Duchenne muscular dystrophy is a genetic disorder caused by mutations in the dystrophin gene located on the X chromosome. It is characterized by progressive muscle weakness starting in early childhood. Clinical features include difficulty walking, cardiac complications like dilated cardiomyopathy, respiratory issues like sleep apnea and hypoventilation, intellectual disabilities in 30% of patients, and orthopedic problems like fractures and scoliosis. Diagnosis involves elevated creatine kinase levels, muscle biopsy, and genetic testing. Management focuses on cardiac, respiratory, orthopedic care as well as corticosteroid therapy to prolong ambulation and improve lung function. Emerging treatments include gene therapy using viral vectors and exon skipping to restore dystrophin production.

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.

22. THANK YOU