Diseases of skeletal muscle - PowerPoint Presentation

Slide1

Diseases of skeletal muscle

Ali Al Khader, M.D.

Faculty of Medicine

Al-Balqa’ Applied University

Email: ali.alkhader@bau.edu.jo

Lecture outline

Skeletal muscle atrophy

Inflammatory myopathies:

-

D

ermatomyositis

Polymyositis

Inclusion body myositis

Muscular dystrophies:

Duchenne muscular dystrophy

Becker muscular dystrophy

Skeletal 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

normal

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

Perifascicular 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

Inflammatory 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

Dermatomyositis, 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

Dermatomyositis, 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

Dermatomyositis, 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

Inflammatory 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

Mononuclear 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

A 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

Muscular 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)

Duchenne 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

Duchenne 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

Duchenne 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

Duchenne 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

Becker muscular dystrophy, clinical course

Presents

in later childhood,

adolescence or

adult

lifeIts course is more slowly progressiveOften with a near normal life expectancy

Duchenne 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

Positive 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

Thank You