Becker’s Muscular Dystrophy (BMD) is a dystrophinopathy manifested as progressive muscle degeneration. Autologous Bone Marrow Mononuclear Cells (BMMNCs) have shown some myogenic potential. The paracrine effects of the BMMNCs reduce the inflammation and are thought to reduce muscle degeneration. We treated a 39 year old dental surgeon suffering from BMD. Muscle strength was reduced when measured using modified Medical Research Council’s Manual Muscle Testing (mMRC-MMT). Static sitting balance was poor. He was wheelchair dependent for ambulation and moderately independent in Activities of Daily Living (ADL). Functional Independence Measure (FIM) score was 93. Musculoskeletal Magnetic Resonance Imaging (MRI-MSK) showed moderate fatty infiltration in the muscles. Three cellular transplantations were carried out. Clinical assessment and the investigations were repeated. Progressive increase in the muscle strength was noted. Ambulation was independent using push-knee splints and minimal assistance when weary. Static and dynamic balance in sitting and standing improved. FIM score increased from 93 to 105. There was no increase in the degree of fatty infiltration, as seen on the MRI-MSK. The case study provides evidence for the putative benefits of cellular therapy in altering the disease progression in BMD. It also suggests augmented clinical benefits of combination of cellular therapy and rehabilitation. 1. Introduction Becker’s Muscular Dystrophy (BMD) is one of the dystrophinopathies caused due to in-frame deletions of the exons of dystrophin gene leading to incomplete translation of its protein product, Dystrophin [1]. This incomplete translation leads to functionally incompetent protein [2]. Dystrophin is essential to maintain the structural integrity of the muscle fibers against the mechanical and contractile stresses [3]. In absence of dystrophin, there is increased breakdown of muscle fibers and increased phagocytosis. In the early phase of the disease, this is compensated by regeneration of new muscle fibers from quiescent satellite cells. However, limited numbers of satellite cells leave the rampant muscle necrosis uncompensated as the disease progresses [4]. Clinically, this is manifested as progressive muscle weakness and wasting leading to loss of functionality. There is a vast variation in the clinical manifestation of this disease [5]. BMD leads to severe loss of function and disability in most part of the life followed by premature death [6]. Management of BMD consists of use of corticosteroids to reduce the inflammatory breakdown of the muscle
References
[1]
B. Darras, D. Miller, and D. Urion, “Dystrophinopathies,” in GeneReviews, R. A. Pagon, T. D. Bird, C. R. Dolan, K. Stephens, and M. P. Adam, Eds., University of Washington, Seattle, Wash, USA, 2000.
[2]
K. Anthony, S. Cirak, S. Torelli, et al., “Dystrophin quantification and clinical correlations in Becker muscular dystrophy: implications for clinical trials,” Brain, vol. 134, no. 12, pp. 3547–3559, 2011.
[3]
D. J. Blake, A. Weir, S. E. Newey, and K. E. Davies, “Function and genetics of dystrophin and dystrophin-related proteins in muscle,” Physiological Reviews, vol. 82, no. 2, pp. 291–329, 2002.
[4]
R. Sch？fer, U. Knauf, M. Zweyer et al., “Age dependence of the human skeletal muscle stem cell in forming muscle tissue,” Artificial Organs, vol. 30, no. 3, pp. 130–140, 2006.
[5]
G. P. Comi, A. Prelle, N. Bresolin, et al., “Clinical variability in Becker muscular dystrophy. Genetic, biochemical and immunohistochemical correlates,” Brain, vol. 117, no. 1, pp. 1–14, 1994.
[6]
A. K. Sharma, P. Badhe, N. Gokulchandran, G. Chopra, M. Lohia, and P. Kulkarni, “Chapter 1:introduction and clinical features,” in Stem Cell Therapy and Other Recent Advances in Muscular Dystrophy, pp. 1–12, NeuroGen Brain and Spine Institute, 1st edition, 2013.
[7]
A. Y. Manzur and F. Muntoni, “Diagnosis and new treatments in muscular dystrophies,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 80, no. 7, pp. 706–714, 2009.
[8]
G. L. Odom, P. Gregorevic, and J. S. Chamberlain, “Viral-mediated gene therapy for the muscular dystrophies: successes, limitations and recent advances,” Biochimica et Biophysica Acta, vol. 1772, no. 2, pp. 243–262, 2007.
[9]
E. L. Herzog, L. Chai, and D. S. Krause, “Plasticity of marrow-derived stem cells,” Blood, vol. 102, no. 10, pp. 3483–3493, 2003.
[10]
M. A. Goodell, K. A. Jackson, S. M. Majka et al., “Stem cell plasticity in muscle and bone marrow,” Annals of the New York Academy of Sciences, vol. 938, pp. 208–220, 2001.
[11]
G. Auda-Boucher, T. Rouaud, A. Lafoux et al., “Fetal muscle-derived cells can repair dystrophic muscles in mdx mice,” Experimental Cell Research, vol. 313, no. 5, pp. 997–1007, 2007.
[12]
J. M. Florence, S. Pandya, W. M. King et al., “Intrarater reliability of manual muscle test (Medical Research Council scale) grades in Duchenne's muscular dystrophy,” Physical Therapy, vol. 72, no. 2, pp. 115–122, 1992.
[13]
K. M. D. Bushby, D. Gardner-Medwin, L. V. B. Nicholson et al., “The clinical, genetic and dystrophin characteristics of Becker muscular dystrophy: II—correlation of phenotype with genetic and protein abnormalities,” Journal of Neurology, vol. 240, no. 2, pp. 105–112, 1993.
[14]
R. V. Carlson, K. M. Boyd, and D. J. Webb, “The revision of the declaration of Helsinki: past, present and future,” British Journal of Clinical Pharmacology, vol. 57, no. 6, pp. 695–713, 2004.
[15]
R. Haas and S. Murea, “The role of granulocyte colony-stimulating factor in mobilization and transplantation of peripheral blood progenitor and stem cells,” Cytokines and Molecular Therapy, vol. 1, no. 4, pp. 249–270, 1995.
[16]
J. A. Miyan, M. Zendah, F. Mashayekhi, and P. J. Owen-Lynch, “Cerebrospinal fluid supports viability and proliferation of cortical cells in vitro, mirroring in vivo development,” Cerebrospinal Fluid Research, vol. 3, article 2, 2006.
[17]
I. L. Weissman, D. J. Anderson, and F. Gage, “Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdifferentiations,” Annual Review of Cell and Developmental Biology, vol. 17, pp. 387–403, 2001.
[18]
S. Kanji, V. J. Pompili, and H. Das, “Plasticity and maintenance of hematopoietic stem cells during development,” Recent Patents on Biotechnology, vol. 5, no. 1, pp. 40–53, 2011.
[19]
J. M. Gimble, A. J. Katz, and B. A. Bunnell, “Adipose-derived stem cells for regenerative medicine,” Circulation Research, vol. 100, no. 9, pp. 1249–1260, 2007.
[20]
C. Blanpain, V. Horsley, and E. Fuchs, “Epithelial stem cells: turning over new leaves,” Cell, vol. 128, no. 3, pp. 445–458, 2007.
[21]
O. Gonzalez-Perez, “Neural stem cells in the adult human brain,” Biological and Biomedical Reports, vol. 2, no. 1, pp. 59–69, 2012.
[22]
A. C. Gyuton and J. E. Hall, “Chapter 6: contraction of skeletal muscle,” in Textbook of Medical Physiology, pp. 72–74, Elsevier, Pennsylvalnia, Pa, USA, 2010.
[23]
J. L. Shadrach and A. J. Wagers, “Stem cells for skeletal muscle repair,” Philosophical Transactions of the Royal Society B, vol. 366, no. 1575, pp. 2297–2306, 2011.
[24]
C. A. Collins, “Satellite cell self-renewal,” Current Opinion in Pharmacology, vol. 6, no. 3, pp. 301–306, 2006.
[25]
J. Rantanen, T. Hurme, R. Lukka, J. Heino, and H. Kalimo, “Satellite cell proliferation and the expression of myogenin and desmin in regenerating skeletal muscle: evidence for two different populations of satellite cells,” Laboratory Investigation, vol. 72, no. 3, pp. 341–347, 1995.
[26]
D. Montarras, J. Morgan, C. Colins et al., “Direct isolation of satellite cells for skeletal muscle regeneration,” Science, vol. 309, no. 5743, pp. 2064–2067, 2005.
[27]
J. Huard, R. Roy, B. Guerette, S. Verreault, G. Tremblay, and J. P. Tremblay, “Human myoblast transplantation in immunodeficient and immunosuppressed mice: evidence of rejection,” Muscle and Nerve, vol. 17, no. 2, pp. 224–234, 1994.
[28]
V. Mouly, A. Aamiri, S. Périé et al., “Myoblast transfer therapy: is there any light at the end of the tunnel?” Acta Myologica, vol. 24, no. 2, pp. 128–133, 2005.
[29]
G. M. Smythe, S. I. Hodgetts, and M. D. Grounds, “Problems and solutions in myoblast transfer therapy,” Journal of Cellular and Molecular Medicine, vol. 5, no. 1, pp. 33–47, 2001.
[30]
J. Meng, F. Muntoni, and J. E. Morgan, “Stem cells to treat muscular dystrophies–where are we?” Neuromuscular Disorders, vol. 21, no. 1, pp. 4–12, 2011.
[31]
C. Dell’Agnola, Z. Wang, and R. Storb, “Hematopoietic stem cell transplantation does not restore dystrophin expression in Duchenne muscular dystrophy dogs,” Blood, vol. 104, pp. 4311–4318, 2004.
[32]
S. Y. Corbel, A. Lee, L. Yi et al., “Contribution of hematopoietic stem cells to skeletal muscle,” Nature Medicine, vol. 9, no. 12, pp. 1528–1532, 2003.
[33]
P. R. Crisostomo, M. Wang, T. A. Markel et al., “Stem cell mechanisms and paracrine effects: potential in cardiac surgery,” Shock, vol. 28, no. 4, pp. 375–383, 2007.
[34]
P. R. Crisostomo, M. Wang, C. M. Herring et al., “Gender differences in injury induced mesenchymal stem cell apoptosis and VEGF, TNF, IL-6 expression: role of the 55 kDa TNF receptor (TNFR1),” Journal of Molecular and Cellular Cardiology, vol. 42, no. 1, pp. 142–149, 2007.
[35]
M. X. Xiang, A. N. He, J. A. Wang, and C. Gui, “Protective paracrine effect of mesenchymal stem cells on cardiomyocytes,” Journal of Zhejiang University B, vol. 10, no. 8, pp. 619–624, 2009.
[36]
M. Gnecchi, Z. Zhang, A. Ni, and V. J. Dzau, “Paracrine mechanisms in adult stem cell signaling and therapy,” Circulation Research, vol. 103, no. 11, pp. 1204–1219, 2008.
[37]
P. M. Chen, M. L. Yen, K. J. Liu, H. K. Sytwu, and B. L. Yen, “Immuno-modulatory properties of human adult and fetal multipotentmesenchymal stem cells,” Journal of Biomedical Sciences, vol. 18, article 49, 2011.
[38]
A. E. H. Emery and C. Gosden, “A neurogenic component in muscular dystrophy,” Journal of Medical Genetics, vol. 11, no. 1, pp. 76–79, 1974.
[39]
H. K. Young, B. A. Barton, S. Waisbren et al., “Cognitive and psychological profile of males with becker muscular dystrophy,” Journal of Child Neurology, vol. 23, no. 2, pp. 155–162, 2008.
[40]
R. Blitzblau, E. K. Storer, and M. H. Jacob, “Dystrophin and utrophin isoforms are expressed in glia, but not neurons, of the avian parasympathetic ciliary ganglion,” Brain Research, vol. 1218, pp. 21–34, 2008.
[41]
L. Luo and H. Y. Zhou, “Co-transplantation of myoblasts and Schwann cells in the therapy of Duchenne muscular dystrophy,” Sichuan Da XueXueBao Yi Xue Ban, vol. 42, no. 1, pp. 101–105, 2011.
[42]
F. Macaluso and K. Myburgh, “Current evidence that exercise can increase the number of adult stem cells,” Journal of Muscle Research and Cell Motility, vol. 33, no. 3-4, pp. 187–198, 2012.
[43]
M. L. Sveen, T. D. Jeppesen, S. Hauerslev, L. K？ber, T. O. Krag, and J. Vissing, “Endurance training improves fitness and strength in patients with Becker muscular dystrophy,” Brain, vol. 131, no. 11, pp. 2824–2831, 2008.
[44]
J. Roque, V. Carvalho, L. Pascoalino, S. Ferreira, E. Bocchi, and G. Guimar？es, “Physical training in becker muscular dystrophy associated with heart failure,” Arquivos Brasileiros de Cardiologia, vol. 97, no. 6, pp. e128–e131, 2011.
[45]
P. Daverat, H. Petit, G. Kemoun, J. Dartigues, and M. Barat, “The long term outcome in 149 patients with spinal cord injury,” Paraplegia, vol. 33, pp. 665–668, 1995.
[46]
A. Sharma, P. Kulkarni, G. Chopra et al., “Administration of autologous bone marrow derived mononuclear cells in children with incurable neurological disorders and injury is safe and improved their quality of life,” Cell Transplantation, vol. 21, supplement 1, pp. S79–S90, 2012.
[47]
A. Sharma, P. Kulkarni, G. Chopra, N. Gokulchandran, M. Lohia, and P. Badhe, “Autologous bone marrow derived mononuclear cells transplantation in duchenne muscular dystrophy,” Indian Journal of Clinical Practice, vol. 23, no. 3, 2012.
