Muscular dystrophies

1. Dr.Manoj Prabhakar.M,
Resident (Dept of Pediatrics)

2. Case Scenario
 Age: 5 ½ years with rare Xp21 mutation with Point
mutation of exon 7 of the dystrophin gene resulting in
complete absence of dystrophin.
 Presentation: (Early ambulatory stage ) - Ambulant,
weight – 50th %, hypertrophy of the calves, +ve Gowers
sign, mild lordosis.
 Problem List: Poor attention, Speech delay,
hyperactivity(reported by mother), proximal weakness
of lower and upper limbs and neck flexors, epistaxis,
poor balance, gait- waddle/flat footed, muscle spasm of
calves.
 Initially presented with developmental delays before he
was diagnosed.

3. Muscular dystrophy is distinguished from all other
neuromuscular diseases by 4 obligatory criteria:
 It is a Primary myopathy
 It has a genetic basis,
 The course is progressive, and
 Degeneration and death of muscle fibers occur at
some stage in the disease.
DEF: The term dystrophy means abnormal
growth.

4.  Duchenne and Becker Muscular dystrophies.
 Emery-Dreifuss Muscular Dystrophy.
 Myotonic Muscular Dystrophy.
 Limb-Girdle Muscular Dystrophies.
 Facioscapulohumeral Muscular Dystrophy.
 Congenital Muscular Dystrophies.
TYPES:

6. Duchenne muscular dystrophy (DMD)
It is the most common hereditary neuromuscular disease
affecting all races and ethnic groups.
 Its characteristic clinical features are progressive
weakness, intellectual impairment, hypertrophy of the
calves, and proliferation of connective tissue in muscle.
 This disease is inherited as an X-linked recessive trait. The
abnormal gene is at the Xp21 locus.
 The incidence is 1 in 3,600 live born infant boys.

7.  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.

8. 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.

10. Posture changes during
progression of DMD

11. Stage 1
– Presymptomatic
Creatine kinase usually elevated
Positive family history
CLNICAL FEATURES

12. Stage 2- Early ambulatory
 Clumsy & Waddling gait, manifesting in children aged
2-6 years
 Progressive weakness in the proximal musculature,
initially in the lower extremities, but later involving
the neck flexors, shoulders, and arms.
 Possible toe-walking
 Can climb stairs

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

14. 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

15. Stage 4 – Early nonambulatory
 Can self-propel for some time
 Able to maintain posture
 Possible development of scoliosis

16. 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
 Contractures may develop

17. Complications
 Cardiomyopathy
 Decreased self-independence and mobility
 Lung failure (cause of death)
 Muscle tightness around joints
 Mental impairment

18. PHYSICAL EXAMINATION
 Generally, neck flexors, wrist extensors, quadriceps, tibialis
anterior, biceps, and triceps muscles are affected more.
 Deep tendon reflexes, slowly diminish and ultimately
disappear
 Calf muscle enlargement (pseudo hypertrophy)
contractures of the iliotibial bands, hip flexors, and heel
cords
 Equinovarus deformity of ankle is universal
 Asymmetric weakening of the paraspinal muscles leads to
kyphoscoliosis, which in turn further compromises
pulmonary and gastrointestinal function.

19. WORK UP
 Serum Creatine Phosphokinase (Elevated)
 Electromyography
 Nerve Conduction Velocity Study
 Molecular diagnosis
 Muscle biopsy
 Imaging Studies
 Electrocardiogram
 Echocardiogram

20. DIFFERENTIAL DIAGNOSIS

21. Differences between DMD & BMD

22. Carrier detection
 Carrier detection is an important aspect of the care
and evaluation of patients with DMD and their family
members
 For many years, CPK testing was the best method for
carrier detection; however, it is elevated in only two
thirds of female carriers
 If affected male in family has a known deletion or
duplication of the dystrophin gene, testing for carrier
status is performed accurately by testing possible
carriers for the same deletion or duplication

23. TREATMENT
 There is no medical cure for this disease. Much can be
done to treat complications and to improve the quality
of life of affected children.
 Cardiac decompensation often responds initially well
to digoxin.
 Preservation of a good nutritional state is important.

24. GENETIC CONSELLING
Genetic counseling can offer many benefits for
families living with Duchenne or Becker
muscular dystrophy, including:
- Education about the disorder
- Coordination and explanation of genetic
testing
- Emotional counseling

25. EXON SKIPPING
In DMD, exon skipping is a potential treatment approach
that is under investigation to correct for specific genetic
mutations and restore production of dystrophin protein.

26.  As the name suggests, the principle of exon
skipping is to encourage the cellular machinery to
‘skip over’ an exon. Small pieces of DNA
called antisense oligonucleotides (AOs) or
‘molecular patches‘ are used to mask the exon
that you want to skip, so that it is ignored during
protein production

27. Drisapersen and eteplirsen are exon 51 skipping
antisense oligonucleotides that bind RNA and skip
(bridge) over the defective exon, thus producing a
shorter but potentially functional dystrophin protein.