This simple presentation well talk about

1. INHERITED
DISORDERS OF
SKELETAL MUSCLE

2. Muscular Dystrophy
Duchenne/
Becker
Emery-Dreifuss,
Congenital
Limb-Girdle,
Distal Myopathy
Onset 2-6 years Childhood to early teens,
infancy
Late childhood-middle
age
Muscle groups
affected
Life expectancy Rarely beyond 20’s varies Middle age +
Inheritance X-linked recessive X-linked recessive,
autosomal dom & rec.
Autosomal dominant &
recessive
Genetic linkage Dystrophin Emerin, lamin, merosin,
etc.
Calpain-3, Dysferlin,
Caveolin-3, α-
sargoglycans, etc.Source: www.mdausa.org

3. X-linked: Dystrophinopathies
 Groupe of hereditary myopathies
 Pathophysiology: defective or absent Dystrophin
 Dystrophin:
– Has integral role in sarcolemmal stability
– Consist in 2 globular heads with flexible rod-shaped center
– Associated in a complex with sarcoglycans & dystroglycans
(transmembrane proteins & glycoproteins)
– Coding gene: on Chromosom X short arm : Xp21 location
– Function loss:  cascade of events (including loss of other
components of dystrophin-associated glycoprotein complex, sarcolemmal
breakdown with attendant Ca ion influx phosphlipase activation,
oxidative cellular injury) and ultimately myonecrosis

4. X- Linked: Ducenne, Beker..
 X- linked, recessive transmission
 Affects males
 Females are Carrier
 Onset: 2-5 years in Duchenne, end 1st decade in
Becker)
 Proximal muscles: mainly , (early)
 Severe disease (+ other systemes: cardiac..)
 death in the 2d decade

5. DUCHENNE MD
 progressive skeletal muscle weakness.
 Absence of the dystrophin protein  weakens the
connections between proteins in the muscle fibers &
the cell membrane. (?the cell membrane becomes
weaker & ruptures)
 As a result: ions such as Ca can move in & out of
the ruptured cell membrane  contraction at the
damaged site  the muscle fibers will break  the
muscle will begin to waste away.

6. Clinically: onset of DMD
 Delayed developmental milestones
 Loss of motor skills
 Characteristic gait
 Calf “hypertrophy” (pseudohypertrophy)
 Clumsiness/frequent falls

7. Symptoms of DMD
 Muscle weakness: Difficulty in walking/running
 Difficulty climbing stairs or hills
&
 Difficulty in rising (Gower’s sign)

8.  DIAGNOSIS:
Clinical,
Lab Invest.: CPK
Neurophysiol. (EMG): myogenic changes
Muscle biopsy
Genetic study (Immunoblot homogenate allow
diffenrentiation between Duchenne & Becker)
 Asymptomatic female
 Foetus diagnsis possible (as early as 8 weeks)

9. DMD: where is the Gene?
 The gene for dystrophin production sits on the X
chromosome.
 If a normal gene for dystrophin is present, then the
protein will be made.
 If the gene is missing or altered, dystrophin may not
be produced at all or only in abnormal forms,
resulting in Duchenne muscular dystrophy

10. Dystrophinopathies. Dystrophic muscle

11. Dystrophinopathies: dystrophin staining
Normal
dystrophin
Intermediate dystrophin
Becker MD
Duchenne dystrophy

12. Treatments for DMD
 To improve breathing:
– O2 therapy
– Ventilator
– Scoliosis surgery
– Tracheotomy

13. Treatments (cont.)
 To improve mobility:
– Physical therapy
– Surgery on tight joints
– Prednisone
– Non-steroidal medications
– Wheelchair

14. Other MD
Limb Girdle MD

15. Common features
– Expression in either male or female sex
– Onset usually in the late first or second decade of
life (but also middle age)
– Usually autosomal recessive and less frequently
autosomal dominant
– Involvement of shoulder or pelvic-girdle muscles
with variable rates of progression
– Severe disability within 20-30 years
– Muscular pseudohypertrophy and/or contractures
uncommon

16. Limb Girdle MD
 LGMD may show an autosomal recessive
(autosomal dominant forms reported)
or sporadic method of inheritance.
 Some forms of LGMD dramatically affect young
adults, while other types progress so slowly that
they are not detected until much later in life.

17.  LGMD protein defects occur in several
pathways
proteins associated with the sarcolemma
proteins associated with the contractile
apparatus
 Various enzymes involved in muscle function.

18. Autosomal recessive LGMD
 This childhood form
 Affects both males and females
 First decade of life. In general
 The course is of gradual progression over years.
 Distribution of weakness is typically in the pelvis (80-90% of
cases)
 later in life, involvement of the shoulder girdle (30%)
 No hypertrophy of the calves (contrast to other forms of MD

19. Scapulo-humeral dystrophy (Erb)
 Involves mainly the upper extremities.
 Autosomal recessive in some cases.
 starts later in life (second to the fifth decades),
 “Benign” (years before it is diagnosed).
 Weakness generally is asymmetric: may spare the
deltoid, supra-spinatus, and infra-spinatus muscles.
 lower extremities involvement very late in life show
 The progression: very slow (normal life
expectancy).
 Minimal, disability

20.  autosomal-recessive disease
 Severe proximal weakness at birth (or within 6/12) Slowly
progressive or nonprogressive. Contractures are common
 central nervous system (CNS) abnormalities can occur.
 Biopsy: signs of dystrophy, a marked  in endomysial and
perimysial connective tissue, and fiber size variability with
small round & immature fibers, less commonly, necrosis
 No distinguishing features (as in congenital myopathies)
Congenital Muscular Dystrophy

21. Congenital Muscular Dystrophy
 The pathophysiology of CMD depend on specific
associated genetic defect (known with 4 of the
CMDs)
 Functions of the disrupted proteins: defined in 2:
– Deficiency of laminin-alpha2 (merosin), a skeletal
muscle extracellular matrix protein that binds the
dystrophin-associated glycoprotein complex (see Picture
1)
– Deficiency of integrin-alpha7 beta1, a skeletal muscle
membrane protein that binds laminin-2
 The pathophysiology of the other CMDs is unknown