Transcript Myopathies doc

MUSCLES DISORDERS
Definition:

Diseases involving the muscle fibers (myogenic)
 Unlike: neuronopathies: secondary to LMN
 Heterogenous etiology, genotype, phenotype…
Devastating evolution…
 No specific treatment for most of them

Myoblasts fusing to form large multi-nucleate
muscle cells
white = fast
(speed)
red = slow
(endurance)
How do the myosin heads coordinate
to slide the actin filament?

They move independently.
If so how do the individual myosin heads avoid
interfering with each other?

They move together like oars on a 8 oar rowing
shell, or the multiple oars of a Roman ship
ATP dependent Calcium pump = Ca++ ATPase pumps
calcium from the cytoplasm surrounding the sarcomers
back into sarcoplasmic reticulum
Common Features:
 Clinical:

Muscle weakness: main feature
Gower’s sign (proximaly dominating deficit)
Contractures
+/- severe: advanced stages
Pain: in inflamm. Disorders only
Atrophy (+/- pseudohypertrophy in X-linked)
Deformity: advanced disease
DTR: normal, diminished or absent
Tone: slightly or normal
Other systems may be involved
Common Features:
 Laboratory Investigations:
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CBC, LFT.. Normal
ESR: high in inflammatory only
U&E: abnormalities in some endocrinopathies and
periodic paralysis
C.K & aldolase: generaly: raised (normal in few
sittings: metabolic, endocrine…)
Lactic acid
Genetic study: location & type of chromozomal
abnormalities:
Common Features:
 Neurophysiology

NCS: normal
 EMG:
– Spontaneous activities +/- in inflammatory disorders
– Interferential tracing
– MUPs: 


small A
Short D
polyphsics
Common Features:
 Pathology

+/- Severe reduction in the muscle fibers
 Muscles fibers are replaced by fat orfibrosis
 Centralized nuclei
 Fibrosis
 + Inflammatory infiltrate in inflamm disorders
 Type / I type II
 Electron microscopy:
– abnormal mithochondries in mithochondriopathies
ETIOLOGY / CLASSIFICATION

Inherited myopathies
– Muscular dystrophies
– Congenital myopathies
– Inherited channelopathies
– Periodic paralysis
– Inherited metabolic myopathies
Disorders of glycolysis
Disorders of oxidative metabolism
Lipid myopathies
Mitochondrial myopathies

Acquired myopathies
Inflammatory myopathies
Acquired metabolic myopathies
Toxic myopathies
 Hereditary transmitted (Muscles
Dystrophies)

X- linked:
-Duchenne
-Becker
( cardiac involv..)
Emery-Dreifuss (+ severe cardiomyopathy)

Non-X linek:
Limb Girdle
Facio-scapulo-humoral
Scapulo-peroneal
Scapulo-humeral

….
Ocular-pharyngeal
 Inflammatory muscle
disorders :
Autoimmune:
Primary dysautoimmune or complicating systemic
diseases: SLE..
– Polymyositis
– Dermatomyositis
Paraneoplastic
Viral
Infective: toxoplasmosis,trichinosis..
Toxic & drug induced muscle disorders.
Muscle Dystrophies
Muscular Dystrophy
Duchenne/
Becker
Emery-Dreifuss,
Congenital
Limb-Girdle,
Distal Myopathy
2-6 years
Childhood to early teens,
infancy
Late childhood-middle
age
Life expectancy
Rarely beyond 20’s
varies
Middle age +
Inheritance
X-linked recessive
X-linked recessive,
autosomal dom & rec.
Autosomal dominant &
recessive
Dystrophin
Emerin, lamin, merosin,
etc.
Calpain-3, Dysferlin,
Caveolin-3, αsargoglycans, etc.
Onset
Muscle groups
affected
Genetic linkage
Source: www.mdausa.org
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
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
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.
Prevalence of

Affects one in 3500
to 5000 newborn
males

1/3 of these with
previous family
history

2/3 sporadic
(1)
DMD
Clinically: onset of DMD

Delayed developmental milestones

Loss of motor skills

Characteristic gait

Calf “hypertrophy” (pseudohypertrophy)

Clumsiness/frequent falls
Symptoms of DMD


Muscle weakness: Difficulty in walking/running
Difficulty climbing stairs or hills
&
 Difficulty in rising (Gower’s sign)
 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)
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
Dystrophin
connects the
myofibrils to a
complex of
proteins
in the muscle
cell membrane.
This in turn
connects to the
extracellular
matrix protein
laminin,
stabilizing the
membrane
Spectrin connects the actin cytoskeleton in Red
Blood Cells to the membrane
What is Utophin?

Utophin is a protein that acts the same as dystrophin
where the nerve cells meet muscular tissue.

Dystrophin and Utophin both help to protect
muscle tissue through wear and tear.

Dystrophin works as a shock absorber to the
muscles. Utophin does also
What is the connection between
Dystrophin and Utophin?
 Studies
done on mice showed that if there is
an abnormally high amount of Utophin in the
body, the symptoms of MD reverse.
Dystrophinopathies. Dystrophic muscle
Dystrophinopathies: dystrophin staining
Normal
dystrophin
Intermediate dystrophin
Becker MD
Duchenne dystrophy
Treatments for DMD
 To improve breathing:
– O2 therapy
– Ventilator
– Scoliosis surgery
– Tracheotomy
Treatments (cont.)

To improve mobility:
– Physical therapy
– Surgery on tight joints
– Prednisone
– Non-steroidal medications
– Wheelchair
Treatments (cont.)

To improve mobility:
– Physical therapy
– Surgery on tight joints
– Prednisone
– Non-steroidal medications
– Wheelchair
Advances in Gene Therapy

Researches have developed "minigenes,"
which carry instructions for a slightly
smaller version of dystrophin, that can fit
inside a virus

Researchers have also created the so-called
gutted virus, a virus that has had its own
genes removed so that it is carrying only the
dystrophin gene
Problems with Gene Therapy

Muscle tissue is large and relatively
impenetrable

Viruses might provoke the immune system
and cause the destruction of muscle fibers
with the new genes
Other MD
Limb Girdle MD
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

Molecular genetics revolutionized LGMD
classification
 Rrecent classification (clinical and molecular
characteristics)
– autosomal dominant (LGMD1)
– autosomal recessive (LGMD2)
– The list continues to expand
– Genetic linkages have been identified for 6 autosomal
dominant and 11 autosomal recessive LGMDs,
– Myofibrillar myopathies share several phenotypic
characteristics with the LGMDs.
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.

LGMD protein defects occur in several
pathways
proteins associated with the sarcolemma
proteins associated with the contractile
apparatus

Various enzymes involved in muscle function.
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
Autosomal recessive LGMD

CPK: elevated (2-3 times)

The inheritance pattern is strongly autosomal
recessive with consanguinity

Positive family history often is reported.

The abnormal gene is linked to chromosome arm
15q.
Pelvifemoral atrophy (Leyden-Mobius)

Most heterogeneous of all limb-girdle dystrophies.
 60-70% of cases are sporadic (few cases: familial)
 Symmetric or asymmetric involvement of the pelvic
girdle.
 Late onset : second to sixth decades.
 Slow progression  clinical arrest (ambulate into 70s)
 The survival rate: seventh decade of life.
 CPK: vary from normal to significant elevation.
 No identified gene yet.
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
Late-onset autosomal myopathy

Third to the fifth decades of life.

The course is benign

Upper & lower extremity weakness :little functional
impairment.

Patients: ambulate well into their 6th and 7th decade

Affects males and females.
Oculopharyngeal

Late onset

Ocular and bulbar symptoms

Slowly progressing
Congenital Muscular Dystrophy

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

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
Muscular dystrophy
Congenital
Limb girdle
Duchenne, Becker
Emery-Dreifuss
Dysferlinopathies

Distal myopathy : Miyoshi (1967, 1986)
– Locus 2p13.3
– DYSF gene mutation (Bashir et al ; Liu et al, 1998)

Type 2B limb girdle myopathy:
– Firstly described in Palestinian families (Mahjneh et al,
1992)
– Chromosome 2p linked (Bashir et al, 1994)

Both MM and LGMD phenotype in the same family

(Illiaroshkin et al ; Weiler et al, 1996)

Distal myopathy : Miyoshi (1967, 1986)
– Locus 2p13.3
– DYSF gene mutation
(Bashir et al ; Liu et al, 1998)

Type 2B limb girdle myopathy:
– Firstly described in Palestinian families
(Mahjneh et al, 1992)
– Chromosome 2p linked
(Bashir et al, 1994)

Both MM and LGMD phenotype in the
same family
(Illiaroshkin et al ; Weiler et al, 1996)
Dysferlinopathies: Epidemiology

Geographical distribution
 MM identified in Japan
 LGMD (Palestinian, Lybian Jews)

Dysferlin mutation 1/3000 Lybian Jews (Argov et
al, 2000)
 Most frequent distal myopathy (except Scandinavia)
 LGMD2B= second cause of LGMD (Tagawa et al)
 Dysferlinopathies : about 25% of unindentified
muscular dystrophy
Dysferlin is located to muscle cell membranes, and is
missing in patients with severe limb girdle muscular
dystrophy
Model
for the
function
of
Dysferlin
in
muscle
repair
Dysferlinopathies: Common traits
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AR inheritance
Normal developmental milestones, sport possible prior to
first symptoms
Onset between 15 – 35 y (young adults)
LL : distal, proximo-distal, or proximal wk calf involvment
++
UL : biceps atrophy, moderate scapular involvment
Facial, bulbar muscles = spared
Normal cardiac and respiratory function
CK
(10 to 123 N)
Unspecific myopathic pattern, necrosis, no vacuoles
Various severity

Distal myopathy
– Posterior leg (Miyoshi myopathy)
– Anterior leg compartment

Proximal myopathy « limb girdle » (LGMD2B)

High CPK

Polymyositis-like

Exercise intolerance
Dysferlin
Myotonic Dystrophy

Myotonic dystrophy
 Autosommal dominant disorder with highly variable
expression of the disease phenotype
 The molecular abnormality is an expansion of a
CTG nucleic acid triplet repeat sequence on the
nineteenth chromosome
 The muscle weakness can be mild
 Marked facial weakness, ptosis
 Greater distal weakness

Difficulty in releasing hand grip. At the bedside,
myotonia

Frontal balding: usually more prominent in men

Premature cataracts, arrhythmias, diabetes, and
testicular atrophy

Myotonia can be a disturbing symptom or does not

In disabling myotonia, quinine, Phenytoin, henytoin

Mexiletine should not be used if cardiac manifestations
Myotonic dystrophy

Type 1 (most common, 98%)
– an expansion of CTG repeats in the DMPK gene on
chromosome 19
– Prevalence in West: 13.5 per 100,000

Type 2
– an expansion of CCTG repeats in the ZNF9 gene on
chromosome 3

Type 3 ?
Inflammatory Myopathies


Age: young/adult
+/- Skin rash
Main feature: weakness + Muscle pain
+tenderness
Investigations
High C.K.
EMG
Muscle biopsy
Diagnosis:
 Treatment Immune suppressive = steroids
FSH
Errance diagnostique
BMD
Maladie hépatique
Myopathie
métabolique
CMT
Polymyosite
0
2
4
6
8
10
Nombre de patients
12
14
16
Metabolic myopathies
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Thyroid disease
Hypothyroid or hyperthyroid
ophthalmopathy
periodic paralysis
Pituitary and adrenal disease
Cushing's syndrome
Steroid myopathy
Adrenal insufficiency
Primary hyperaldosteronism
Acromegaly
Hyperparathyroidism Hypoparathyroidism
MYASTHENIA GRAVIS
MYASTHENIA GRAVIS
DEFINITION: Disorder of the NMJ (postsynaptic membr)
Forms:

Transient neonatal (~10% of neonate myasthenic mothers)
– Different prognosis, effective treatment

Congenital myasthenia
 Common myasthenia gravis
– Any age: 2 pics: 20-30 (F > M) & 60-70 M > F)
– Usually progressing (remission are possible but: relapse later)
MYASTHENIA GRAVIS
CLINICAL FEATURES
Onset: insidious
Fluctuating weakness:  with exercise
Fatigability (worsening with exercise & improvement in rest)
Precipitating factors: Infection, Pregnancy, stress, hot
temperature, drugs: muscle relaxants, BZDZ,phenytoin
antibiotics (neomycin)
Clinical presentation:
Ocular: – ptosis, diplopia opthalmoplegia
Bulbar: dysphagia, dysphonia, +/-facial weakness
Generalized: +/-respiratory muscles weakness  risk of
death
MYASTHENIA GRAVIS
Clsassification: Osserman classification
I ocular
II (A & B):
mild to moderate generalised, ++/- drug
response, no crises
III Acute fulminant + crises, risk of death, high mortality
IV late severe MG
Associated disorder:Dysthyroidism
Rh. Arthritis, P. anaemia, SLE
The Spectrum of autoimmune Diseases
Organ specific
Systemic
Hashimoto’s thyroiditis
Pernicious anaemia
Insulin dependent diabetes
Myasthenia gravis
Multiple sclerosis
Ulcerative colitis
Rheumatoid arthritis
Systemic lupus erythematous
PATHOPHYSIOLOGY

Neuromuscular junction transmission autoimmune
disorder (Post synaptic membrane)

Destruction of the Ach. receptors on the post
synaptic membrane by the AB  insufficient muscle
fibers contraction

Ach.receptor Anti-bodies:
– circulating: level can be done
– Origine: thymus (hyperplasia, thymoma)

association of HLA, A1 + B8.
Tr
B cell
IL-6, etc
Cytokines
Auto reactive
T cell
Genetically
predisposed
Tissue damage
Cytokines
CD8
 Diagnosis

Clinical presentation, excrcise test, rest test
 Tensilon Test: 10 mg Edrophonium IV carrefullty &
slowly
 Investigations
 Investigations

Laboratory Investigations.
– Acetycholine receptor antibodies level
– Straited muscle AB, other antibodies

Neurophsiology
– EMG: decrement test

Imaging: Chest x-ray and chest CT scan / MRI

Others: PFT…..
MANAGEMENT
 Medical treatment
Anticholinesterase
Immunosupressant:
 Plasmaphoresis
 Immunoglobulins
 Surgery: Thymectomy
Steroids
Azathioprin
Prognosis

Remission ~ 30 %.
– More likely in patient with short history
– Less in prominent thymic hyperplasia/thymoma

Approach through suprasternal or transsternal
– (extensive, large thymectomy)

Medical treatment:
may be D/C, need for low doses, same doses
or worsening + other ttt
Myasthenic crises

Severe situation
 Needs urgent management
 Diferentiate from cholinergic crises
Myasthenic syndrome

Clinically: differences
 Pathophysiology: presynaptic membrane
 Neurophsiology: increament
 Poor response to Anti Ch-esterase
 Etiology: paraneoplastic