1. Duchenne Muscular Dystrophy
Hari Krishnan Nair
Observer, Critical Care Medicine

2. Introduction
•An inherited progressive myopathic disorder
•X-linked recessive form of muscular dystrophy
•Affects 1 in 3600 boys
•Caused by mutations in the dystrophin gene, and hence is termed “dystrophinopathy”

3. Dystrophinopathies
•Duchenne muscular dystrophy (DMD) is associated with the most severe clinical symptoms
•Becker muscular dystrophy (BMD) has a similar presentation to DMD, but typically has a later onset and a milder clinical course
•Patients with an intermediate phenotype may be classified clinically as having either mild DMD or severe BMD

4. Etiopathogenesis

5. Genetics and Pathogenesis
•Caused by mutations of the dystrophin gene located on chromosome Xp21.2
–Deletions
•Around 72% of patients
–Partial gene duplications
•6 – 10% of patients
–Point mutations
•In the coding sequence or the splicing sites

6. Dystrophin
•Dystrophin is located on the cytoplasmic face of the plasma membrane of muscle fibers, functioning as a component of a large, tightly associated glycoprotein complex .
•Provides mechanical reinforcement to the sarcolemma and stabilizes the glycoprotein complex, shielding it from degradation.
–In its absence, the glycoprotein complex is digested by proteases. Loss of these membrane proteins may initiate the degeneration of muscle fibers, resulting in muscle weakness.
Deficiency of a glycoprotein component of the dystrophin complex in dystrophic muscle. Ervasti JM, Ohlendieck K, Kahl SD, Gaver MG, Campbell KP. Nature. 1990;345(6273):315.

8. Pathogenesis
•Muscle cell membrane damage related to the loss of dystrophin may permit the pathologic entry of extracellular calcium into muscle fibers.
•The excess cytosolic calcium can activate calpains, which promote muscle proteolysis .

9. Clinical Features

10. Clinical Features
•Clinical onset of muscular weakness usually occurs between 2 and 3 years of age.
•Histologic and laboratory evidence of a myopathy may be observed from birth.

11. Weakness
•Proximal before distal limb muscles
•Lower before upper extremities
•Difficulty running, jumping, and walking up steps
•Waddling gait
•Lumbar lordosis
•Pseudohypertrophy of calf muscles, due to fat infiltration
•Patients are usually wheelchair-bound by the age of 12

14. Gowers Sign
•Patient uses his hands and arms to "walk" up his own body from a squatting position
–due to lack of hip and thigh muscle strength
Gowers WR. Clinical lecture on pseudohypertrophic muscular paralysis. Lancet 1879;ii,73-5.

15. Gowers Sign
•Patient with DMD demonstrating the Gowers maneuver.
–The prone position.
–The bear position.
–Moving the hands up the thighs to help upright the trunk and augment knee extension.
–The upright position.

17. Cardiac complications
•Primary dilated cardiomyopathy
•Conduction abnormalities
–Intra-atrial and inter-atrial conduction defects
–Arrhythmias, primarily supraventricular tachycardia

18. Cardiomyopathy
•Characterized by extensive fibrosis of the posterobasal left ventricular wall
–tall right precordial R waves
–increased R/S ratio
–deep Q waves in leads I, aVL, and V5-6
•As the disease progresses, fibrosis can spread to the lateral free wall of the left ventricle.
•Significant mitral regurgitation due to involvement of posterior papillary muscle

19. Cardiomyopathy
•Incidence
–By 14 years: One-third of patients
–By 18 years: One half of patients
–Older than 18 years: All patients
•Despite the high incidence of DCM, the majority of children with DMD are relatively asymptomatic until late in the disease course, probably because of their inability to exercise
•Heart failure and arrhythmias may develop in the late stages of the disease
The incidence and evolution of cardiomyopathy in Duchenne muscular dystrophy. Nigro G, Comi LI, Politano L, Bain RJ. Int J Cardiol. 1990;26(3):271.

20. Respiratory complications
•Chronic respiratory insufficiency due to restrictive lung disease is inevitable in all patients.
–Vital capacity increases as predicted until around age 10 years; after this time it starts to decrease at a rate of 8-12% per year.
–When vital capacity reaches less than 1 liter the risk of death within the next one to two years is relatively high.
•Obstructive sleep apnea
–1st decade
•Hypoventilation
–2nd decade

21. Intellectual disability
•In around 30% of patients
•Average IQ is 85
–normally distributed one standard deviation below the population norms
–Verbal IQ is more impaired than performance IQ
•Intellectual disability is not correlated with the severity of weakness
•Higher incidence of ADHD
Leibowitz D, Dubowitz V. Intellect and behaviour in Duchenne muscular dystrophy. Dev Med Child Neurol 1981;23:577-90.

22. Orthopedic Complications
•Long bone fractures
•21% of DMD patients had experienced fractures.
–Most common mechanism was falling
–About half of the fractures occurred among patients who were ambulatory
•Osteoporosis is present in most patients. Bone mineral density begins early and continues to diminish with age.
Fracture prevalence in Duchenne muscular dystrophy. McDonald DG, Kinali M, Gallagher AC, Mercuri E, Muntoni F, Roper H, Jardine P, Jones DH, Pike MG. Dev Med Child Neurol. 2002;44(10):695.

23. Orthopedic Complications
•Progressive scoliosis in nearly all patients
–Scoliosis, in combination with progressive weakness, results in impaired pulmonary function, and eventually, respiratory failure.
Progression of scoliosis in Duchenne muscular dystrophy. Smith AD, Koreska J, Moseley CF. J Bone Joint Surg Am. 1989;71(7):1066.

24. Malignant hyperthermia
•Patients with DMD are thought to have increased risk of malignant hyperthermia, or at least malignant hyperthermia-like reactions if exposed to inhalational anesthetics such as halothane, or succinylcholine.
Wedel DJ. Malignant hyperthermia and neuromuscular disease. Neuromuscul Disord 1992;2:157-64.
Wang JM, Stanley TH. Duchenne muscular dystrophy and malignant hyperthermia-two case reports. Can Anaesth Soc J 1986;33:492-7.

25. Diagnosis

26. Diagnosis
•The diagnosis of a dystrophinopathy is suspected based upon:
–Characteristic age and sex
–Presence of symptoms and signs suggestive of a myopathic process
–Markedly increased serum creatine kinase values
–Myopathic changes on electromyography and muscle biopsy
–A positive family history suggesting X-linked recessive inheritance

27. Serum muscle enzymes
•Markedly raised serum CK level, 10-20 times the upper limit of normal
–Levels peak at 2-3 years of age and then decline with increasing age, due to progressive loss of dystrophic muscle fibres
•Elevated serum ALT, AST, aldolase and LDH

28. Electromyography
•Needle electromyography
–Short duration, low amplitude polyphasic motor unit potentials in proximal muscles
–Over time, some of these areas become electrically silent

29. Muscle biopsy
•Gold standard for diagnosis
•Performed when genetic testing is negative, or the clinical phenotype is atypical

30. Molecular Genetic Testing
•Multiplex polymerase chain reaction (PCR), covering 18 exons at the deletion hotspots detected 90-98% of all deletions
•Multiplex ligation-dependent probe amplification (MLPA) has provided a more sensitive technique for detecting deletions.
•If MLPA testing is negative, the DMD gene can be tested for point mutations.

31. Muscle MRI
•Muscle MRI is usually not performed in DMD for diagnosis, but may be a useful noninvasive tool to evaluate progression of muscle involvement over time.

32. Genetic Analysis
•Molecular genetic testing is indicated for patients with an elevated serum CK level and clinical findings suggestive of a dystrophinopathy.
•The diagnosis is established if a disease-causing mutation of the dystrophin gene (DMD) is identified
–Deletion of one or more exons of DMD gene
–Duplication of one or more exons of DMD
–Small insertions/deletions/point mutations/splicing mutations of DMD gene

33. Management

34. Cardiac disease
•Cardiac surveillance with ECG and echocardiogram and Holter monitoring, beginning at 10 years and continuing on an annual basis.
•Early treatment of dilated cardiomyopathy with ACE inhibitors and beta blockers
–improvement in LV function
Jefferies JL, Eidem BW, Belmont JW, Craigen WJ, Ware SM, Fernbach SD, et al . Genetic predictors and remodeling of dilated cardiomyopathy in muscular dystrophy. Circulation 2005;112:2799-804.

35. Respiratory disease
•Baseline pulmonary function tests and respiratory evaluations beginning at age 8 to 9 years.
–Spirometry, early morning and daytime carbondioxide levels monitoring
•Annual polysomnography
–To detect sleep disordered breathing and nocturnal hypoventilation
•Pneumococcal vaccine and annual flu vaccination

36. Respiratory disease
•Acute respiratory deteriorations due to infections require early management with antibiotics, chest physiotherapy and respiratory support.
•Nocturnal noninvasive intermittent positive pressure ventilation (NIPPV) for hypercapnia
–Life expectancy has increased to an average of 25 and even 30 years in patients who receive NIPPV.
Eagle M, Baudouin SV, Chandler C, Giddings DR, Bullock R, Bushby K. Survival in Duchenne muscular dystrophy: Improvements in life expectancy since 1967 and the impact of home nocturnal ventilation. Neuromuscul Disord 2002;12:926-9.

37. Orthopedic problems
•Passive stretching
•Night splints
•Surveillance radiographs for scoliosis
•Maintenance of bone density
–Monitoring of vitamin D levels and supplementing calcium and vitamin D

38. Corticosteroid Therapy
•Prednisolone, prednisone and deflazacort have been the only drugs shown to be effective to date in DMD.
•Prednisolone/prednisone
–0.75mg/kg/day
•Deflazacort
–0.9mg/kg/day
•A common regimen is to offer corticosteroids at the time of decline of muscle strength and frequent falls, and to cease treatment when the child is no longer ambulant.
•Preservation of respiratory muscle function, cough strength and cardiac function, with a lower incidence of dilated cardiomyopathy.
Biggar WD, Harris VA, Eliasoph L, Alman B. Long-term benefits of deflazacort treatment for boys with Duchenne muscular dystrophy in their second decade. Neuromuscul Disord 2006;16:249-55.

39. Prednisone – Merits and Demerits
•Average muscle strength increased by 11% with prednisone treatment compared with placebo.
–Strength increased significantly by 10 days, reached a maximum at 3 months, and was maintained at 6 and 18 months.
•Forced vital capacity improved significantly (10.5% higher) after 6 months of daily prednisone.
•Weight gain, diabetes, Cushingoid appearance, hypertension, gastrointestinal bleeding and compression fractures.

40. Prednisone Regimen
•Prednisone (0.75mg/kg per day or 10mg/kg per week given over two weekend days) in patients > 5 years of age.
•Optimally, should be maintained at this dose.
•In case of side effects
–A gradual tapering of prednisone to as low as 0.3 mg/kg per day

41. Deflazacort
•In contrast with prednisone, alternate day treatment with deflazacort (2mg/kg every other day) for 2 years was beneficial in one study.
–The mean prolongation of ambulation was 13 months.
Deflazacort in Duchenne dystrophy: study of long-term effect. Angelini C, Pegoraro E, Turella E, Intino MT, Pini A, Costa C. Muscle Nerve. 1994;17(4):386.

42. Other drug therapies
•Oxandrolone, an anabolic steroid has shown some promise in increasing quantitative muscle strength in a randomized prospective trial.
•Cyclosporine therapy showed some improvement in muscle strength.
Fenichel GM, Griggs RC, Kissel J, Kramer TI, Mendell JR, Moxley RT, et al . A randomized efficacy and safety trial of oxandrolone in the treatment of Duchenne dystrophy. Neurology 2001;56:1075-9.

43. Gene Therapy
•Viral vectors
–Recombinant adeno-associated viral (rAAV) vectors that carry critical regions of the DMD gene
•Antisense oligonucleotide exon skipping
–To redirect splicing and induce exon skipping
–Restoring the reading frame and producing a partially functioning dystrophin.
•Utrophin
–A protein homologue of dystrophin in the sarcolemma
–May compensate for dystrophin deficiency if it is upregulated.

44. Thank You