Muscular dystrophy, a gene linked disorder

1. Muscular Dystrophies
• Progressive hereditary degenerative diseases of
the skeletal muscle
• Intact spinal motor neurons, muscular nerves, and
nerve endings in the presence of severe
degenerative changes in muscle fibers
• General features:
– symmetrical distribution of weakness and atrophy
– intact sensation
– preservation of reflexes
– heredofamilial
• Classified by clinical types, pattern of inheritance
and by the abnormal gene or it’s protein product

2. Etiology
• The abnormal gene and the gene product for Duchenne and
Becker identified by Kunkel in 1986
• Dystrophin is the protein encoded by the affected gene
• Dystrophin absent in Duchenne and structurally abnormal
in Becker
• Dystrophin in normal skeletal and cardiac muscle is
localized in the sarcolemma (cytoplasmic site) and
interacts with F-actin of the cytoskeleton (reinforcing
structure of muscle cell)
• Dystrophin also bound to a complex of sarcolemmal
proteins known as dystrophin associated proteins (DAP)

3. Etiology
• Loss of dystrophin leads to disruption of the
dystroglycan-protein complex rendering the
sarcolemma susceptible to breaks during
contraction
• These defects are shown to allow ingress of
EC fluid and calcium which activate
proteases and cause protein degradation
• Leakage of CK into serum is then seen

5. Duchenne MD
• Incidence rate 13-33 per 100,000 male
births annually
• X-linked recessive
• 30% of cases represent new mutations
• Females can present disease if only one
chromosome is present (Turner) or due to
inactivation of the normal paternal X
chromosome in large proportion of
embryonic cells (decreased expression of
the normal dystrophin allele)

6. Clinical findings
• Recognized usually in third year of life due
to delay in motor milestones or due to
frequent falls
• Latter sway back and waddling gait (weak
gluteus medius) as well as climbing stairs
become more affected
• Elevated CK may be the first clue

7. Clinical findings
• Muscles mostly affected
– early: illiopsoas, quadriceps, gluteal
– latter: pretibial, pectoral girdle (serratus,
pectorals, latissimus) and upper limbs (biceps,
brachioradialis)
• Muscles pseudo-hypertrophied
– gastronemius, lateral vastus and deltoid
– have rubbery feel and are less strong and
hypotonic than normals

8. Clinical findings
• Weakness of abdominal and paravertebral
muscles - lordotic posture and protuberant
abdomen when standing and rounded back
when sitting
• Weak extensors of the knee and hip -
difficult to climb stairs or from a chair
• Use of hands to compensate for weakness
when rising from sitting position or from
floor

10. Gower’s maneuver
• 4 point position
• Hands up to thigh
alternately

11. Clinical Findings
• Contractures contribute to eventual loss of
ambulation
• Scoliosis appears due to unequal weakening of
paravertebral muscles usually after walking is not
possible
• As muscle atrophy progresses DTR’s are lost
• Bones are thin and demineralized
• Can have mild mental retardation
• Although smooth muscle is usually spared heart is
usually affected

12. Clinical Findings
• Cardiac problems:
– Arrhythmias
– prominent R waves in right precordial leads and deep Q
waves in left precordial and limb leads as result of
replacement fibrosis of the basal part of the left
ventricular wall
• Death is usually 2dary to pulmonary infection and
respiratory failure or in some due to cardiac
decompensation
• No more than 25% of patients survive beyond 25
years

14. Becker Muscular Dystrophy
• Incidence estimated to be 3-6 per 100,000 male births
• X-linked disorder
• Later onset than Duchenne (mean age 12 years but range
5-45 y/o)
• Affects same muscles as Duchenne’s MD
• Patient non-ambulatory at 25-30 y/o
• Death in 5th decade in most
• Less frequent cardiac involvement
• Serum CK 25-200 times normal
• EMG: fibrillations, positive waves, low amplitude
polyphasic MUP

15. Facioscapulohumeral MD
• Slowly progressive or nearly complete arrest
• Usually autosomal dominant 4 q35
• Subvariety w/o facial weakness
• Onset usually 6-20 y/o
• Difficulty raising arms above head and winging of
the scapulae first manifestations
• Invariably weakness of lower trapezius and sternal
part of pectoralis
• Deltoids unusually large and strong
• Weak orbicularis oculi and oris, zygomaticus

16. Facioscapulohumeral MD
• Eventually atrophy involves sternomastoid,
serratus, rhomboid, erector spinae, latissimus and
deltoids
• Winged and elevated scapulae, prominent
clavicles
• Popeye arm: upper arm thinner than forearm
• Pelvic muscles involved later and milder
• Can be asymmetrical
• CPK can be normal or mildly elevated
• Rare cardiac involvement

17. Scapular winging
• Weak (serratus, lower
trapezius, rhomboids)
stabilizers of scapula
cause winging
• Scapular angles can be
seen when facing the
patient

18. Facioscapulohumeral MD
• Foot drop might be seen
• Early in the disease weakness can be
asymmetrical
• Rare cardiac involvement
• CPK normal or slightly elevated

20. Scapuloperoneal MD
• Autosomal dominant, Chromosome 12
• Typically involves muscles of the neck, shoulder,
upper arms, anterior tibial and peroneal groups
• Onset usually in early or middle adulthood
• Walking becomes difficult due to foot drop
• Symptoms in arms and shoulders usually seen
later
• Progression slow in most cases

22. Limb-girdle MD
• Heterogeneous group
• Children of both sexes affected
• No hypertrophy (besides SCARMD)
• Adults can have weakness in either pelvic or shoulder
girdle or both, if later onset more benign course
• Most commonly heredited as autosomal recessive
(2A-2J),
• Also AD (1A-1E) forms, AD good prognosis
• EMG myopathic, CK normal or only moderately
elevated, cardiac involvement infrequent

23. AD Limb Girdle Dystrophies
• LGMD 1
• Onset is varied from 4-38 years
• CPK is slightly or moderately increased
• Can have flexion contractures of elbows, ankles,
and IPJ but non-disabling
• Slow progression with long periods of arrest
• Normal longevity
• Some with facial and cardiac involvement
• Includes defects in proteins located in myofibril,
cell membrane and EC (collagen proteins)

24. AR Limb Girdle Dystrophies
• LGMD 2
• Affects males and females equally
• Shoulder and pelvic girdles affected
• Defects in proteins located on cell membranes but
also on myofibril+nucleus (calpain 3)
• SCARMD (2C-2F)- clinically similar to DMB,
from 3-12 y/o onset, CPK 10-100 times normal,
hypertrophy and joint contractures, rare cardio
involvement
• Some have involvement of distal lower extremities
(dysferlinopathy)

27. Emery- Dreifuss Muscular
Dystrophy
• X-linked, chromosome Xq28 -emerin
• Age of onset: childhood- adulthood
• Weakness first upper arm and pectoral girdle; later pelvic
girdle and distal muscles in Lexts
• Early appearance of contractures in elbow flexors,
extensors of the neck and posterior calf muscles
• No pseudohypertrophy
• Usually accompanied by severe cardiomyopathy with
variable s/a and a/v conduction defects
• Death secondary to cardiac problems although general
course is benign in most

29. Oculopharyngeal Dystrophy
• Autosomal dominant; chr 14q11.2-14q13
• Usually late onset (after 45th y/o)
• Bilateral ptosis and dysphagia noticed as
progressive difficulty in swallowing and
change in voice, can progress to cachexia
• External ocular muscles, shoulder and
pelvic muscles can later become weak
• CK and aldolase might be normal
• EMG only altered in the affected muscle

30. LGMD