DUCHENNE MUSCULAR DYSTROPHY

A brief presentation on Duchenne muscular dystrophy

1. Duchenne Muscular Dystrophy BY ANIEDU, UGOCHUKWU I. ( B.Sc , MD(in view)

2. Overview History Introduction Genetics Pathogenesis Clinical features/Diagnosis Prognosis Treatment Summary and Conclusion References

3. HISTORY The disease was first described by the Neapolitan physician Giovanni Semmola in 1834 and Gaetano Conte in 1836 DMD is named after the French neurologist  Guillaume Benjamin Amand Duchenne  In an 1861 publication, Duchenne established the diagnostic criteria that are still used William Richard Gowers was the first to deduce the genetic basis for the disease In 1986, Louis M. Kunkel provided molecular genetic confirmation of the X-linked recessive inheritance pattern

4. INTRODUCTION The muscular dystrophies are a group of genetically determined, progressive diseases of skeletal muscle They are non-inflammatory and have no neurological cause Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy affecting 1 in 3500 males born worldwide. Seen in males only ( expect in females with TURNER’S SYNDROME)

5. GENETICS DMD is inherited in an  X-linked recessive pattern (defect at Xp21 locus) Females will typically be carriers for the disease while males will be affected The son of a carrier mother has a 50% chance of inheriting the defective gene from his mother. The daughter of a carrier mother has a 50% chance of being a carrier or having two normal copies of the gene.

6. Pathogenisis The disorder is caused by a mutation in the  dystrophin  gene , the largest gene located on the human  X chromosome  which codes for the protein dystrophin Without dystrophin , muscles are susceptible to mechanical injury and undergo repeated cycles of necrosis and regeneration. Ultimately, regenerative capabilities are exhausted or inactivated

7. Dystrophin  is responsible for connecting the cytoskeleton  of each muscle fiber to the underlying basal lamina The absence of  dystrophin  permits excess calcium  to penetrate the sarcolemma leading to mitochondrial dysfunction mitochondrial dysfunction gives rise to an amplification of stress-induced cytosolic calcium signals and an amplification of stress-induced  reactive-oxygen species (ROS) production.

8. Increased oxidative stress within the cell damages the sarcolemma   and eventually results in the death of the cell. Muscle fibers undergo  necrosis  and are ultimately replaced with  adipose and connective tissue

9. CLINICAL FEATURES/DIAGNOSIS Age of onset is between 2-6 years of age Stage 1 – Presymptomatic Creatine kinase usually elevated Positive family history

10. Stage 2- Early ambulatory clumsy & Waddling gait , manifesting in children aged 2-6 years; secondary to hip girdle muscle weakness Inexorable progressive weakness in the proximal musculature , initially in the lower extremities, but later involving the neck flexors, shoulders, and arms Meryon’s sign child slips through examiner’s grasp when lifted under arms Possible toe-walking Can climb stairs

11. Gower's sign - 'climbing up legs' using the hands when rising from the floor

12. Stage 3- Late ambulatory More difficulty walking Around age 8 years, most patients notice difficulty with ascending stairs and respiratory muscle strength begins a slow but steady decline Cannot arise from the floor The forced vital capacity begins to gradually wane, leading to symptoms of nocturnal hypoxemia such as lethargy and early morning headaches

13. Stage 4 – Early nonambulatory Can self-propel for some time Able to maintain posture Possible development of scoliosis Stage 5 – Late nonambulatory Scoliosis may progress, especially when more wheelchair dependent If wheelchair bound and profoundly weak, patients develop terminal respiratory or cardiac failure , usually by the early 30s poor nutritional intake can also be a serious complication in individuals with severe end-stage DMD Contractures may develop

14. PROGNOSIS most are unable to ambulate independently by age 10 most are wheelchair dependent by age 15 most die of cardio respiratory problems by age 25-30

15. TREATMENT There is no cure yet for DMD, however case and symptom management such as: physical therapy positioning aids - used to help the child sit, lie, or stand braces and splints - used to prevent deformity, promote support, or provide protection medications nutritional counseling psychological counseling is currently successful

16. SUMMARY AND CONCLUSION Conclusively, there are many clinical trials in process , like administering Albuterol (beta adrenergic receptor agonist drug that increases strength and muscle mass ) also, they want to treat with Utrophin (sometimes can be substituted for dystrophin ) Embryonic stem cell transplants is another treatment they are looking into.   It is hoped that injecting healthy, nonspecialized stem cells into DMD victims will cause the stem cells to specialize and produce structurally and functionally correct dystrophin .   If dystrophin can be produced , it may slow the progression of the disease, or cure it altogether.

17. references Deconinck , N., & Dan, B. (2007). Pathophysiology of duchenne muscular dystrophy: current hypotheses.  Pediatric neurology ,  36 (1), 1-7. Hoffman EP, Dressman D (2001) Molecular pathophysiology and targeted therapeutics for muscular dystrophy. Trends Pharmacol Sci 22: 465–470 Nowak, K. J., & Davies, K. E. (2004). Duchenne muscular dystrophy and dystrophin: pathogenesis and opportunities for treatment.  EMBO reports ,  5 (9), 872-876 . Ouyang L, Grosse SD, Kenneson A. Health Care Utilization and Expenditures for Children and Young Adults With Muscular Dystrophy in a Privately Insured Population. J Child Neurol .  2008 Aug;23 (8):883-8 . Hughes, M. I., Hicks, E. M., Nevin , N. C., & Patterson, V. H. (1996). The prevalence of inherited neuromuscular disease in Northern Ireland. Neuromuscular Disorders ,  6 (1), 69-73.

18. Gulati , S., Saxena, A., Kumar, V., & Kalra , V. (2005). Duchenne muscular dystrophy: prevalence and patterns of cardiac involvement.  Indian journal of pediatrics ,  72 (5), 389-393. Bushby , K., Bourke, J., Bullock, R., Eagle, M., Gibson, M., & Quinby , J. (2005). The multidisciplinary management of Duchenne muscular dystrophy. Current Paediatrics ,  15 (4), 292-300. Chung, B., Wong, V., & Ip , P. (2003). Prevalence of neuromuscular diseases in Chinese children: a study in southern China.  Journal of child neurology ,  18 (3), 217-219 Manzur AY, Kuntzer T, Pike M, Swan A, Glucocorticoid corticosteroids for Duchenne muscular dystrophy (Cochrane review). The Cochrane Library, Chichester UK, Wiley, 2004. Bushby K, Muntoni F, Urtizberea A, Hughes R, Griggs R. Report on the 124th ENMC International Workshop: Treatment of Duchenne muscular dystrophy; defining the gold standards of management in the use of corticosteroids. 2–4 April 2004, Naarden , The Netherlands. Neuromuscul Disord 2004;14(8–9):526–34. Moxley III RT, Ashwal S, Pandya S, et al. Practice parameter: corticosteroid treatment of Duchenne dystrophy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2005;64(1):13–20. Cervellati S, Bettini N, Moscato M, Gusella A, Dema E, Maresi R. Surgical treatment of spinal deformities in Duchenne muscular dystrophy: a long term follow-up study. Eur Spine J 2004;13(5):441–8.

19. Finder JD, Birnkrant D, Carl J, et al. Respiratory care of the patient with Duchenne muscular dystrophy: ATS consensus statement. Am J Respir Crit Care Med 2004;170(4):456–65. Eagle, M., Bourke, J., Bullock, R., Gibson, M., Mehta, J., Giddings, D., ... & Bushby , K. (2007). Managing Duchenne muscular dystrophy--the additive effect of spinal surgery and home nocturnal ventilation in improving survival. Neuromuscular disorders: NMD ,  17 (6), 470. Bushby KMD, Muntoni F, Bourke JP. The management of cardiac complications in muscular dystrophy and myotonic dystrophy. Proceedings of 107th ENMC Workshop. Neuromuscul Disord 2003;13:166–72. American Academy of Pediatrics Section on Cardiology and Cardiac Surgery. Cardiovascular health supervision for in dividuals aff ected by Duchenne or Becker muscular dystrophy. Pediatrics 2005; 116: 1569–73 Bushby , K., Bourke, J., Bullock, R., Eagle, M., Gibson, M., & Quinby , J. (2005). The multidisciplinary management of Duchenne muscular dystrophy. Current Paediatrics ,  15 (4), 292-300. Parsons, E. P., Clarke, A. J., & Bradley, D. M. (2004). Developmental progress in Duchenne muscular dystrophy: lessons for earlier detection.  European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society ,  8 (3), 145. Essen, A. J., Busch, H. F. M., Meerman , G. J., & Kate, L. P. (1992). Birth and population prevalence of Duchenne muscular dystrophy in The Netherlands. Human genetics ,  88 (3), 258-266.

20. Drousiotou A, Ioannou P, Georgiou T, et al. Neonatal screening for Duchenne muscular dystrophy: a novel semiquantitative application of the bioluminescence test for creatine kinase in a pilot national program in Cyprus. Genet Test 1998; 2: 55–60. Bradley D, Parsons E. Newborn screening for Duchenne muscular dystrophy. Semin Neonatol 1998; 3: 27–34. Emery AE. Population frequencies of inherited neuromuscular diseases—a world survey Neuromuscul Disord 1991; 1: 19–29 . Ciafaloni E, Fox DJ, Pandya S, Westfield CP, Puzhankara S, Romitti PA, et al. Delayed diagnosis in Duchenne muscular dystrophy: data from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet ). J Pediatr 2009 Sept;155(3):380-5. Fowler WM Jr. Role of physical activity and exercise training in neuromuscular diseases. Am J Phys Med Rehabil 2002; 81 ( suppl ): S187–95. Fowler WM Jr. Rehabilitation management of muscular dystrophy and related disorders: II. Comprehensive care. Arch Phys Med Rehabil 1982; 63: 322–28

21. THANK YOU