Atormac
Neurology India
menu-bar5 Open access journal indexed with Index Medicus
  Users online: 3820  
 Home | Login 
About Editorial board Articlesmenu-bullet NSI Publicationsmenu-bullet Search Instructions Online Submission Subscribe Videos Etcetera Contact
  Navigate Here 
 Search
 
  
 Resource Links
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
    Article in PDF (517 KB)
    Citation Manager
    Access Statistics
    Reader Comments
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this Article
   Duchenne Muscula...
  Inheritance of DMD
  Pathogenesis of DMD
   Clinical Feature...
   Standard of Care...
   Experimental The...
  Summary
   References

 Article Access Statistics
    Viewed219    
    Printed6    
    Emailed0    
    PDF Downloaded24    
    Comments [Add]    

Recommend this journal

 


 
Table of Contents    
COMMENTARY
Year : 2019  |  Volume : 67  |  Issue : 3  |  Page : 717-723

Duchenne muscular dystrophy: Still an incurable disease


Department of Physical Therapy, University of Florida, Gainesville, Florida, USA

Date of Web Publication23-Jul-2019

Correspondence Address:
Dr. Harneet Arora
Department of Physical Therapy, University of Florida, Gainesville, Florida
USA
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.263203

Rights and Permissions



How to cite this article:
Arora H. Duchenne muscular dystrophy: Still an incurable disease. Neurol India 2019;67:717-23

How to cite this URL:
Arora H. Duchenne muscular dystrophy: Still an incurable disease. Neurol India [serial online] 2019 [cited 2019 Aug 23];67:717-23. Available from: http://www.neurologyindia.com/text.asp?2019/67/3/717/263203




Muscular dystrophies (MDs) are heterogeneous, genetic muscle disorders.[1],[2],[3],[4],[5],[6] Genetic mapping techniques have helped to identify more than 50 diseases, caused by specific gene mutations, which constitute MDs.[1],[7],[8] Muscle histology has identified changes in the fiber size, the presence of necrotic areas in muscles, and subsequently, the fatty infiltration in MDs.[9],[10],[11] MDs are classified according to their phenotypic features, inheritance patterns, age of onset, and the rate of disease progression.[7],[10] They present clinically with progressive muscle degeneration and weakness, which affects different muscles in different variations.[1],[12],[13],[14],[15] DMD is the most common form of MDs among children.[10],[16]


  Duchenne Muscular Dystrophy Top


Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder, caused by out-of-frame mutations in the dystrophin gene, leading to an absence of the dystrophin protein.[17],[18],[19],[20] It has an incidence of 1 in 3500–5000 live male births.[14],[17],[21],[22],[23],[24] It mostly affects males, who are diagnosed between the ages of 3 and 5 years when their motor milestones are delayed, compared with those of their peers.[10],[14],[25] Females are non-symptomatic carriers most of the time, but in 5%–22% of the cases, they exhibit clinical symptoms ranging from mild muscle weakness to severe cardiac involvement.[26],[27],[28] DMD is diagnosed by increased serum creatine kinase (CK) levels, muscle biopsy, genetic testing, and observed clinical features.[2],[14],[29],[30] The purpose of this article is to focus on the causes, pathogenesis, and potential treatments of this disease, globally as well as specifically in the Indian population. The literature search was done through PubMed and Google Scholar for selecting the articles titled with DMD.


  Inheritance of DMD Top


DMD is inherited in a X-linked recessive fashion. Since females have two X chromosomes, in the event that there is a mutation in one of them, they still have the second X chromosome to produce a normal dystrophin gene. Therefore, female carriers are usually unaffected, barring rare cases of abnormal X chromosome inactivation.[7] Symptomatic female carriers show similar DMD features of proximal muscle weakness, increased serum creatine kinase (CK) levels, and hypertrophy of calf muscles, as reported by Padma et al. (1996).[31] Males, on the other hand, have only one X chromosome. Thus, mutation in their X chromosome would always result in DMD. Therefore, two-thirds of the DMD cases are the result of an X-linked recessive pattern and one-third of the cases are due to spontaneous mutations.[7]


  Pathogenesis of DMD Top


The dystrophin gene, the largest gene known, is present on the Xp21 chromosome.[9],[10],[30],[32],[33] It is approximately 2.2–2.3 megabases in size.[10],[32],[33] Various mutations can occur on this gene, such as deletions (60%–65%), duplications (5%–10%), and point mutations (remaining cases).[30],[32],[34] The “reading-frame hypothesis” states that in DMD, there are out-of-frame mutations that cause an early stoppage of protein translation and lead to an absence of dystrophin. This characteristic of DMD differentiates it from Becker muscular dystrophy (BMD), where in-frame mutations occur and form an abnormal but partially functional dystrophin protein.[9],[25],[35],[36] In DMD cases in India, the reading-frame rule is observed and also there has been an increase in new mutations in North Indian DMD/BMD patients.[37] However, it has been observed that there have been no ethnic differences in deletion mutations across different parts of India.[38] Genetic studies have shown to be valuable markers for diagnosing DMD, as reported by a study done in South India,[39] and deletion mutations have been more prevalent in Northern, Southern, Western, and Eastern India.[39],[40],[41] The prenatal diagnosis can be helpful, so parents can make an informed choice.[42]

The dystrophin protein is normally present in the inner surface of sarcolemma.[19],[25],[43] The main functions of dystrophin are the stabilizing of muscle cell membranes and the linking of internal cytoskeleton to the extracellular matrix.[25],[30],[44],[45] Dystrophin acts like a shock absorber during contraction of the muscle.[33] In DMD, due to the absence of dystrophin, there is an abnormal permeability and fragility of cell membranes,[29],[44] which increases the chance of muscle damage at any given stress level and is particularly pronounced in high force muscle contractions.[46]

The various mechanisms involved in muscle damage are mechanical damage, an increase in intracellular calcium level, impairment of signaling molecules, and an increase in immune cells. They are described as below:

Mechanical damage: Dystrophin helps in the transmission of force between the intracellular cytoskeleton and the extracellular matrix. A lack of dystrophin causes increased stress on the cell membrane, even with normal muscle contractions.[7],[20],[44],[47],[48] It also leads to an increase in the permeability of the muscle membrane.[47],[48]

Increase in intracellular calcium level: Damage of a muscle membrane causes an increase in the intracellular calcium concentration.[7],[20],[21],[44],[47],[48],[49] This leads to the protease activation, especially of calpains, which further causes necrosis of fibers.[7],[20],[44],[48]

Impairment of signaling molecules: Dystrophin supports the signaling molecule, neuronal nitric oxide synthase (nNOS), through its dystrophin–glycoprotein complex (DGC).[7],[48] nNOS forms nitric oxide (NO), whose primary function is to maintain vascular tone by reacting with free radicals.[48] Absence of dystrophin causes downregulation of nNOS and its displacement into the cytoplasm from the plasma membrane.[20],[44],[48] This leads to the reduced production of NO and causes muscle damage associated with free radicals.[21],[48],[50] It also leads to vasoconstriction, and ultimately, ischemia of the muscle.[20],[44],[50]

Increase in immune cells: Increased inflammation is also considered to play a role in the pathogenesis of DMD. There are increased levels of cluster of differentiation (CD)4+ and CD8+ T cells found in the dystrophic muscles, causing more muscle damage and fibrosis.[21],[29],[44],[51]

Boys with DMD are born with a normal muscle function.[29] As they age, there is a decrease in functional mass and a degeneration of the muscle fibers, followed by fibrofatty tissue replacement. There is appearance of fibers with central nuclei, the marker of regeneration. By the time a boy reaches his teenage years, reduced muscle fibers are present and fibrofatty tissue is highly prevalent.[7],[29]


  Clinical Features of DMD Top


Patients with DMD exhibit progressive muscle weakness, from the proximal to distal direction.[13],[17],[52],[53],[54],[55],[56] Boys with DMD exhibit a waddling gait, clumsiness, flat feet, and an inability to walk until 18 months of age.[26],[29] When they start walking around 18–24 months of age, boys have a wide-based gait, have a difficulty in running, and present with an increased lordosis of the spine due to weakness in the hip extensors.[2],[14],[29],[54] Moreover, they struggle with getting up from the floor, jumping, walking on their toes, and they fall frequently.[54] They also often exhibit head lag when they sit up from a lying position due to weakness of neck flexor muscles.[14],[54] When these boys stand up from a supine position, they tend to place their hands on their knees, exhibiting what is referred to as the “Gowers' sign.”[2],[14],[29] They also exhibit enlargement of calf muscles, referred to as pseudohypertrophy, when the fatty tissue replaces degenerated muscle.[32] A “Valley sign” has been described to characterize patients with DMD where there was depression of the posterior axillary fold, with hypertrophied or preserved muscles on its two sides, as measured from the back.[57] The clinical features and the pattern of losing major milestones are independent of the ethnicity and have been shown to be similar between the Indian and the Western populations.[56]

Boys with DMD have increased difficulty in walking and lose the ability to both rise from the floor and climb stairs.[26] Boys typically lose the ability to walk by the age of 10–12 years,[17],[21] without steroid treatment. However, they can still sustain their posture.[26] Scoliosis is usually seen, which affects their respiration and worsens as a boy becomes increasingly non-ambulatory.[26],[54],[55] Upper limb functions decline at a later stage which leads to difficulty in performing activities of daily living such as eating, bathing, and brushing teeth. At this point, they also find it difficult to sustain their posture.[26]

Other clinical features, such as joint contractures, are usually first seen in the ankles and then in the hips, knees, elbows, and wrists. Long bone fractures due to falls, and osteoporosis are other orthopedic complications present in boys with DMD.[54],[55] Impaired cognition, attention deficit hyperactive disorder, autism spectrum disorder, and obsessive compulsive disorder have also been reported in some cases.[14],[58] As the disease progresses, boys become increasingly dependent on others for assistance with their activities of daily living.[59] Dilated cardiomyopathy is usually seen after the age of 10 years and is evident in all patients of 18 years or older.[54],[60] As boys with DMD age, respiratory and cardiac problems continue to worsen, ultimately leading to their death.[17],[21],[26],[29],[54]


  Standard of Care for DMD Top


DMD is currently incurable, but many experimental therapeutic strategies are currently in clinical trials.[21],[47] The current management of DMD focuses on the multidisciplinary approach for treating symptoms and improving the quality of life and function.[55],[61],[62],[63]

Musculoskeletal management

Contractures are commonly seen in these patients, so appropriate physiotherapy is essential to maintain the range of motion. In physiotherapy, stretching, proper positioning of the joints, and range of motion exercises are recommended to prevent contractures.[64],[65] Orthoses can be used either to prevent or minimize contractures. A study reported in India showed that the use of ankle foot orthosis has the potential of prolonging ambulatory status.[66] Spinal corset can be used to reduce scoliosis. In a few cases, surgery can be considered as an option to correct contractures or scoliosis.[7],[55],[62] There is not enough evidence to suggest the type of exercise that may be beneficial in this population.[62],[67] Swimming is recommended for aerobic conditioning of the muscles.[55],[62] Since fractures are commonly seen in these patients, splints or casts can be used for fracture healing.[62] Vitamin D and calcium supplements can be considered for maintaining bone health.[54],[55]

Respiratory management

Airway clearance techniques, including manual and mechanical assisted cough, can be used to prevent respiratory complications. Respiratory infections can be treated with antibiotics and chest physiotherapy.[54],[55],[68],[69],[70] Noninvasive ventilation is suggested when patients start experiencing hypoventilation.[54],[55],[62],[68],[71]

Cardiac management

Echocardiography is used for detecting cardiac dysfunction.[72] Angiotensin-converting enzyme (ACE) inhibitors are considered to be the first-line drugs in cardiac management.[13],[21],[54],[55],[62],[69],[70] Beta blockers can be used with ACE inhibitors for even more beneficial results.[13],[69]

Glucocorticoid therapy

Glucocorticoids have been shown to delay the loss of ambulation in patients with DMD by 1–2 years.[73],[74],[75] They also reduce the chance of scoliosis.[62] Currently, prednisone with a daily dose of 0.75 mg/kg or deflazacort with a daily dose of 0.9 mg/kg are the recommended drugs.[4],[26],[54],[55],[63],[76] Weight gain, behavioral problems, vertebral and long bone fractures, stunted growth, puberty delay, hypertension, and cataracts are some of the common side effects seen in glucocorticoid-treated boys.[7],[21],[25],[45],[55],[77] In a recent study, it has been observed that treatment with deflazacort would result in delayed deterioration of ambulation and maintenance of key motor functions, when compared with prednisone.[78] However, a study reported in India showed that prednisolone has more effects than deflazacort.[79] Thus, the use of steroids and prednisolone versus deflazacort still remains controversial.


  Experimental Therapeutic Strategies Top


There are many experimental therapeutic strategies in preclinical and clinical trials that look promising for slowing down disease progression in DMD in the future. Below is a review of some of the major strategies.

Stem cell therapy

Muscle stem cells (myoblasts) have a capacity for differentiation into muscle cells. Promising results were seen when myoblasts were transplanted into immunosuppressed mdx mice, a mouse model for DMD.[7],[12],[20],[54] Unfortunately, these results could not be replicated in boys with DMD because of their immune responses.[7],[20] Another limitation of myoblasts is that they do not travel long distances in muscles and die soon after injection.[25] A study performed in various hospitals of India showed that the administration of umbilical cord mesenchymal stem cells resulted in the stability of muscle power and could be used as a potential treatment in DMD.[80]

Gene replacement therapy

The large size of the dystrophin gene and the relatively limited packaging capacity of viral vectors necessitate the creation of micro- and mini-dystrophin genes for delivery.[20],[21],[81],[82],[83] Recombinant adeno-associated viral (rAAV) vectors are used to carry micro- and mini-dystrophins.[12],[20],[54] This therapy showed successful results in mdx mice, but failed to replicate the results in boys with DMD. The reason behind its failure is the immune responses shown by boys with DMD.[20],[21] Recently, a study showed that delivery of micro-dystrophin using AAV vector could reduce inflammation and fibrosis in skeletal muscles of DBA/2J-mdx mice, a severe mouse model for DMD;[84] though this therapy has not been tested clinically as yet.

Stop codon read through drugs

Aminoglycoside antibiotics like gentamicin help in reading through premature stop codons. Gentamicin has its application in identifying nonsense mutations in the dystrophin gene,[12],[20],[25] but its major disadvantage is that it causes toxicity in patients with DMD.[20],[25],[63] PTC124 (ataluren) is another synthetic drug that can read through premature stop codons, thus allowing full translation and formation of the functional protein.[20],[21],[54],[55],[69] It is a well-tolerated drug and is also used for nonsense mutations.[25],[54] Unfortunately, in phase 2b of its clinical trial, ataluren failed to show a significant effect in its primary outcome measure – the six-minute walk test (6 MWT), which caused the clinical trial to be terminated.[20],[25],[55] A significant effect was seen in patients with DMD who received a low dose of the drug, after subsequent post hoc analysis.[25] Based on this, ataluren has been conditionally approved in Europe for patients with DMD and has started its phase 3 clinical trial.[21],[25] Recently, phase 3 clinical trial results demonstrated that ataluren showed a 15 meter improvement in the 6 MWT from baseline to 48 weeks but with no statistical significance.[63],[85],[86] The Food and Drug Administration (FDA) had initially refused to review the drug's application, stating that the drug does not show efficacy;[63],[87] however, they recently conducted a review and did not approve ataluren.

Exon skipping drugs

Exon skipping drugs use antisense oligonucleotides to skip exons in the pre-mRNA phase, restoring the reading frame of dystrophin. These drugs form a partially functional dystrophin, thus converting DMD to BMD.[21],[25],[54],[55] Successful results have been observed in mdx mice.[20] Drisapersen and eteplirsen are two of the drugs in clinical trials for patients with DMD. Both of them skip exon 51 and can be used in 13% of the DMD population.[20],[25] Drisapersen failed to show a significant improvement in the 6 MWT in its phase 3 clinical trial over a 48-week treatment,[25],[86],[88],[89] which has led to the discontinuation of further clinical trials. Eteplirsen showed promising results when tested on 12 patients in the phase 2 trial and it is currently completing a phase 3 clinical trial.[21] Recently, the FDA has granted conditional approval to eteplirsen.[63],[90],[91],[92]

Utrophin upregulation

Utrophin is structurally very similar to dystrophin.[7],[12],[20],[21],[25],[86] It is thought that utrophin can substitute for dystrophin deficiency, when it is upregulated.[7],[12],[29],[54] Utrophin upregulation has shown effective results in the mdx mice and the golden retriever MD, a dog model for DMD.[20] Clinical trials for the drug SMT C1100 are ongoing to upregulate utrophin expression in patients with DMD.[20],[21],[25],[54] A phase 1 clinical trial showed that this drug is well tolerated by boys with DMD.[63] The drug was in phase 2 of its clinical trial.[63],[75] Recent results of its phase 2 proof-of-concept trial showed that the drug did not show efficacy at its primary endpoint and the researchers decided to discontinue their study.

Phosphodiesterase 5A inhibitors

Absence of dystrophin leads to the displacement of neuronal nitric oxide synthase (nNOS) from the dystrophin glycoprotein complex (DGC), resulting in decreased nitric oxide (NO) production. Reduction in NO leads to muscle ischemia.[21] Phosphodiesterase 5A (PDE5A) inhibitor drugs like sildenafil and tadalafil have a vasodilatory effect that could help to reduce muscle ischemia. After showing promising results in mdx mice,[21],[25] a clinical trial was initiated. Unfortunately, sildenafil showed no improvement in cardiomyopathy in a phase 2, double-blind, randomized study of patients with DMD.[86]

NF-κB inhibitors

Activation of nuclear factor (NF)-κB results in the degradation of muscle proteins, which produces pro-inflammatory mediators like cytokines and chemokines. Activated NF-κB is seen in patients with DMD. The drug edasalonexent (CAT-1004) has been developed to inhibit the NF-κB pathway and is currently in a phase 1/2 clinical trial.[92] This drug was shown to be safe and well-tolerated in patients with DMD in phase 1 of its clinical trial.[93] However, it was recently reported that the drug did not show significant improvement in boys with DMD after 12 weeks of treatment.[92] Recently, the phase 2 clinical trial was completed. Positive results were found and phase 3 clinical trial was being started.

Myostatin and insulin growth factor-1

Myostatin inhibits muscle growth.[21],[25] Myostatin antibodies have been used in reducing muscle pathology in mdx mice, but similar results were not found in patients with DMD.[25] In a recent phase 2 clinical trial, myostatin inhibitors showed a trend of maintaining performance on the 6-minute walk test in the treatment group, but no statistical difference could be found between the placebo and treated groups.[94] Insulin growth factor-1 helps in muscle growth.[21] Its use in increasing the size of muscle fibers is currently being investigated in a clinical trial.[25]

Histone deacetylase inhibitors

Histone deacetylase (HDAC) inhibitors help in the regeneration of muscles and reduce fibrosis and fatty infiltration in mdx mice. Givinostat, a HDAC inhibitor, has shown to improve muscle growth in mdx mice. This drug is starting a phase 2 clinical trial.[21],[92] It is assumed that this drug delays the progression of DMD in patients at an early stage of the disease.[95]

CRISPR/Cas9

CRISPR/Cas9 is used for gene editing, where Cas9 nuclease is used to cleave DNA sequences with the help of a single-guide RNA.[96] It has already been shown that this method can re-establish expression of dystrophin in patient-derived induced pluripotent stem cells (iPSCs) and in murine iPSCs.[97] It can restore partial dystrophin expression and enhance muscle function in the mdx mice.[96],[98],[99],[100] However, its efficacy and safety have not been tested in patients with DMD so far,[97] though it is projected that this method can treat about 80% of the patients.[75] CRISPR/Cas9 gene editing has several challenges such as the unknown efficacy, the specificity of delivery vehicles, and the possibility of off-target effects. Translatability of the majority of in vitro research to in vivo delivery methods in the clinic is another challenge. Immune responses to delivery vehicles and Cas9 peptides may also be a hurdle, as with any gene therapy. These challenges need to be overcome in the future.[101]


  Summary Top


MDs are a heterogeneous group of disorders, characterized by progressive muscle weakness. DMD is one of the most common forms of MD and mostly affects boys. DMD is caused by the absence of the dystrophin protein, which leads to abnormal membrane permeability and fragility of the cell membrane. This permeability and fragility make the cell membrane more susceptible to damage. In the early stages, the affected muscles undergo numerous cycles of damage and repair, but in later stages, there is a progressive replacement by fat and fibrotic tissue. Boys with DMD exhibit progressive muscle weakness in the proximal to distal direction, which leads to gradual functional decline. There is no known cure for DMD, and glucocorticoids are the only drugs which have been shown to delay the loss of ambulation by 1–2 years. Many drugs in clinical trials have shown success preclinically in animals but have shown minimal success in humans. There are significant barriers in the treatment of DMD. It is worth noting that the use of a single drug may not be successful in treating DMD and it may be helpful to administer multiple drugs, targeting different pathways, for successful treatment of DMD.[82] Moreover, most of the clinical trials target ambulatory patients with DMD, thus excluding roughly two-thirds of patients with DMD who are no longer able to walk.

DMD is not an easy disease to live with, especially in the traditional Indian setting, where there are social taboos and absence of much-needed infrastructure to help these patients. It becomes difficult for the patients and their families to get counseling support because of psychosocial issues.[41] In a recent MD conference, I was made aware that there were not many clinical trials going on in India, unlike the practice in the United States or Europe. It is disheartening for the patients and their families that they would not be able to participate in the potential therapies. Thus, there is an urgent need for creating more awareness about this disease, and pharmaceutical companies need to be encouraged to conduct clinical trials in India. There has been stem cell research going on in India, which is promising, but more is needed to fight this incurable disease.



 
  References Top

1.
Durbeej M, Campbell KP. Muscular dystrophies involving the dystrophin-glycoprotein complex: An overview of current mouse models. Curr Opin Genet Dev 2002;12:349-61.  Back to cited text no. 1
    
2.
El-Bohy AA, Wong BL. The diagnosis of muscular dystrophy. Pediatr Ann 2005;34:525-30.  Back to cited text no. 2
    
3.
Burch PM, Pogoryelova O, Goldstein R, Bennett D, Guglieri M, Straub V, et al. Muscle-derived proteins as serum biomarkers for monitoring disease progression in three forms of muscular dystrophy. J Neuromuscul Dis 2015;2:241-55.  Back to cited text no. 3
    
4.
Flanigan KM. The muscular dystrophies. Semin Neurol 2012;32:255-63.  Back to cited text no. 4
    
5.
Govoni A, Magri F, Brajkovic S, Zanetta C, Faravelli I, Corti S, et al. Ongoing therapeutic trials and outcome measures for Duchenne muscular dystrophy. Cell Mol Life Sci 2013;70:4585-602.  Back to cited text no. 5
    
6.
Sinha R, Sarkar S, Khaitan T, Dutta S. Duchenne muscular dystrophy: Case report and review. J Fam Med Prim Care 2017;6:654-6.  Back to cited text no. 6
    
7.
Lovering RM, Porter NC, Bloch RJ. The muscular dystrophies: From genes to therapies. Phys Ther 2005;85:1372-88.  Back to cited text no. 7
    
8.
Kang PB, Griggs RC. Advances in muscular dystrophies. JAMA Neurol 2015;72:741-2.  Back to cited text no. 8
    
9.
Emery AE. Muscular dystrophy into the new millennium. Neuromuscul Disord 2002;12:343-9.  Back to cited text no. 9
    
10.
Emery AE. The muscular dystrophies. BMJ 1998;317:991-5.  Back to cited text no. 10
    
11.
Barakat-Haddad C, Shin S, Candundo H, Lieshout PV, Martino R. A systematic review of risk factors associated with muscular dystrophies. Neurotoxicology 2016;62:55-62.  Back to cited text no. 11
    
12.
Hsu YD. Muscular dystrophy: From pathogenesis to strategy. Acta Neurol Taiwan 2004;13:50-8.  Back to cited text no. 12
    
13.
Beynon RP, Ray SG. Cardiac involvement in muscular dystrophies. QJM 2008;101:337-44.  Back to cited text no. 13
    
14.
Wicklund MP. The muscular dystrophies. Continuum (Minneap Minn) 2013;19(6 Muscle Disease):1535-70.  Back to cited text no. 14
    
15.
Lue YJ, Lin RF, Chen SS, Lu YM. Measurement of the functional status of patients with different types of muscular dystrophy. Kaohsiung J Med Sci 2009;25:325-33.  Back to cited text no. 15
    
16.
Dalkilic I, Kunkel LM. Muscular dystrophies: Genes to pathogenesis. Curr Opin Genet Dev 2003;13:231-8.  Back to cited text no. 16
    
17.
Hoffman EP, Brown RH, Jr, Kunkel LM. Dystrophin: The protein product of the Duchenne muscular dystrophy locus. Cell 1987;51:919-28.  Back to cited text no. 17
    
18.
Aartsma-Rus A. Dystrophin analysis in clinical trials. J Neuromuscul Dis 2014;1:41-53.  Back to cited text no. 18
    
19.
Watkins SC, Hoffman EP, Slayter HS, Kunkel LM. Immunoelectron microscopic localization of dystrophin in myofibres. Nature 1988;333:863-6.  Back to cited text no. 19
    
20.
Fairclough RJ, Bareja A, Davies KE. Progress in therapy for Duchenne muscular dystrophy. Exp Physiol 2011;96:1101-13.  Back to cited text no. 20
    
21.
Blat Y, Blat S. Drug discovery of therapies for Duchenne muscular dystrophy. J Biomol Screen 2015;20:1189-203.  Back to cited text no. 21
    
22.
Emery AE. Population frequencies of inherited neuromuscular diseases – A world survey. Neuromuscul Disord 1991;1:19-29.  Back to cited text no. 22
    
23.
Mendell JR, Shilling C, Leslie ND, Flanigan KM, al-Dahhak R, Gastier-Foster J, et al. Evidence-based path to newborn screening for Duchenne muscular dystrophy. Ann Neurol 2012;71:304-13.  Back to cited text no. 23
    
24.
Young CS, Hicks MR, Ermolova NV, Nakano H, Jan M, Younesi S, et al. A single CRISPR-Cas9 deletion strategy that targets the majority of DMD patients restores dystrophin function in hiPSC-derived muscle cells. Cell Stem Cell 2016;18:533-40.  Back to cited text no. 24
    
25.
Guiraud S, Aartsma-Rus A, Vieira NM, Davies KE, van Ommen GJ, Kunkel LM. The pathogenesis and therapy of muscular dystrophies. Annu Rev Genomics Hum Genet 2015;16:281-308.  Back to cited text no. 25
    
26.
Bushby K, Finkel R, Birnkrant DJ, Case LE, Clemens PR, Cripe L. et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: Diagnosis, and pharmacological and psychosocial management. Lancet Neurol 2010;9:77-93.  Back to cited text no. 26
    
27.
Giliberto F, Radic CP, Luce L, Ferreiro V, de Brasi C, Szijan I. Symptomatic female carriers of Duchenne muscular dystrophy (DMD): Genetic and clinical characterization. J Neurol Sci 2014;336(1-2):36-41.  Back to cited text no. 27
    
28.
Leyser M, Marques FJ, Elias MA, Diniz Gonsalves MC, da Silva OS, Jr, Carvalho RS, et al., Classic manifestations of Duchenne dystrophy in a young female patient: A case report. Eur J Paediatr Neurol 2013;17:212-8.  Back to cited text no. 28
    
29.
Sussman M. Duchenne muscular dystrophy. J Am Acad Orthop Surg 2002;10:138-51.  Back to cited text no. 29
    
30.
Allen DG, Whitehead NP, Froehner SC. Absence of dystrophin disrupts skeletal muscle signaling: Roles of Ca2+, reactive oxygen species, and nitric oxide in the development of muscular dystrophy. Physiol Rev 2016;96:253-305.  Back to cited text no. 30
    
31.
Padma MV, Jain S, Sarkar C, Maheshwari MC, Chitra S. Duchenne muscular dystrophy in a female patient: A case report. Neurol India 1996;44:124-5.  Back to cited text no. 31
[PUBMED]    
32.
Worton RG. Duchenne muscular dystrophy: Gene and gene product; Mechanism of mutation in the gene. J Inherit Metab Dis 1992;15:539-50.  Back to cited text no. 32
    
33.
Aartsma-Rus A, Ginjaar IB, Bushby K. The importance of genetic diagnosis for Duchenne muscular dystrophy. J Med Genet 2016;53:145-51.  Back to cited text no. 33
    
34.
Falzarano MS, Scotton C, Passarelli C, Ferlini A. Duchenne muscular dystrophy: From diagnosis to therapy. Molecules 2015;20:18168-84.  Back to cited text no. 34
    
35.
Koenig M, Beggs AH, Moyer M, Scherpf S, Heindrich K, Bettecken T, et al. The molecular basis for Duchenne versus Becker muscular dystrophy: Correlation of severity with type of deletion. Am J Hum Genet 1989;45:498-506.  Back to cited text no. 35
    
36.
Muntoni F, Torelli S, Ferlini A. Dystrophin and mutations: One gene, several proteins, multiple phenotypes. Lancet Neurol 2003;2:731-40.  Back to cited text no. 36
    
37.
Sinha S, Mishra S, Singh V, Mittal RD, Mittal B. High frequency of new mutations in North Indian Duchenne/Becker muscular dystrophy patients. Clin Genet 1996;50:327-31.  Back to cited text no. 37
    
38.
Banerjee M, Verma IC. Are there ethnic differences in deletions in the dystrophin gene? Am J Med Genet 1997;68:152-7.  Back to cited text no. 38
    
39.
Swaminathan B, Shubha GN, Shubha D, Murthy AR, Kiran Kumar HB, Shylashree S, et al. Duchenne muscular dystrophy: A clinical, histopathological and genetic study at a neurology tertiary care center in Southern India. Neurol India 2009;57:734-8.  Back to cited text no. 39
[PUBMED]  [Full text]  
40.
Basak J, Dasgupta UB, Banerjee TK, Senapati AK, Das SK, Mukherjee SC. Analysis of dystrophin gene deletions by multiplex PCR in eastern India. Neurol India 2006;54:310-1.  Back to cited text no. 40
[PUBMED]  [Full text]  
41.
Nadkarni JJ, Dastur RS, Viswanathan V, Gaitonde PS, Khadilkar SV. Duchenne and Becker muscular dystrophies: An Indian update on genetics and rehabilitation. Neurol India 2008;56:248-53.  Back to cited text no. 41
[PUBMED]  [Full text]  
42.
Maheshwari M, Vijaya R, Kabra M, Arora S, Shastri SS, Deka D, et al., Prenatal diagnosis of Duchenne muscular dystrophy. Natl Med J India 2000;13:129-31.  Back to cited text no. 42
    
43.
Fairclough RJ, Wood MJ, Davies KE. Therapy for Duchenne muscular dystrophy: Renewed optimism from genetic approaches. Nat Rev Genet 2013;14:373-8.  Back to cited text no. 43
    
44.
Deconinck N, Dan B. Pathophysiology of Duchenne muscular dystrophy: Current hypotheses. Pediatr Neurol 2007;36:1-7.  Back to cited text no. 44
    
45.
Flanigan KM. Duchenne and Becker muscular dystrophies. Neurol Clin 2014;32:671-88, viii.  Back to cited text no. 45
    
46.
Petrof BJ, Shrager JB, Stedman HH, Kelly AM, Sweeney HL. Dystrophin protects the sarcolemma from stresses developed during muscle contraction. Proc Natl Acad Sci U S A 1993;90:3710-4.  Back to cited text no. 46
    
47.
Allen DG, Whitehead NP. Duchenne muscular dystrophy – What causes the increased membrane permeability in skeletal muscle? Int J Biochem Cell Biol 2011;43:290-4.  Back to cited text no. 47
    
48.
Wallace GQ, McNally EM. Mechanisms of muscle degeneration, regeneration, and repair in the muscular dystrophies. Annu Rev Physiol 2009;71:37-57.  Back to cited text no. 48
    
49.
Franco A, Jr., Lansman JB. Calcium entry through stretch-inactivated ion channels in mdx myotubes. Nature 1990;344:670-3.  Back to cited text no. 49
    
50.
Rando TA. Role of nitric oxide in the pathogenesis of muscular dystrophies: A “two hit” hypothesis of the cause of muscle necrosis. Microsc Res Tech, 2001;55:223-35.  Back to cited text no. 50
    
51.
Spencer MJ, Montecino-Rodriguez E, Dorshkind K, Tidball JG. Helper (CD4(+)) and cytotoxic (CD8(+)) T cells promote the pathology of dystrophin-deficient muscle. Clin Immunol 2001;98:235-43.  Back to cited text no. 51
    
52.
Bakker JP, De Groot IJ, Beelen A, Lankhorst GJ. Predictive factors of cessation of ambulation in patients with Duchenne muscular dystrophy. Am J Phys Med Rehabil 2002;81:906-12.  Back to cited text no. 52
    
53.
Davis MFS, Scherer KH, Miller TM, Meaney FJ. Measuring disease severity in Duchenne and Becker muscular dystrophy. J Meth Measure Soc Sci 2010;1:8-18.  Back to cited text no. 53
    
54.
Yiu EM, Kornberg AJ. Duchenne muscular dystrophy. Neurol India 2008;56:236-47.  Back to cited text no. 54
[PUBMED]  [Full text]  
55.
Yiu EM, Kornberg AJ. Duchenne muscular dystrophy. J Paediatr Child Health 2015;51:759-64.  Back to cited text no. 55
    
56.
Singh RJ, Manjunath M, Preethish-Kumar V, Polavarapu K, Vengalil S, Thomas PT, et al. Natural history of a cohort of Duchenne muscular dystrophy children seen between 1998 and 2014: An observational study from South India. Neurol India 2018;66:77-82.  Back to cited text no. 56
[PUBMED]  [Full text]  
57.
Pradhan S. New clinical sign in Duchenne muscular dystrophy. Pediatr Neurol 1994;11:298-300.  Back to cited text no. 57
    
58.
Banihani R, Smile S, Yoon G, Dupuis A, Mosleh M, Snider A. et al. Cognitive and neurobehavioral profile in boys with Duchenne muscular dystrophy. J Child Neurol 2015;30:1472-82.  Back to cited text no. 58
    
59.
Uchikawa K, Liu M, Hanayama K, Tsuji T, Fujiwara T, Chino N. Functional status and muscle strength in people with Duchenne muscular dystrophy living in the community. J Rehabil Med 2004;36:124-9.  Back to cited text no. 59
    
60.
Nigro G, Comi LI, Politano L, Bain RJ. The incidence and evolution of cardiomyopathy in Duchenne muscular dystrophy. Int J Cardiol 1990;26:271-7.  Back to cited text no. 60
    
61.
Vignos PJ, Jr., Spencer GE, Jr., Archibald KC. Management of progressive muscular dystrophy in childhood. JAMA 1963;184:89-96.  Back to cited text no. 61
    
62.
Bushby K, Finkel R, Birnkrant DJ, Case LE, Clemens PR, Cripe L. et al., Diagnosis and management of Duchenne muscular dystrophy, part 2: Implementation of multidisciplinary care. Lancet Neurol 2010;9:177-89.  Back to cited text no. 62
    
63.
Reinig AM, Mirzaei S, Berlau DJ. Advances in the treatment of Duchenne muscular dystrophy: New and emerging pharmacotherapies. Pharmacotherapy 2017;37:492-9.  Back to cited text no. 63
    
64.
Birnkrant DJ, Bushby K, Bann CM, Apkon SD, Blackwell A, Brumbaugh D, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: Diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol 2018;17:251-67.  Back to cited text no. 64
    
65.
Suthar R, Sankhyan N. Duchenne muscular dystrophy: A practice update. Indian J Pediatr 2018;85:276-81.  Back to cited text no. 65
    
66.
Gupta A, Nalini A, Arya SP, Vengalil S, Khanna M, Krishnan R, et al. Ankle-foot orthosis in Duchenne muscular dystrophy: A 4 year experience in a multidisciplinary neuromuscular disorders clinic. Indian J Pediatr 2017;84:211-5.  Back to cited text no. 66
    
67.
Markert CD, Case LE, Carter GT, Furlong PA, Grange RW. Exercise and Duchenne muscular dystrophy: Where we have been and where we need to go. Muscle Nerve 2012;45:746-51.  Back to cited text no. 67
    
68.
Birnkrant DJ, Bushby KM, Amin RS, Bach JR, Benditt JO, Eagle M, et al. The respiratory management of patients with Duchenne muscular dystrophy: A DMD care considerations working group specialty article. Pediatr Pulmonol 2010;45:739-48.  Back to cited text no. 68
    
69.
Rinaldi R, Mayer M, Dichiaro M. Current concepts in the management of Duchenne muscular dystrophy. Curr Phys Med Rehab Rep 2013;1:65-71.  Back to cited text no. 69
    
70.
Birnkrant DJ, Bushby K, Bann CM, Alman BA, Apkon SD, Blackwell A, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: Respiratory, cardiac, bone health, and orthopaedic management. Lancet Neurol 2018;17:347-61.  Back to cited text no. 70
    
71.
Wagner KR, Lechtzin N, Judge DP. Current treatment of adult Duchenne muscular dystrophy. Biochim Biophys Acta 2007;1772:229-37.  Back to cited text no. 71
    
72.
Gulati S, Saxena A, Kumar V, Kalra V. Duchenne muscular dystrophy: Prevalence and patterns of cardiac involvement. Indian J Pediatr 2005;72:389-93.  Back to cited text no. 72
    
73.
Angelini C. The role of corticosteroids in muscular dystrophy: A critical appraisal. Muscle Nerve 2007;36:424-35.  Back to cited text no. 73
    
74.
Balaban B, Matthews DJ, Clayton GH, Carry T. Corticosteroid treatment and functional improvement in Duchenne muscular dystrophy: Long-term effect. Am J Phys Med Rehabil 2005;84:843-50.  Back to cited text no. 74
    
75.
Mendell JR, Rodino-Klapac LR. Duchenne muscular dystrophy: CRISPR/Cas9 treatment. Cell Res 2016;26:513-4.  Back to cited text no. 75
    
76.
Angelini C, Peterle E. Old and new therapeutic developments in steroid treatment in Duchenne muscular dystrophy. Acta Myol 2012;31:9-15.  Back to cited text no. 76
    
77.
Merlini L, Cicognani A, Malaspina E, Gennari M, Gnudi S, Talim B, et al. Early prednisone treatment in Duchenne muscular dystrophy. Muscle Nerve 2003;27:222-7.  Back to cited text no. 77
    
78.
Shieh PB, McIntosh J, Jin F, Souza M, Elfring G, Narayanan S. et al. Deflazacort vs prednisone/prednisolone for maintaining motor function and delaying loss of ambulation: A post hoc analysis from the ACT DMD trial. Muscle Nerve 2018; doi: 10.1002/mus. 26191.  Back to cited text no. 78
    
79.
Petnikota H, Madhuri V, Gangadharan S, Agarwal I, Antonisamy B. Retrospective cohort study comparing the efficacy of prednisolone and deflazacort in children with muscular dystrophy: A 6 years' experience in a South Indian teaching hospital. Indian J Orthop 2016;50:551-7.  Back to cited text no. 79
[PUBMED]  [Full text]  
80.
Rajput BS, Chakrabarti SK, Dongare VS, Ramirez CM, Deb KD. Human umbilical cord mesenchymal stem cells in the treatment of Duchenne muscular dystrophy: Safety and feasibility study in India. J Stem Cells 2015;10:141-56.  Back to cited text no. 80
    
81.
Chakkalakal JV, Thompson J, Parks RJ, Jasmin BJ. Molecular, cellular, and pharmacological therapies for Duchenne/Becker muscular dystrophies. Faseb J 2005;19:880-91.  Back to cited text no. 81
    
82.
Malik V, Rodino-Klapac LR, Mendell JR. Emerging drugs for Duchenne muscular dystrophy. Expert Opin Emerg Drugs 2012;17:261-77.  Back to cited text no. 82
    
83.
Lai Y, Yue Y, Duan D. Evidence for the failure of adeno-associated virus serotype 5 to package a viral genome > or = 8.2 kb. Mol Ther 2010;18:75-9.  Back to cited text no. 83
    
84.
Hakim CH, Wasala NB, Pan X, Kodippili K, Yue Y, Zhang K, et al. A five-repeat micro-dystrophin gene ameliorated dystrophic phenotype in the severe DBA/2J-mdx model of Duchenne muscular dystrophy. Mol Ther Methods Clin Dev 2017;6:216-30.  Back to cited text no. 84
    
85.
Therapeutics P. PTC announces results from Phase 3 ACT DMD clinical trial of Translarna™ (ataluren) in patients with Duchenne muscular systrophy. 2015. Available from: http://ir.ptcbio.com/releasedetail.cfm?releaseid=936905. [Last cited on 2018 Jan 04, Last accessed on 2018 Jan 04].  Back to cited text no. 85
    
86.
Shimizu-Motohashi Y, Miyatake S, Komaki H, Takeda S, Aoki Y. Recent advances in innovative therapeutic approaches for Duchenne muscular dystrophy: From discovery to clinical trials. Am J Transl Res 2016;8:2471-89.  Back to cited text no. 86
    
87.
Carroll J. PTC: With no evidence of Duchenne MD efficacy, FDA barred regulators' doors to ataluren. 2016; Available from: http://www.fiercebiotech.com/regulatory/ptc-no-evidence-of-duchenne-md-efficacy-fda-barred-regulators-doors-to-ataluren. [Last cited on 2018 Jan 04, Last accessed on 2018 Jan 04].  Back to cited text no. 87
    
88.
Wood MJ. To skip or not to skip: That is the question for duchenne muscular dystrophy. Mol Ther 2013;21:2131-2.  Back to cited text no. 88
    
89.
Goemans N, Tulinius M, Kroksmark A-K, Wilson R, van den Hauwe M, Campion G. Comparison of ambulatory capacity and disease progression of Duchenne muscular dystrophy subjects enrolled in the drisapersen DMD114673 study with a matched natural history cohort of subjects on daily corticosteroids. Neuromuscul Disord 2017;27:203-13.  Back to cited text no. 89
    
90.
Dowling JJ. Eteplirsen therapy for Duchenne muscular dystrophy: Skipping to the front of the line. Nat Rev Neurol 2016;12:675-6.  Back to cited text no. 90
    
91.
Aartsma-Rus A, Krieg AM. FDA approves Eteplirsen for Duchenne muscular dystrophy: The next chapter in the Eteplirsen Saga. Nucleic Acid Ther 2017;27:1-3.  Back to cited text no. 91
    
92.
Guiraud S, Davies KE. Pharmacological advances for treatment in Duchenne muscular dystrophy. Curr Opin Pharmacol 2017;34:36-48.  Back to cited text no. 92
    
93.
Donovan JM, Zimmer M, Offman E, Grant T, Jirousek M. A novel NF-kappaB inhibitor, Edasalonexent (CAT-1004), in development as a disease-modifying treatment for patients with Duchenne muscular dystrophy: Phase 1 safety, pharmacokinetics, and pharmacodynamics in adult subjects. J Clin Pharmacol 2017;57:627-39.  Back to cited text no. 93
    
94.
Campbell C, McMillan HJ, Mah JK, Tarnopolsky M, Selby K, McClure T, et al. Myostatin inhibitor ACE-031 treatment of ambulatory boys with Duchenne muscular dystrophy: Results of a randomized, placebo-controlled clinical trial. Muscle Nerve 2017:55:458-64.  Back to cited text no. 94
    
95.
Sandoná M, Consalvi S, Tucciarone L, Puri PL, Saccone V. HDAC inhibitors for muscular dystrophies: Progress and prospects. Expert Opinion on Orphan Drugs 2016;4:125-7.  Back to cited text no. 95
    
96.
Nelson CE, Hakim CH, Ousterout DG, Thakore PI, Moreb EA, Castellanos Rivera RM, et al. In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy. Science 2016;351:403-7.  Back to cited text no. 96
    
97.
Bengtsson NE, Seto JT, Hall JK, Chamberlain JS, Odom GL. Progress and prospects of gene therapy clinical trials for the muscular dystrophies. Hum Mol Genet 2016;25(R1):R9-17.  Back to cited text no. 97
    
98.
Long C, Amoasii L, Mireault AA, McAnally JR, Li H, Sanchez-Ortiz E, et al. Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy. Science 2016;351:400-3.  Back to cited text no. 98
    
99.
Hu J, Xia E, Yang L, Xiao, X. Gene editing: A new step and a new direction toward finding a cure for Duchenne muscular dystrophy (DMD). Genes Dis 2016;3:101-2.  Back to cited text no. 99
    
100.
Tabebordbar M, Zhu K, Cheng JK, Chew WL, Widrick JJ, Yan WX, et al. In vivo gene editing in dystrophic mouse muscle and muscle stem cells. Science 2016;351:407-11.  Back to cited text no. 100
    
101.
Dai W-J, Zhu L-Y, Yan Z-Y, Xu Y, Wang Q-L, Lu X-J. CRISPR-Cas9 for in vivo gene therapy: Promise and hurdles. Mol Ther Nucleic Acids 2016;5:e349.  Back to cited text no. 101
    




 

Top
Print this article  Email this article
   
Online since 20th March '04
Published by Wolters Kluwer - Medknow