Duchenne muscular dystrophy

Neuromuscular movement disorder

1. Shyala Chand Duchenne Muscular Dystrophy

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 ” 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

3. Genetics and Pathogenesis X linked disorder. 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 .

4. 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 .

5. 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 .

6. Clinical onset of muscular weakness usually occurs between 2 and 3 years of age. Weakness Cardiac Complications Respiratory Complications Intellectual Disability Orthopedic Complications Clinical Features

7. 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

8. 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 .

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

10. 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

11. 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

12. 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. Progressive scoliosis in nearly all patients Scoliosis, in combination with progressive weakness, results in impaired pulmonary function, and eventually, respiratory failure.

13. 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 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 and LDH

14. Gold standard for diagnosis Performed when genetic testing is negative, or the clinical phenotype is atypical Needle electromyography Short duration, low amplitude polyphasic motor unit potentials in proximal muscles Over time, some of these areas become electrically silent s Electromyography Muscle biopsy

15. Muscle MRI is usually not performed in DMD for diagnosis, but may be a useful non-invasive tool to evaluate progression of muscle involvement over time. 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. Molecular Genetic Testing Muscle MRI

16. Management 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 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

17. Baseline pulmonary function tests and respiratory evaluations beginning at age 8 to 9 years. Spirometry , early morning and daytime carbon dioxide levels monitoring Annual polysomnography – To detect sleep disordered breathing and nocturnal hypoventilation Pneumococcal vaccine and annual flu vaccination Acute respiratory deteriorations due to infections require early management with antibiotics, chest physiotherapy and respiratory support. Nocturnal non-invasive 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. Respiratory disease

18. 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.

19. Prednisone 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. In case of side effects – A gradual tapering of prednisone to as low as 0.3 mg/kg per day

20. Deflazacort FDA on Feb. 9, 2017, approved deflazacort (brand name Emflaza ) to treat DMD. 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.

21. 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 .

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