MYASTHENIA GRAVIS
Neuromuscular junction disorder
An autoimmune diseases caused by
autoantibodies.
Target is neuromuscular junction with
fluctuating muscle weakness.
 Inherited
o Dystrophinopathies
1. Duchenne Muscular
Dystrophy, DMD
2. Becker Muscular
Dystrophy, BMD
 Acquired
o Inflammatory Myopathies
1. Polymyositis
2. Dermatomyositis
3. Inclusion body
myositis
AETIOLOGY
Autoantibodies block the function of
postsynaptic acetylcholine receptors at
motor end plates.
Results in degradation and depletion of
the receptors.
30 percent of patient, young, have
thymic hyperplasia meanwhile 10 percent
of patients have thymoma.
These thymic lesions may perturb
tolerance to self-antigens, thereby
setting the stage for the generation of
autoreactive T and B cells.
Thymic abnormalities are usually absent in
cases of MG that occur in
Older patients or that are not
associated with anti-acetylcholine
receptor autoantibodies.
Other pathogenic Antibodies:
 Muscle specific kinase, MuSK
 Low density lipoprotein receptor
related protein, LRP4
PATHOGENESIS
Antibody; anti acetylcholine receptor,
AChR antibodies blocks the receptor and
degrade the receptors at the
postsynaptic membrane and induce
damage by complement fixation. Net
result; depleted of acetylcholine
receptors and postsynaptic membrane
alteration in morphology.
 Sudden onset of the disorder
 In early stage, patient may feel
fine in the morning  develops
diplopia and speech slurs later in
the day.
 Always begins with ocular muscle
weakness
 Muscle weakness degree varies
greatly among individuals.
 Muscle weakness severity
fluctuates dramatically; sometimes
over only few minute periods.
 Hallmark; repetitive use of muscles
makes the weakness more severe
(diagnostically useful)

After 30-60s reading aloud
facial weakness; inability to
hold the mouth closed;
‘hanging jaw sign’
 Myasthenia-Fatigue Recovery Test
‘Simpson plus’
 Upward gaze test
 Antibody test:
 Anti-acetylcholine receptor
(Ach R) antibodies
 ice pack test
 Diplopia and ptosis due to
extraocular muscle involvement;
common
 Fascial weakness; inability to hold
the mouth closed  hanging jaw
sign
 can be unilateral or
bilateral.
 Myasthenic crisis:
 Complication of myasthenia
gravis characterized by
worsening of muscle
weakness resulting in
respiratory failure.
 Long-term immunomodulatory
therapy:
 Steroid use may cause or
aggravate osteoporosis,
cataracts, hyperglycemia,
weight gain, avascular
necrosis pf hip,
hypertension, opportunistic
infection and other
complications, gastritis or
peptic ulcer disease.
1. INHERITED
 Dystrophinopathies
 Duchenne Muscular
Dystrophy (DMD)
 Becker Muscular
Dystrophy (BMD)
2. ACQUIRED
 Inflammatory Myopathies
 Polymyositis
 Dermatomyositis
 Inclusion body
myositis
o Links the cytoskeleton
actin to the extracellular
matrix.
o Dystrophin provides
mechanical stability to the
myofibril and its cell
membrane during muscle
contraction.
o Involve in signaling
pathways; interacts with
nitric oxide synthase, which
generates NO.
DYSTROPHINOPATHIES
x-linked recessive disease
DMD is more common than BMD.
Aetiology: dystrophin gene mutations
Gene;
 Located on the short arm of X
chromosome, Xp21
 One of the largest human genes,
hence vulnerability to sporadic
mutations.
 Most common mutations are
deletion, point mutations.
Protein;
 Found in skeletal, cardiac muscle,
brain and peripheral nerves.
 Part of dystrophin-glycoprotein
complex, DGC
o Large multi-protein
complex consists of
dystrophin and other
proteins; dystroglycans,
sarcoglycans, syntrophins,
dystrobrevins.
Pathogenesis
Mutations in the dystrophin gene on the
X chromosome causing defect in DGC.
Results in;
 Transient membrane tear
o Constant Calcium influx;
activate proteases
increased on going
myofibril damage and
necrosis.
o Regenerated myofibril
either damaged again or
replaced by fibrosis and
fat.
o Hence, produce muscle
weakness and
pseudohyperthropy.
Enlargement of the muscles of the lower
leg associated with weakness, termed
pseudohyperthropy.
Severity of the disease correlates with
the degree of the dystrophin deficiency.
Investigation
Serum Creatine Kinase level; high
Muscle biopsy; fibrosis, adipocytes,
dystrophin in muscle cells.
Clinical Features
Duchenne;
Walking is often delayed.
The first indications of muscle weakness
are clumsiness and inability to keep up
with peers.
Weakness begins in the pelvic girdle
muscles.
Extends to the shoulder girdle.
Mutations in Duchenne dystrophy result in
severe absence of dystrophin.
Mutations in Becker dystrophy result in
production of abnormal truncated
dystrophin.
 Disrupt intracellular signaling,
reduced NO.
o Damaged and necrosis of
myofibril
o Muscle replaced by fibrosis
and fat.
o Muscle weakness and
pseudohyperthropy.
Normal at birth; very early motor
milestones are met
Why DMD is more severe than BMD?
INCIDENCE
DMD
More
common
Early
BMD
Less
common
Late
ONSET
AGE OF ONSET,
2-5
8-10
Y/O
AMBULATION,
Till 9-11 Beyond 15
AGE
CONTRACTURES
Early
Later
INTELLIGENCE Subnormal Normal
LIFE SPAN
Shorter Normal
Electromyography; shows weakness is
caused by muscle destruction rather than
by nerves damage.
Genetic testing; looks for mutation of
the dystrophin gene.
Complications
DMD;
 Contracture, scoliosis, respiratory
insufficiency, pneumonia, cardia
decompensation.
BMD; Cardiac failure
ACQUIRED; Inflammatory of Myopathies
Polymyositis
Aetiology
Autoimmune disorder
Pathogenesis
Increased expression of MHC class I
molecules on myofibrils and
predominantly endomysia inflammatory
infiltrates containing CD8 and cytotoxic T
cells and leads to myofibril necrosis and
subsequent.
Clinical manifestation
Weakness affects many different muscle
in the body, especially the shoulder, hips
and thigh muscle, but there is no skin
rash.
Dermatomyositis
Aetiology
Believed to have an autoimmune basis.
Pathogenesis
Type 1 interferon-induced gene products
are strongly upregulated in affected
muscles.
Some patients have autoantibodies that
are relatively specific for
dermatomyosities; these include
antibodies against Mi-2, a nuclear helicase
and p155 and p140, proteins with
uncertain functions.
Clinical manifestation
Affect the joints, esophagus, lungs and
less commonly, the heart.
Produce skin rash.
Inclusion Body Myositis
Aetiology
Degenerative process with secondary
inflammatory changes, unclear causes
Pathogenesis
Aggregates of the same proteins that
accumulate in the brains of patients with
neurodegenerative diseases;
hyperphosphorylated, amyloid derived
from b-amyloid precursor protein and
TDP-43; lead to some speculate
degenerative disorder of aging.
Clinical manifestation
Progressive muscle weakness; quadriceps,
distal upper extremity muscles and
dysphagia.
Complications
Aspiration pneumonia
Hypoventilation
Interstitial lung disease, ILD
Dysphagia