Disorders of skeletal

muscle
Dr. Nazish Mazari
 LEARNING OBJECTIVES
• Classify myopathies

• Define muscular dystrophies

• Correlate pathogenesis of DMD & BMD

with clinical features
Diseases of Skeletal Muscle
 Neurogenic Neuromuscular
atrophy junction
disorders Myopathies Tumors

Inherited Acquired

Metabolic Channelo
Mitochondrial Congenital Muscular
pathies Dystrophies

systemic Electrolyte- Endocrine

disease mediated Infectious Inflammatory Toxic
 Myopathy
• Myopathies are a heterogeneous group of
disorders primarily affecting the skeletal muscle
structure, metabolism or channel function.

• They usually present with muscle weakness

interfering in daily life activities.

• Muscle pain is also a common finding.

• Some myopathies are associated with

rhabdomyolysis.
Muscular dystrophies
• A heterogeneous group of inherited disorders
of muscle, often beginning in childhood, that
lead to progressive weakness and muscle
wasting.

• Histologically, muscle fibers undergo

degeneration and are replaced by fibrofatty
tissue and collagen.

• This feature distinguishes dystrophies from

myopathies, which also present with muscle
weakness.
• Duchenne Muscular Dystrophy (DMD)

• Becker Muscular Dystrophy(BMD)

X LINKED INHERITED
DISORDERS
• DMD is the most severe and common form of
muscular dystrophy, with an incidence of about 1
per 3500 live male births.

• DMD becomes clinically manifest by the age of 5

years.

• It leads to wheelchair dependence by 10 to 12

years of age, and thereafter progresses
relentlessly.

• Although BMD involves the same genetic locus, it

is less common and much less severe than DMD.
Pathogenesis (DMD & BMD)

• Mutations in the dystrophin gene on short

arm of X chromosome

• Dystrophin, a part of dystrophin glycoprotein

complex, stabilizes muscle cell during
contraction
 Pathogenesis (DMD & BMD)

Dystrophin glycoprotein complex

defect
Muscle cell memb tears during
contraction
Calcium influx
disrupt intracellular signalling
Myofiber degeneration
 Morphology

• Histopathologic abnormalities common to DMD

and BMD include:

1) Variation in fiber size (diameter) due to the

presence of both small and enlarged fibers

2) Increased numbers of internalized nuclei

3) Degeneration of muscle fibers

4) Proliferation of endomysial connective tissue

• In later stages the muscles eventually
become almost totally replaced by fat and
connective tissue.
A, Duchenne muscular dystrophy (DMD) showing variation in muscle fiber
size, increased endomysial connective tissue, and regenerating fibers (blue
hue). B, Western blot showing absence of dystrophin in DMD and altered
dystrophin size in Becker muscular dystrophy (BMD) compared with control
Cross-section of muscle shows extensive replacement of muscle fibers
by adipose (fat) cells.
 DMD & BMD
• Clinical features
– Inability to keep up with peers due to muscle weakness
– Pelvic girdle muscles get involved first and then shoulder girdle
– Enlargement of calf muscles pseudohypertrophy
– cognitive impairment is a component of the disease and is
sometimes severe enough to be considered a form of mental
retardation
– High serum CK (creatine kinase) enzyme levels in first decade of
life which then falls later
– Death results from respiratory insufficiency, pneumonia, cardiac
decompensation
• BMD(Becker’s muscular dystrophy) is less
common
• It is less severe than DMD
• Boys with BMD develop symptoms at a
later age than those with DMD
• Onset occurs later in childhood or in
adolescence
• There is a slower and more variable rate
of progression
Gower’s sign
 Other dystrophies
• Limb girdle muscular dystrophies
• Myotonic dystrophy
– Autosomal dominant
– Mutation in dystrophia myotonia protein
kinase (DMPK) gene
– In this disease, sustained involuntary
contraction of a group of muscles occurs
– Such patients often complain of stiffness and
difficulty releasing their grip, for instance after
a handshake
 ION CHANNEL MYOPATHIES
(CHANNELOPATHIES)
• A group of familial diseases with myotonia,
relapsing episodes of hypotonic paralysis
(induced by vigorous exercise, cold, or a
high-carbohydrate meal), or both
• hyperkalemic, hypokalemic, and
normokalemic periodic paralysis
• caused by mutations in genes that encode
ion channels
Malignant hyperpyrexia (malignant
hyperthermia):
• A rare clinical syndrome
• Characterized by a marked hypermetabolic state
(tachycardia, tachypnea, muscle spasms, and later
hyperpyrexia)
• Triggered by anesthetics, most commonly halogenated
inhalational agents (halothane, enflurane, isoflurane )
and succinylcholine

• The clinical syndrome may occur in

predisposed individuals with hereditary
muscle diseases, including congenital
myopathies, dystrophinopathies, and
metabolic myopathies.
• Upon exposure to anesthetic, uncontrolled
efflux of calcium from the sarcoplasm occurs.

• This leads to tetany, increased muscle

metabolism, and excessive heat production.

• Diagnosis can be made either by identifying

the genetic mutation or by exposing biopsied
muscle to the anesthetic agent and observing
contraction.
 CONGENITAL MYOPATHIES

• Characterized by onset in early life, nonprogressive or

slowly progressive course, proximal or generalized
muscle weakness, and hypotonia.

• Those affected at birth or in early infancy may present

as “floppy infants” because of hypotonia or may have
severe joint contractures (arthrogryposis)

• Examples:
– Nemaline myopathy
– Myotubular myopathy
 MYOPATHIES ASSOCIATED WITH
INBORN ERRORS OF METABOLISM
• Lipid Myopathies
– Blockage in fatty acid oxidation leading to accumulation of
lipid droplets within muscle
– Fatty acids provide energy for muscle contraction
– With a metabolic block in fatty acid oxidation, the required
energy is not available, resulting in symptoms

• Mitochondrial Myopathies (Oxidative Phosphorylation

Diseases)
 Drug induced myopathies

• Steroid myopathy: Proximal muscle

weakness and atrophy can occur as a result
of the deleterious effects of steroids on
muscle

• Chloroquine can produce a proximal

myopathy in humans

• Statin-induced myopathy can occur with

use of any of the statins (e.g., atorvastatin,
simvastatin, pravastatin)
 Toxic myopathies

– Thyrotoxic myopathy
• Myofiber necrosis, regeneration and
interstitial lymphocytosis

– Ethanol myopathy
• Result of binge drinking
• Myocyte swelling, necrosis and
regeneration
 Inflammatory myopathies

• Polymyositis
– Autoimmune
– Endomysial inflammatory infiltrates containing
CD8+ T-cells
– Myofiber necrosis and regeneration
• Dermatomyositis
– Autoimmune basis
– an inflammatory disorder of the skin as well as
skeletal muscle

• Inclusion body myositis

– Degenerative disorder of aging
– Involvement of distal muscles
– weakness may be asymmetric