observed, associated with myoglobinuria and leading to a diagnosis of rhabdomyolysis; this is more commonly seen in BMD than in DMD, presumably because BMD allows more strenuous activity, which may precipitate such episodes. Importantly, CK is not the only enzyme elevated in serum. The transaminases aspartate aminotransferase and alanine aminotransferase are elevated and correlate with serum CK ; in this case, they are derived from muscle, not liver, yet patients occasionally present following extensive workup for hepatic disease, even including liver biopsy. For this reason, γ-glutamyl transferase level should be used as a marker of liver injury in DMD patients. Similarly, renal function may be assessed by use of cystatin C rather than serum creatinine or creatinine clearance, because both of these are routinely decreased in patients with DMD.
Mutation analysis
Mutation analysis of the DMD gene has largely replaced muscle biopsy as the first diagnostic test performed after serum CK testing. Testing of genomic DNA derived from lymphocytes is readily available. Detailed mutational analysis now represents the standard of care, not only because it may provide prognostic information but also because it facilitates genetic counseling and potentially more importantly may determine suitability for specific novel therapies, as discussed later.
The implications of DMD mutations are outlined in Fig. 1 . The DMD gene consists of 79 exons spread over more than 2.4 million nucleotides on the X chromosome, and deletions of one or more these exons account for 65% of cases of dystrophinopathy. This enormous size of the DMD gene originally precluded detailed mutational analysis, and early clinical diagnostic tests interrogated around 25 exons within the 2 deletion hot-spot regions of the gene by use of a multiplex PCR approach. This method frequently did not define the extent of a multiexon deletion, nor could it detect duplications, which represent around 6% of all mutations. It could also not detect point mutations, and sequencing of the entire greater than 11 kilobase cDNA (from muscle-derived RNA) was required. Over the past decade, nearly complete mutational analysis has become possible. Exon copy number can be reliably assessed by a multiplex ligation dependent probe amplification technique, or by comparative genomic hybridization array, each of which allows determination of exon copy number in both hemizygous men and in carrier women. Sequence analysis is required to detect the remaining mutations, including nonsense, small subexonic insertions or deletions, missense, or splice site mutations. These mutations may be detected by traditional Sanger sequencing or next-generation sequencing methods. For practical purposes in the clinic, the method itself is not important as long as the entire coding region is sequenced, because point mutations are typically “private” mutations.
Mutational analysis of genomic DNA as described above thus detects around 95% of mutations. Importantly, one class of mutations is not detected by current genomic DNA approaches. Point mutations that occur deep within the large introns of DMD may activate a cryptic splice site; as a result, an intronic fragment may be included in the assembled mature mRNA as a pseudo-exon. Such mutations likely account for less than 5% of all dystrophinopathy patients, but are important to be aware of because they can only be diagnosed via muscle biopsy, followed by sequencing of cDNA derived from muscle mRNA.
An additional clinical challenge is presented by patients who represent exceptions to the reading frame rule, which is accurate 90% of the time. At diagnosis, parents typically request prognostic information based on the results of the mutation analysis, and the reading frame rule-based prediction may be misleading. For example, large in-frame deletions affecting the N-terminal dystrophin actin binding domain 1 and extending into the central rod domain may in fact be associated with DMD rather than BMD. Similarly, predicted “nonsense mutations” within exons 23 to 42, a region in which deletion of any single exon maintains the reading frame, may alter splice definition elements such that the exon containing the mutation is not spliced into the mature mRNA, resulted in an open reading frame and a BMD phenotype. Therefore, particularly in the absence of an informative family history regarding the implication of a given mutation, prognostication or phenotypic classification cannot rely solely on the results of mutation analysis, but must take into account the entire clinical picture, including age at presentation, consistency of the examination findings with the predicted phenotype, and, if available, the results of any dystrophin expression studies on muscle biopsy.
Families affected by DMD and BMD should be provided with genetic counseling, and carrier testing should be offered to each mother unless there is an extensive X-linked family history that defines her as an obligate carrier. However, one-third of all cases are de novo, consistent with Haldane’s rule, so direct testing of the mother’s DNA is warranted. The risk of germline mosaicism, which may be as high as 10%, should be addressed with a genetic counselor.
Muscle biopsy
The role of muscle biopsy in the diagnosis of DMD and BMD has become less important as molecular mutation analysis has improved. However, as previously discussed, muscle biopsy is still required to establish the mutational mechanism in some patients. Furthermore, absent or altered dystrophin expression remains the gold standard of diagnosis of a dystrophinopathy.
The degree of histopathology present in the muscle biopsy depends in part on the age of the patient in the muscle sampled. Absence of dystrophin results in loss of muscle fiber integrity, and a cascade of myofiber necrosis, phagocytosis, and regeneration is associated with fibrosis and fatty replacement. Pathologically, it is these chronic and end-stage pathologic changes that are termed dystrophic. In BMD, the degree of pathologic abnormality may be less severe, with more moderate variation in muscle architecture and less fibrosis, although the degree of these changes may vary.
Dystrophin protein expression can be assessed by either immunofluorescent (IF) or immunohistochemical (IHC) staining of muscle sections, or by immunoblot (Western blot) analysis of homogenized tissue. Clinical laboratories make use of 3 antibodies with one directed toward each of the N-terminal, C-terminal, and central rod domains; in this fashion, if a BMD protein is missing only one of these epitopes, the presence of dystrophin can still be detected. In clinical practice, IF or IHC staining demonstrates localization of dystrophin and allows semiquantitative descriptors of amount (ie, “absent,” “reduced,” “traces”). As shown in Fig. 2 A, in normal muscle, dystrophin decorates the sarcolemmal membrane evenly; in BMD muscle, staining is reduced and often patchy, and in DMD, it is absent. However, it is important to note that biopsies from DMD patients can frequently show clusters of fibers with significant dystrophin expression. Termed “revertant fibers,” they occur due to secondary alterations in the DMD gene—typically, altered mRNA splicing resulting in some mRNA with an open reading frame resulting in the expression of dystrophin—and are found in up to 50% of patient biopsies. Immunoblot analysis (see Fig. 2 B) provides information on protein size and allows more quantitative assessment; values of less than 3% in association with DMD and greater than 20% in association with BMD have been described and are still cited by some diagnostic laboratories. The presence of internal yet in-frame BMD deletions frequently result in abundant dystrophin of diminished size (see Fig. 2 B).
Management
Although DMD commonly presents because of its effect on skeletal muscle, the disease affects multiple systems. As examples, both cardiac muscle and brain are directly affected by absence or alteration of dystrophin expression; ventilation becomes impaired because of diaphragmatic weakness, and bone density is diminished, a finding compounded by corticosteroid therapy. Once boys are in a wheelchair, cardiac and pulmonary care become increasingly important, and scoliosis is frequent. Nocturnal ventilatory support and assistive cough devices become necessary, and adaptive therapies play an increasingly large role. For this reason, management is frequently provided within a multidisciplinary clinic, making use of specialists from multiple disciplines. Universal care standards have been defined, but at a minimum, DMD patients should be seen yearly by a neurologist or rehabilitation physician, a cardiologist, a pulmonologist, physical and occupational therapists, and a nutritionist. Additional input may be required from endocrinologists, orthopedic surgeons, social workers, and palliative care specialists.
Medical Management
Corticosteroids
The corticosteroids prednisone and deflazacort are the only medications that have been shown to affect the clinical course of DMD and, although the precise mechanism of their effect is unknown, their use is considered standard of care. The classic randomized placebo-controlled trial of prednisone demonstrated that treatment of 0.75 mg per kilogram per day resulted in improved muscle strength by 6 months, whereas a dose twice that showed no additional benefit with significantly more side effects. Deflazacort at an equivalent dose of 0.9 mg per kilogram per day has also frequently been used, with a generally equivalent efficacy but a potentially less marked side effect profile, in particular, in relation to weight gain. Nevertheless, the side effects of both drugs are marked. Weight gain often results in obesity. Osteoporosis due to muscle weakness is exacerbated, often leading to long bone and vertebral body fracture. Short stature and delayed puberty are common.
In an effort to minimize the side effects, a variety of alternative regimens are in use. These alternative regimens include prednisone on a 10 days on and 10 days off regimen, or for the first 10 days a month. A weekend dosing regimen of 10 mg per kilogram per week (divided on weekend days) has been shown to be roughly equivalent to daily dosing in terms of efficacy, with a similar side effect regimen. Despite a consensus that treatment with some corticosteroid regimen will increase ambulation by up to 1 to 3 years, these regimens have not been well characterized head to head in clinical trials. The ongoing National Institutes of Health–sponsored multicenter FOR-DMD trial is a randomized double-blinded trial that should provide clear information on the relative efficacy and side effects of these alternate regimens.
Several other outstanding issues regarding corticosteroid therapy exist. One issue is at what age to initiate corticosteroid therapy, and at what age to stop it. Published recommendations suggest starting therapy between ages 2 and 5 years in boys whose strength has plateaued or is declining. Although treatment in boys who have reached the motor plateau is clearly recommended, earlier treatment may be beneficial, and in fact, may be associated with a longer-term benefit. The second issue is how exactly to alter dosing as boys grow. Most practitioners do not adhere strictly to a 0.75 mg per kilogram dose of prednisone at every visit, but instead modify dosing related to tolerance and side effects. A third issue regards the use of corticosteroids after the boy has lost ambulation. The use of low-dose steroids in nonambulant boys may result in diminished scoliosis and improved ventilation, but standard dosing by weight may result in significant obesity and further respiratory impairment.
Cardiac
Cardiomyopathy is a major feature of DMD. Although the median age of onset has been described as around 14 to 15 years, other studies estimate the incidence is as high as 25% by age 6 years and 59% by 10 years. Clearly, the importance of cardiomyopathy has come to the forefront over the past decades, as improvements in ventilatory and orthopedic care have prolonged life. Cardiac MRI may be used to demonstrate cardiac fibrosis and the diastolic dysfunction that is present before systolic dysfunction is noted. However, in most clinical settings, systolic dysfunction is first detected by standard clinical echocardiograms. For this reason, a baseline echocardiogram is recommended at diagnosis, with screening echocardiograms every 2 years up to age 8 years, and yearly after age 10 years. Cardiomyopathy is typically treated with afterload reduction, using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers; some data suggest that use of these drugs should be initiated before symptoms occur, although these studies are limited. Although systolic dysfunction is often emphasized in cardiac care, cardiac conduction disturbances are frequent and may require Holter monitoring for assessment. In BMD, cardiomyopathy is also frequent and may be severe, even necessitating cardiac transplantation. The age of onset of cardiomyopathy is likely largely related to the structure and features of the residual dystrophin protein.
Nonpharmacologic Management
Pulmonary
Because pulmonary insufficiency is the major cause of mortality, aggressive management of pulmonary insufficiency has been the greatest contributor to prolonged life and quality of life in adults with DMD. Routine use of mechanical insufflator/exsufflator (eg, CoughAssist) devices decreases pulmonary morbidity, and their early use should be considered. Forced vital capacity typically declines after loss of ambulation, and as pulmonary function declines, the incidence of nocturnal hypoxemia and hypercapnia increases. Thorough evaluation of these variables during sleep is critical in early identification of these issues, so yearly polysomnograms after loss of ambulation are indicated. Introduction of nocturnal ventilation, typically, with bilevel continuous positive airway pressure ventilation, can improve quality of life by decreasing morning headaches and general fatigue while improving sleep efficiency.
Spine/scoliosis
Scoliosis ultimately affects up to 77% of boys with DMD and is typically seen after loss of ambulation, but it may be delayed or minimized by use of steroids. Orthopedic consultation should be considered for curves past 20°, and yearly radiographs may be needed to assess progression. Nocturnal ventilation combined with spinal stabilization has been shown to prolong survival into the fourth decade.
Contractures
Regular use of night splints can decrease contracture progression because they provide a stretch or maintain ankle position across several hours. A dynamic splint has the potential to provide a passive muscle stretch throughout the night, whereas a solid brace will maintain the ankle in a 90° position. Often dynamic splints are recommended because they can provide a continuous stretch to the muscle over an extended period of time. A combination of active, active-assisted, and passive stretching can be implemented throughout the day alongside splints or in the child unable to withstand nightly use of splints. Other muscle groups prone to contracture and targeted for passive stretching are the iliotibial band, hip flexors, hamstrings, and elbow and finger flexors. Although an aggressive stretching program may not prevent progression of contracture, it may delay the progression and maintain patient comfort.
Use of bracing during the day is not recommended in ambulatory children with DMD or BMD. Gait deviations are compensatory mechanisms used to prolong ambulation in the presence of progressive muscle weakness. Use of ankle-foot-orthoses (AFOs) are often misprescribed in this population and can lead to reduced walking speed, decreased stability, and increased falls. In rare instances, AFO use can be useful in individual cases to temporarily prolong ambulation in the presence of severe ankle instability.
Exercise
Parents frequently ask whether exercise is beneficial for improving strength. Progressive, high-intensity, resistive exercises are not recommended in DMD and BMD because of the impaired muscle regeneration process. Similarly, activities requiring repetitive eccentric contractions are also to be avoided because of the potential to damage dystrophic muscles. Some limited data support the recommendation of maintaining an active lifestyle in an attempt to maintain strength by limiting atrophy because of nonuse or muscle damage because of overwork. Encouraging patients to be active in functional activities (ie, swimming, walking, playing with friends) is likely to be helpful in maintaining strength and establishing some normalcy in childhood.
Balancing activity with components of energy conservation to limit fatigue throughout the day is also important in maximizing participation and independence in children and adults with DMD and BMD. Consultation with a physical therapist in the community or school-based program is often helpful in assisting patients and families find ways to conserve energy throughout the day. For example, using a wheelchair to transition between classes or move long distances in the community conserves energy, thus allowing the child to participate in meaningful activities rather than expending all their energy getting to the activity location. Mastering energy conservation techniques requires effective collaboration between the child, family, and therapist, especially during phases of transition.
Functional Outcomes
Currently available outcome measures are used clinically to predict loss of function and in research to measure change over time after introduction of a therapeutic agent. Children with DMD tend to improve scores on functional tests until the age of 7 years, at which point their function begins to decline. Timed functional tests, such as time to rise from the floor, 10 m walk/run test, timed stair climbing, and timed walking tests such as the 6-minute walk test (6MWT), are easy to implement in a clinical setting and can predict the loss of function, including ambulation, based on performance. For example, a child taking greater than 12 seconds to walk 10 m or unable to rise from the floor is highly likely to lose the ability to ambulate independently within 1 year. The 6MWT has become the accepted standard for measuring change across clinical trials. Although the rate of decline on the 6MWT varies between cohorts, a 30-m change on the 6MWT is considered the minimal clinically significant change. More specifically, a child walking less than 350 m is at a high risk for a significant function decline, with those walking less than less than 325 m being at risk for an imminent loss of ambulation. The North Star Ambulatory Assessment (NSAA) is an evaluator-administered scale designed for children with DMD. The NSAA grades a child’s ability on 17 items, and the total score has been shown to correlate to 6MWT and functional decline over time.
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