Skeletal muscle diseases
a. The muscular dystrophies.
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- Describe their pathogenesis.
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- Describe their morphology.
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- Discuss their clinical picture and management.
b. The disease of neuromuscular junctions- MG
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- Describe their pathogenesis.
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- Discuss their morphology.
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- Discuss the clinical picture and management.
• Reference: Robbins Basic Pathology, 8th edition (pages 827 – 830).
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Diseases of Muscles
• What are the differences between the disease of
Muscular Dystrophy and Myopathy? Are they related or
totally separate diseases?
• Myopathies: disorders with structural changes or functional
impairment of the muscle “Weakness”. Not include U\L
motor neuron lesion or MG. Include many types e.g.: MD.
• Types:-Inflammatory, Congenital, Metabolic, Endocrine,
Hereditary, Toxic\drug
• Dystrophy: mean progressive loss of muscles(any types
of muscles) ( 1-in 8,000 people)
• Myopathy versus Neruogenic?
• Myopathy= ( Bilateral & symmetrical),
Neurogenic= (Asymmetric).
A- The muscular dystrophies- Definition
• Muscular dystrophy (MD) is a heterogeneous groups of familial
inherited muscle disorders, each with unique phentotyic & genetic
features lead to degeneration of skeletal muscle fibers.
• MD recognized by progressive muscle weakness and muscle wasting.
(generalized or localized).
• Age: started in infancy or childhood, other appear later middle age
• Affected sites: different Skeletal muscles groups, others may involve.
• Limitation:
• Difficulties with walking or Maintaining posture, Muscle spasms.
Neurological, Behavioral, Cardiac, other Functional limitations.
Who Discovered Muscular Dystrophy
• Each diseases of (muscular dystrophy) was discovered
by different person. > 43 types.
• Muscular Dystrophy “MD” types:
• common
• 1- X-linked MD “Duchene MD”
• 2- Becker Muscular dystrophy.
• 3- Myotonic Dystrophy “ syndrome”
• Less common
- 4- Fascioscapulohumeral muscular dystrophy;-Autosomal dominant
- 5- Oculopharyngeal muscular dystrophy;--autosomal dominant, - 6- Congenital muscular dystrophies;- autosomal recessive
Duchene’s Muscular dystrophy (DMD)
• Is most commonest and most fatal (x-linked recessive), non-
inflammatory muscular myopathy in children-boys.
• Etiology -
caused by mutation in the dystrophin gene
“X-linked inherited” (Deletion of DNA segment or single gene
defect in short X- chromosome) deficiency of muscle protein
dystrophin fragility
• Prevalence: range 1- 3,000 to 1 – 3,500 boys. (all over the world)
• Risk Because these are inherited disorders, risk include a family
history of muscular dystrophy.
• Clinical features; progressive-Proximal weakness
• Presented at birth and become evident at 3 – 5 years-Boys
• Gower’s maneuver- positive, lordosis, poor balance cont.
• Joint contraction, scoliosis, decreased pulmonary function.
(DMD, BMD) Pathogenesis
• DYSTROPHIN- encode by DNA for  anchor & interact
all cells membrane protein support the whole
membrane structure and connection between inside of
the cell to outside.
• DMD - Caused by mutation in the dystrophin gene
“X-linked inherited” (Deletion of DNA segment or
single gene defect in short X- chromosome)
deficiency of muscle protein dystrophin or
Production of bad dystrophin (with no function)
Protein damage + membrane gaps increase+ calcium
influx  necrosis (Dystrophy)
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Bekers Muscular Dystrophy- same like DMD but less
severe and slow progression
Duchene’s Muscular dystrophy (DMD)
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Investigations;
• Blood CK levels- raised, EMG- Reduced amplitude,
• Muscle biopsy: Small groups of necrotic muscle fibers, regeneration,
replaced by fat& fibrous stroma.
• Abnormal Sacromere structure
• Dystrophin protein deficiency demonstrated by special stain.
• Molecular application for assessment of gene mutation
• Management:
• No treatment , Mainly supportive therapy ( Physiotherapy, physical
therapy).
• Steroid- prednisolone : significantly slow the disease progression.
• https://www.youtube.com/watch?v=KA8W5UfE4ts
MMD- Clinical features
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MDM-Clinical features
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Backer ‘s muscular dystrophy- BMS
X-linked recessive inheritance
Less severe form of dystrophy,
Dystrophin protein is deficient.
rd
th
Onset 5 – 15 years or even 3 or 5 decade.
• Clinical features:
• Muscle wasting resemble Duchene’s.
• Proximal muscle weaknesses of lower extremities
occur first. Cardiac muscle may be involved.
• Investigation: results- similar like in Duchene’s
• Management: No satisfactory treatment yet.
Patients may survive till 5th decade.
Morphology – DMD, BMS
(1) Variation in fiber size (diameter)+ hypercontraction
(2) Increased numbers of internalized nuclei (beyond the normal range
of 3% to 5%).
(3) Degeneration, necrosis (segemental& group) -phagocytosis .
(4) Regeneration of muscle fibers.
(5) Proliferation of endomysial connective tissue.
• in advanced cases muscle fibers undergo degeneration and
are replaced by fibrofatty tissue and collagen.
• This feature distinguishes dystrophies from other
myopathies, which also present with muscle weakness
Internal central nuclei: Multiple
NORMAL DYS-1 test
Degeneration , regeneration,
Inflammation
replaced by fibrofatty tissue
NEGATIVE DYS-1 test
Myotonic dystrophy
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Progressive disease in which the muscles and are slow relax
after contraction- commonly dystrophy in adult.
(Myotonia= is an inability to relax muscles at wil)
Adolescence\adult onset -slow, children –congenital- rapid
Etiology: is Autosomal dominant genetic disorder with
triple repeat mutation.
The correlation between disease severity , age at onset and
approximate size of triple mutation.
Investigation:
Muscle biopsy-atrophy with internalized
nuclei.
EMG- show myotonia
Molecular test
• Management: No satisfactory treatment yet.
• Phenytoin lead to delayed the relaxation.
Myotonic dystrophies- Pathogenesis
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Myotonia- inability to relax muscles.
• Inherited as an autosomal dominant trait 
• Repeat expansion of trinucleotide CTG on chromosome 19
• This will affect the mRNA for the dystrophia myotonia
protein kinase (DMPK) is an enzyme that in humans is
encoded by the DMPK gene (CA channles, GTPase)
Sustained involuntary contraction.
• Sustained involuntary contraction of a group of muscles &
stiffness, shrinkage, wasting (hands, legs, neck, face).
Inherited as an autosomal dominant trait Affect DMPK 
Involuntary sustained muscle contraction and stiffness
Clinical features:
• Facial muscle weakness
• Ptosis, frontal baldness,
• Gyanecomastia
• Neck muscles weakness
• Distal limbs muscles weak
• Diaphragm muscle weak
• Respiratory failure.
• Dysphagia
• Cardiac muscle involvement “cardiomyopathy”
• Mental retardation.
• Proximal muscle are
spared along the course.
Morphology of MMS
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Mytonic dystrophy- (MS) :
1) All features in No. (1-5) +
2) Presence of multiple internal nuclei
3) Ring fiber:
formed by a bundle of peripheral myofibrils that
are circumferentially oriented (PATH stain, EM).
• 4) Relative selective atrophy.
• 5) Degeneration and regeneration seen in severely
affected muscles.
Mytonic dystrophy
Fiber size variation- Internal nuclei in some fibersPyknotic nuclear clumps
Esterase
Internal nuclei: Multiple
NADH stain
Pyknotic nuclear clumps
the disease of neuromuscular junctions.
Myasthenia Gravis - MG
• MG- is a Chronic autoimmune neuromuscular muscle disease
causedb.by
immune-mediated
loss
of acetylcholine
receptor, chr.
Discuss
the disease of
neuromuscular
junctions.
by Varying degree of fluctuates
weaknesses. (MG = grave
Definition
muscle weakness).
• Affect area: Muscle neuro-transmitter
• Prevalence: of about 30,000 in 100,000 persons.
• Age: any age group, but commonly (F< 40 yrs , M> 60) of life.
• Sex: Any gender, commonly affect female> male, older equally
• Evidence based nearly all cases: decrease in the number of
muscle acetylcholine receptors (AChRs), and circulating
antibodies to the AChR are present in nearly all cases.
• Risk- thymic abnormalities are common in these patients
MG-PATHOGENESIS
• Autoimmune basis:
• Autoantibodies usually against the the nicotinic AChR lead to loss of
functional AChRs at the neuromuscular junction by:
• (1) Fixing complement - causing direct injury to the postsynaptic
membrane.
• (2) Increasing the internalization and degradation of the receptors.
• (3) Inhibiting binding of acetylcholine.
• HLA & environmental association.
Outcomes:
• A) Communication between nerves and muscles is
disrupted (action potential affected)
• B) Sensory as well as autonomic functions are not
affected.
• C) Electrophysiologic studies are notable for diminished.
Neuromuscular junctions diseases- Morphology
• 1- Muscle biopsy- (light microscopic):
• a) Specimens are usually unrevealing.
• b) In severe cases type 2 fiber atrophy due to disuse may be
found.
• 2- Electron microscopy:
• a) The postsynaptic membrane is simplified, and there is loss
of AChRs from the region of the synapse.
• b) Immune complexes and the complement membrane attack
complex (C5–C9) can be found along the postsynaptic
membrane as well.
• 3- Administration of anticholinesterase agents- Test
• 4- Nerve conudcting studies
• 5- CT- scan for thymus assessment
• 6- Blood screening for auto-antibodies (anti-AChR or MuSK)
Clinical features
• 1- Voluntary muscle Weakness begins with the
extraocular muscles; drooping eyelids (ptosis) and
double vision (diplopia) facial expression,
swallowing, arms , legs.
• 2- Generalized weakness- the weakness fluctuates
over days, hours, or even minutes.
( Aggravated- with exercised)
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• 3- Intercurrent medical conditions
can lead to exacerbations.
• 4- Respiratory compromise
(major cause of mortality)
Management
• 1- Avoid stress, exercise,+ Better ventilatory support.
• 2- Anticholinesterase drugs.
• 3- Steroid- prednisone+ Immunosuppressant=cyclosporin.
• 4- Plasmapheresis + Immunoglobulin .
• 5- Thymectomy wen thymic lesions are present.+ BM
transplant.
• No preventive measure can be adopted.
• Prognosis- MG not affect life expectancy, can practicing
daily activity even.
• Myasthenia crisis- respiratory muscle weakness (ARF)
SUMMARY OF MD
Muscular Dystrophy- clinical features
Type
Onset Age
(years)
Clinical Features
Other organ
systems involved
Duchenne
Before 5
1.Progressive
weakness of girdle
muscles.
2.unable to walk after
age 12
3.progressive
kyphoscoliosis
4.Respiratory failure
in 2dor 3d decade.
Cardiomyopathy
Mental impairment
Becker
early
childhood to
adult
1.Progressive
weakness of girdle
muscles
2. able to walk after
age 15.
1.3. Respiratory
failure may develop
by 4th grade
Cardiomyopathy
5-25yr
Muscular dystrophy – clinical features
Type
Onset Age
(years)
Clinical Features
Other organ systems
involved
Congenital
At birth or
within 1st few
months
.Hypotonia, contractures,
delayed milestones
Progression to
respiratory failure in
some;
CNS and
Eye abnormalities
Facioscapulohumer
al
Before age 20
Slowly progressive
weakness of face,
shoulder girdle, and foot
dorsiflexion
Deafness
Coat’s (eye) disease
Oculopharyngeal
5th to 6th
decade
Slowly progressive
weakness of extraocular,
pharyngeal, and limb
muscles
______
Myotonic
ADULTONSET
, 2nd decade,
Congenital
onset
Slowly progressive
weakness of face,
shoulder girdle, and
foot dorsiflexion
inability to relax muscles
Cardiac conduction
defects
Mental impairment
Cataracts, hypersomnia
Frontal baldness
Gonadal atrophy