Corticosteroids in Duchenne Muscular Dystrophy: A Reappraisal

Wong, Brenda; Christopher, Caroline

doi:10.1177/088307380201700306

Cited by 74 publications

(45 citation statements)

References 33 publications

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“…Corticosteroid therapy also leads to side effects; as yet, there is no consensus regarding its use as standard treatment for DD. 3 The specific cellular events responsible for the beneficial effects of corticosteroid therapy in DD are not known. Investigators have proposed various possibilities based mainly on observations in mouse models of muscular dystrophy and on a limited number of studies in patients.…”

mentioning

confidence: 99%

Practice Parameter: Corticosteroid treatment of Duchenne dystrophy [RETIRED]

Moxley¹,

Ashwal²,

Pandya³

et al. 2005

Neurology

279

183

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Abstract-Background:The Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society develop practice parameters as strategies for patient management based on analysis of evidence. Objective: To review available evidence on corticosteroid treatment of boys with Duchenne dystrophy. Methods: Relevant literature was reviewed, abstracted, and classified. Recommendations were based on a four-tiered scheme of evidence classification, and areas for future research are defined. Results: Seven class I studies and numerous less rigorous trials all demonstrated that corticosteroid treatment for 6 months with prednisone (0.75 or 1.5 mg/kg/day) increased muscle strength, performance, and pulmonary function and significantly slowed the progression of weakness. Two class I trials examined the effect of lower dosage of prednisone (0.30 and 0.35 mg/kg/day), demonstrated lesser but similar benefits, and showed a lower frequency of side effects (e.g., weight gain). The only significant side effects in all class I trials were weight gain and development of a cushingoid facial appearance. One longer-term trial of daily prednisone (0.3 to 0.7 mg/kg/day), a class III study, showed prolongation of functional ability and slower progression of weakness in patients during 3 years of treatment. One class IV, open trial of alternate-day prednisone (2 mg/kg for 2 months, then two-thirds dose every other day) extended ambulation by approximately 2 years in treated compared with untreated patients. Deflazacort, a corticosteroid similar in structure to prednisone, produced similar improvement in muscle strength and function with a similar side effect profile. Conclusions: Prednisone has been demonstrated to have a beneficial effect on muscle strength and function in boys with Duchenne dystrophy and should be offered (at a dose of 0.75 mg/kg/day) as treatment. If side effects require a decrease in prednisone, tapering to dosages as low as 0.3 mg/kg/day gives less robust but significant improvement. Deflazacort (0.9 mg/kg/day) can also be used for the treatment of Duchenne dystrophy in countries in which it is available. Benefits and side effects of corticosteroid therapy need to be monitored. The offer of treatment with corticosteroids should include a balanced discussion of potential risks. NEUROLOGY 2005;64:13-20 Duchenne dystrophy (DD), an X-linked, recessive disorder, with onset before age 5 years, is the most common and severe form of childhood muscular dystrophy.1-3 The specific molecular defect is an absence or marked deficiency of dystrophin, a large membrane-associated protein that is part of the dystrophin-glycoprotein complex.1 Affected boys develop neck flexor, anterior abdominal, hip, and shoulder girdle muscle weakness in early childhood, with loss of ambulation between ages 7 and 12. 4,5 Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Death usually occurs in the 20s, with the chance of...

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mentioning

confidence: 99%

Practice Parameter: Corticosteroid treatment of Duchenne dystrophy [RETIRED]

Moxley¹,

Ashwal²,

Pandya³

et al. 2005

Neurology

279

183

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“…There is currently no effective treatment for the disease. Glucocorticoid treatment is the current standard of care which delays the loss of ambulation by 3-4 years 7,8 but shows no long treatment benefit and is often associated with debilitating side effects [9][10][11] . The urgency to seek a therapy for DMD has resulted in parallel efforts to develop exon skipping 12,13 , termination codon read through 14 , dystrophin gene replacement or editing therapies 15,16 and non-dystrophin strategies [17][18][19] such as utrophin modulation 20,21 .…”

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confidence: 99%

Identification of serum protein biomarkers for utrophin based DMD therapy

Guiraud

Edwards

Squire

et al. 2017

Neuromuscular Disorders

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Despite promising therapeutic avenues, there is currently no effective treatment for Duchenne muscular dystrophy (DMD), a lethal monogenic disorder caused by the loss of the large cytoskeletal protein, dystrophin. A highly promising approach to therapy, applicable to all DMD patients irrespective to their genetic defect, is to modulate utrophin, a functional paralogue of dystrophin, able to compensate for the primary defects of DMD restoring sarcolemmal stability. One of the major difficulties in assessing the effectiveness of therapeutic strategies is to define appropriate outcome measures. In the present study, we utilised an aptamer based proteomics approach to profile 1,310 proteins in plasma of wild-type, mdx and Fiona (mdx overexpressing utrophin) mice. Comparison of the C57 and mdx sera revealed 83 proteins with statistically significant >2 fold changes in dystrophic serum abundance. A large majority of previously described biomarkers (ANP32B, THBS4, CAMK2A/B/D, CYCS, CAPNI) were normalised towards wild-type levels in Fiona animals. This work also identified potential mdx markers specific to increased utrophin (DUS3, TPI1) and highlights novel mdx biomarkers (GITR, MYBPC1, HSP60, SIRT2, SMAD3, CNTN1). We define a panel of putative protein mdx biomarkers to evaluate utrophin based strategies which may help to accelerate their translation to the clinic.Duchenne muscular dystrophy (DMD) is a lethal X-linked recessive disorder caused by mutations in the dystrophin gene 1 . This disorder affects 1 in 5000 boys 2 and is characterized by a progressive muscle wasting leading to loss of ambulation by 8-12 years of age 3 and death by early adulthood due to cardiorespiratory failure 4 . Dystrophin, an essential link between the dystrophin associated protein complex (DAPC) at the sarcolemma and the cytoskeleton, maintains the strength, flexibility and stability in skeletal muscles 5 . In the absence of dystrophin, the myofibres are more susceptible to contraction-induced injury which results in muscle wasting and premature death 6 . There is currently no effective treatment for the disease. Glucocorticoid treatment is the current standard of care which delays the loss of ambulation by 3-4 years 7,8 but shows no long treatment benefit and is often associated with debilitating side effects [9][10][11] . The urgency to seek a therapy for DMD has resulted in parallel efforts to develop exon skipping 12,13 , termination codon read through 14 , dystrophin gene replacement or editing therapies 15,16 and non-dystrophin strategies [17][18][19] such as utrophin modulation 20,21 . However, despite the recent accelerated approval of Exondys 51 (eteplirsen) in US, disappointing clinical trials results 22 and failure of approval from the FDA for Ataluren 23 and Kyndrisa 24 drugs rekindle discussions about clinical trials designs and endpoints. We have focused on utrophin modulation because it is applicable to all DMD patients irrespective of their dystrophin mutation. Utrophin is found at the sarcolemma in utero and is progressive...

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“…Treatment of both human DMD patients and GRMD dogs with the glucocorticoid prednisone has been shown to slow disease progression and produce short-term functional improvements in dystrophic muscle [7,[13][14][15]. To determine if prednisone treatment affected the levels of γ cyto -actin in skeletal muscle from dystrophin-deficient dogs, four controls and four GRMD dogs were administered daily treatment with 2 mg/kg prednisone from one week to six months of age.…”

Section: Resultsmentioning

confidence: 99%

Cytoplasmic γ-actin expression in diverse animal models of muscular dystrophy

Hanft

Bogan

Mayer

et al. 2007

Neuromuscular Disorders

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We recently showed that cytoplasmic γ-actin (γ cyto -actin) is dramatically elevated in striated muscle of dystrophin-deficient mdx mice. Here we demonstrate that γ cyto -actin is markedly increased in golden retriever muscular dystrophy (GRMD), which better recapitulates the dystrophinopathy phenotype in humans. γ cyto -Actin was also elevated in muscle from α-sarcoglycan null mice, but not in several other dystrophic animal models, including mice deficient in β-sarcoglycan, α-dystrobrevin, laminin-2, or α7 integrin. Muscle from mice lacking dystrophin and utrophin also expressed elevated γ cyto -actin, which was not restored to normal by transgenic overexpression of α7 integrin. However, γ cyto -actin was further elevated in skeletal muscle from GRMD animals treated with the glucocorticoid prednisone at doses shown to improve the dystrophic phenotype and muscle function. These data suggest that elevated γ cyto -actin is part of a compensatory cytoskeletal remodeling program that may partially stabilize dystrophic muscle in some cases where the dystrophinglycoprotein complex is compromised.

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Corticosteroids in Duchenne Muscular Dystrophy: A Reappraisal

Cited by 74 publications

References 33 publications

Practice Parameter: Corticosteroid treatment of Duchenne dystrophy [RETIRED]

Practice Parameter: Corticosteroid treatment of Duchenne dystrophy [RETIRED]

Identification of serum protein biomarkers for utrophin based DMD therapy

Cytoplasmic γ-actin expression in diverse animal models of muscular dystrophy

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