Ali Al Khader MD Faculty of Medicine AlBalqa Applied University Email alialkhaderbauedujo Lecture outline Skeletal muscle atrophy Inflammatory myopathies D ermatomyositis Polymyositis ID: 921204
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Slide1
Diseases of skeletal muscle
Ali Al Khader, M.D.
Faculty of Medicine
Al-Balqa’ Applied University
Email: ali.alkhader@bau.edu.jo
Slide2Lecture outline
Skeletal muscle atrophy
Inflammatory myopathies:
-
D
ermatomyositis
Polymyositis
Inclusion body myositis
Muscular dystrophies:
Duchenne muscular dystrophy
Becker muscular dystrophy
Slide3Skeletal muscle atrophy
…a common
feature of
many
disordersCauses:-Loss of innervation (neurogenic injury)-Disuse-Cachexia-Old age-Primary myopathies (inflammatory or others)
Certain patterns
of atrophy are suggestive of specific
underlying etiologies:
-Cluster/Group atrophy
…neurogenic disease…see next slide
-Perifascicular atrophy
…dermatomyositis
-Type II fiber atrophy
…corticosteroids and disuse
Slide4normal
checkerboard
appearance (enzyme stain)
In a normal muscle, some of the fibers are of type 1 and others are of type 2…each neuron gives branches to a group of fibers of the same type (for example: the fibers supplied by neuron X must be of type 1, while those supplied by neuron Y must be of type 2)
*neuron + its branches + fibers supplied by its branches =
motor unit
neuron
If denervation occurs,
group atrophy
is the result
This is called:
type grouping
…as you see, the type of fibers is converted now according to which neuron is now supplying
Cluster/Group atrophy
Elsevier. Kumar et al. Robbins and
Cotran
pathologic basis of diseases
9
th…modified
Slide5Perifascicular atrophy
Normally:
…note the presence of lymphocytes…this is a case of dermatomyositis
Check
http
://
people.eku.edu/ritchisong/301notes3.htm
for references
Check
https
://
www.studyblue.com/notes/note/n/pathology-pictures/deck/6713881
for references...modified
Slide6Inflammatory myopathiesDermatomyositis
A systemic autoimmune disease
Proximal myopathy + skin manifestations
The
most common
inflammatory myopathy in childrenIn 15-24% of adult cases, it is associated with malignancy and manifests as a paraneoplastic disorder
T
ypically associated with
skin
manifestations
M
ay
have systemic manifestations such as interstitial lung disease
Prognosis in adults is worse than in childrenBecause there is damage in the muscle here (myopathy), we will find the following:
-Elevated serum creatine kinase-EMG (electromyography) will show: myopathic
changes
Slide7Dermatomyositis, pathogenesisAutoimmune damage to small blood vessels contributes to
muscle injury
As
with some other autoimmune diseases such as
SLE,
type 1 interferon-induced gene products are strongly upregulated in affected muscles…this signal increases with disease activitySome patients have autoantibodies that are relatively specific for dermatomyositis; these include antibodies against Mi-2 (a nuclear helicase), anti-Jo1 and anti-p155 and
anti-p140
…role in disease not proven yet
Slide8Dermatomyositis, morphology in the affected musclePerivascular & perimysial
mononuclear
cell infiltrates with plasma
cells
“Dropout” of capillaries
The presence of so-called “tubuloreticular inclusions” in endothelial and inflammatory cells…an ultrastructural featureMyofiber damage in a perifascicular patternFibrosis and fat replacement may occur late
Slide9Dermatomyositis, clinical picture
Slowly progressive muscle
weakness
and muscle pain…Which muscles??
Telangiectasias
(dilated capillary loops) in the nail folds, eyelids, and gums…because this disease is mainly caused by small vessel damageGottron papules (scaly eruptions rash on the knuckles, elbows or knees) & heliotrope rash (blue-purple discoloration around the eyes along with swelling, mainly
upper eyelids)…anti-Mi2 antibodies are especially associated with these features and can be detected in blood
Other rashes: mechanic’s hand (rough, crackled
skin at tips and lateral aspects of the fingers
resulting
in irregular, dirty
appearing lines
), V neck sign (above breasts) & Shawl sign (upper back)Also interstitial lung disease, arthritis, dysphagia & cardiac involvement can occurRaynaud phenomenon also may accompany the disease…What is Raynaud
phen.??
Elsevier. Kumar et al. Robbins and
Cotran
pathologic basis of diseases
9
th…modified…
(Courtesy Dr. Dennis Burns, Department of Pathology, University of Texas Southwestern Medical School,
Dallas, Texas.)
Check
http
://
www.odermatol.com/odermatology/22013doi/ourd.20132.38.pdf
for references
Check
https
://
medsynapses.blogspot.com/2017/02/dermatomyositis.html
for references
Slide10Inflammatory myopathiesPolymyositis
An
adult-onset inflammatory
myopathy that
shares
myalgia, weakness and other manifestations of dermatomyositis but lacks its distinctive cutaneous featuresAs in dermatomyositis, patients typically develop symmetric proximal muscle involvement…autoantibodies similar to those of dermatomyositis may also be present
…manifestation such as lung & heart involvement, Raynaud phenomenon and
dysphagia may also be present
Also has an immunologic basis
Unlike dermatomyositis, vascular injury is not believed
to have
a major role in polymyositis
Slide11Mononuclear inflammatory cell infiltrates are present, but in contrast to dermatomyositis, these are usually endomysial
in location
Degenerating necrotic, regenerating, and atrophic
myofibers
typically found in a random or patchy distributionThe perifascicular pattern of atrophy that is characteristic of dermatomyositis is absentFibrosis and fat replacement may occur late
Polymyositis, morphology
Slide12A disease of late adulthood that typically affects patients older than 50 years The
most common inflammatory myopathy in
patients older
than age 65
years
Slowly progressive muscle weakness that tends to be most severe in the quadriceps and the distal upper extremity musclesDysphagia from esophageal and pharyngeal muscle involvement is not uncommonInflammatory myopathies
Inclusion body myositis
The morphologic
hallmark is
the presence of
rimmed vacuoles
…these contain
aggregates
of
hyperphosphorylated
tau, Aβ-amyloid, TDP-43 & ubiquitin
It does
not respond well
to immunosuppressive agents
, a
feature suggesting that inflammation
is a
secondary
event
Laboratory studies
usually show modestly elevated
creatine
kinase levels
Most
myositis-associated autoantibodies are
absent…However, antibody
to cN1A has recently been described
These are cytoplasmic inclusions
Slide13Muscular dystrophies (in general)S
everal
inherited
disorders of
skeletal muscle that have in common
progressive muscle damage that typically manifests itself between childhood and adulthoodWith the exception of congenital muscular dystrophies, these diseases do not present in infancyWe will discuss the X-linked muscular dystrophies with
dystrophin mutation (mainly Duchenne
and Becker Muscular
Dystrophy)
Slide14Duchenne and Becker Muscular Dystrophy
(
X-Linked Muscular Dystrophy with Dystrophin
Mutation)
The most common muscular
dystrophiesMutations that disrupt the function of a large structural protein called dystrophinSometimes referred to as
dystrophinopathies
The most
common early onset form is referred to as
Duchenne muscular dystrophy
Becker muscular
dystrophy is a second relatively common
dystrophinopathy
that is characterized by later disease onset and a milder phenotypeAs with many X-linked diseases, female carriers of dystrophin mutations may
be mildly symptomatic due to unfavorable X-chromosome inactivation
Slide15Duchenne and Becker Muscular Dystrophy, pathogenesis
L
oss-of-function
mutations in the
dystrophin gene
on the X chromosomeDystrophin, is a key component of the dystrophin glycoprotein complex (DGC)Dystrophin is thought to provide
mechanical stability to the
myofiber
and its
cell membrane
during muscle
contraction
…it also has a role in signal transduction
Many mutations, so variable phenotypes (Duchenne, Becker, other dystrophinopathies)Mutations in Duchenne are more severe (deletions, frame shift mutations)
DGC
Elsevier. Kumar et al. Robbins and
Cotran
pathologic basis of diseases
9
th…modified
Slide16Duchenne and Becker Muscular Dystrophy, morphology
Changes are similar, but more pronounced in Duchenne
Degenerating necrotic, regenerating, and atrophic
myofibers
,
usually no inflammation except for the presence of myophagocytosisBoth are marked by chronic muscle damage that outpaces the capacity for repair…so: fibrosis and fatty replacementImmunohistochemical studies for dystrophin
show absence of the normal
sarcolemmal
(= membrane of muscle fiber) staining
pattern in Duchenne muscular
dystrophy and reduced
staining in Becker muscular dystrophy
normal
abnormal
Elsevier. Kumar et al. Robbins and
Cotran
pathologic basis of diseases
9
th…modified
Slide17Duchenne muscular dystrophy, clinical course
Normal at birth
Walking is often delayed
The
first indications
of muscle weakness are clumsiness and inability to keep up with peersWeakness begins in the pelvic girdle muscles and then extends to the shoulder girdle
Enlargement of the
muscles of the lower leg associated with
weakness, termed
pseudohypertrophy
, is often
present
The
mean age of wheel chair dependence is around 9.5 yearsWorsening respiratory reserve, and sleep hypoventilationHeart (cardiomyopathy and arrhythmias, particulary in
older patients) & CNS (may cause mental retardation) are also affectedThe mean age of death for patients with Duchenne muscular dystrophy is 25 to 30 years of age…due to resp. failure, pulmonary infections or heart failure
Slide18Becker muscular dystrophy, clinical course
Presents
in later childhood,
adolescence or
adult
lifeIts course is more slowly progressiveOften with a near normal life expectancy
Slide19Duchenne and Becker Muscular Dystrophy, lab investigations
Serum
creatine
kinase is
markedly elevated
during the first decade of life due to ongoing muscle damage …then falls as the disease progresses and muscle mass is lostThe presence of a dystrophin mutation can be confirmed by genetic studies
Slide20Positive Gower sign in Duchenne and Becker muscular dystrophy
…due to proximal lower limb muscle weakness
…not only in Duchenne & Becker
It describes
a patient that has to use
his
hands and arms to "walk" up
his
own body from a
squatting position
Slide21Thank You