OS 211: Integration, Coordination and Behavior

LEC 12: DISEASES OF THE MUSCLE

Exam # 1| Dra. Mina Astejada| Dec. 5, 2012

OUTLINE
I. Introduction D. Channelopathies
myopathies o Congenital fiber-type disproportion
II. Classification of Myopathies E. Mitochondrial myopathy
III. Hereditary myopathies F. Metabolic myopathy o Central core disease
A. Congenital myopathy IV. Acquired myopathies o Nemaline myopathy
B. Muscular myopathy A. Inflammatory myopathy Congenital myotonic dystrophy
C. Myotonia myopathy B. Toxic myopathy
Congenital muscular dystrophy
Glycogen storage diseases
I. INTRODUCTION: SKELETAL MUSCLE
(acid maltase and phosphorylase deficiencies)
 Composition: Lipid storage diseases (carnitine deficiency)
o 75%: water
PRESENTING AT CHILDHOOD - usually presents with “psychomotor
o 20%: protein (1) membrane protein, (2) contractile protein
development abnormalities” (standing, running not appropriate with
o 5%: (1) high-energy phosphates, (2) urea, (3) lactic acid, (4) Ca,
age)
Mg, P, (5) enzymes, (6) amino acids, lipids, and carbohydrates
 Function: generate force for contraction o Centronuclear myopathy
Congenital
 Any abnormality of the proteins will result in the loss of integrity of o Congenital fiber-type disproportion
myopathies
the muscle that will result to muscle weakness o Central core disease
Endocrine o Hypokalemia
metabolic o Hypocalcemia
disorders o Hypercalcemia
Glycogen storage disease (acid maltase deficiency)
Mitochondrial myopathies
o Duchenne
Muscular o Becker
dystrophies: o Emery-Dreifuss
psychomotor o Fascioscapulohumeral
delay o Limb-girdle
o Congenital

PRESENTING AT ADULTHOOD
Distal myopathies
Centronuclear myopathy
o Thyroid
Endocrine o Parathyroid
Figure 1.Skeletal muscle structure at a molecular level. Any
myopathies o Adrenal
abnormalities in any one of these proteins result in myopathy.
o Pituitary
o Polymyositis
II. CLASSIFICATION OF MYOPATHIES
o Dermatomyositis (wide range, can start
A. Associated Signs and Symptoms Inflammatory
from juvenile)
myopathies
o IBM
Negative Positive o Viral (HIV)
Weakness (ineffective Myotonia– sustained contraction or o Acid maltase,
contraction or loss of muscle loss of relaxation (weak when lying Metabolic
o Lipid storage disease,
fiber itself) (may be proximal down) – ask to grip then relax. If the myopathies
o Debrancher
or distal) – most common px sustains grip  grip myotonia Phosphorylase B kinase deficiency
symptom of px with muscle Myoglobinuria: (tea-colored or o Becker
disease; generally proximal pinkish urine secondary to o Emery-Dreifuss
dominant weakness rhabdomyolysis) Muscular
o Fascioscapulohumeral
Fatigue Cramps dystrophies
o Limb-girdle
Exercise intolerance Contractures o Myotonic
Muscle atrophy Myalgias Mitochondrial myopathies
Nemaline myopathy
B. Based on Age of Onset o Alcohol
Most muscle diseases, including the muscular dystrophies, o Corticosteroids
congenital myopathies, and inflammatory myopathies, are defined Toxic myopathies o Local injection of narcotis
by pathological findings. Please note that congenital myopathies, in o Colchicines
particular, are classified based on the pathological findings, for o Chloroquine
example, nemaline bodies and central cores, as you just saw. In
these diseases, by definition, a diagnosis is based on the C. Based on Etiology
morphologic findings in the muscle biopsy and cannot be made
without muscle pathology findings. In such cases, molecular Hereditary Acquired
diagnosis may play only a confirmatory role; however, now we
know that even such diseases are genetically heterogeneous. Channelopathies Drug-induced myopathies (statins)
Therefore, in the future, these diseases will be further classified by Congenital myopathies Endocrine myopathies (thyrotoxic)
genetic abnormalities
PPT Inflammatory myopathies
Metabolic myopathies
(dermatomyositis, polymyositis, IBM)
PRESENTING AT BIRTH - usual presentation is “floppy baby” Myopathies assoc. w/ systemic
Mitochondrial myopathies disease (cancer) or autoimmune
Congenital myotonic dystrophy
diseases (SLE myositis)
Congenital o Centronuclear myopathy
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Muscular dystrophies Toxic myopathies
Myotonias
D. Based on Pathologic Features
 Muscular dystrophy
o You should be able to see necrotic, regenerating process
o Necrotic fibers are acidic (pinkish)
o Regenerating fibers are more basophilic (blue) due to increase
in ribosomes and proteins during regeneration
 Congenital myopathy
o Nemaline myopathy
o Central core disease
o Myotubular myopathy
o Centronuclear myopathy
o Congenital fiber type disproportion
 Inflammatory myopathy
o Marked cell infiltration of muscle fibers
 Others
o Distal myopathy with rimmed vacuoles
o Hereditary inclusion body myopathy
o Myofibrillar myopathy
o Cytoplasmic body myopathy
o Myoclonus epilepsy with ragged red fibers
III. HEREDITARY MYOPATHIES
A. Congenital Myopathy
 A clinically, genetically and pathologically heterogeneous (some
benign, some serious) disorder defined by the presence of
particular histological features
 causes loss of muscle tone and muscle weakness in infancy and
delayed motor milestones, such as walking, later in childhood.
 Onset is often at birth or early childhood
 Floppy infant with variable, generalized hypotonia
 Long “myopathic” face is a common feature - reflects
involvement of the facial muscles
 Normal intelligence, only facies affected (CNS, PNS spared)
 Generally non-progressive; often benign (does not involve CNS)
 Diaphragmatic involvement: may be disproportionate to overall
muscle weakness
 Inheritance: AR, AD or X-linked
 CK (Creatine kinase): usually normal or slightly elevated (not due
to destructive mechanism, in contrast to muscular dystrophy
wherein muscular membrane is destroyed)
 Treatment: none, supportive only
Figure 2.” Floppy infant” facies of baby with Congenital myopathy
CLASSIFICATION BASED ON HISTOLOGIC FINDINGS
 NOTE: muscle biopsy needed for diagnosis
JOM, CARLO, CHRIS
Figure 3. Different Types of Congenital Myopathy Based on
Histology. A.Central Core Disease, B. Centronuclear Myopathy, C.
Nemaline Myopathy, D. Congenital Fiber Type Disproportion
HISTOLOGIC FINDINGS
o Core structures present in muscle fibers
o Allelic/associated with Malignant
Hyperthermia (upon administration of
A. Central core
general anesthesia; can be fatal)
o Gene: Ryanodine receptor (RyR1) – Ca
contraction coupling
o Muscle fibers with peripheral halo, central
intense staining (mitochondria), central
nucleation. Normally, nucleus is at
B.Centronuclear/
periphery but here at H&E stain, it is central
Myotubular
o Gene: *”Just nice to know.”
Myopathy
 Myotubularin (MTM1) X-linked
 Dynamin (DNM2) Autosomal
 Autosomal or sex-linked
o (Nemaline bodies) Rod-like structures are
intense staining seen at the periphery of
C. Nemaline
muscle fibers
Myopathy
o Gene: : ACTA1, nebulin, -tropomyosin, -
tropomyosin, slow troponin
o ‘Disproportion’ because Type 2B (brown
fibers) is deficient
D. Congenital
o Decrease in size of Type 1 (dark fibers)
fiber type
compared to Type 2A (white fibers)
disproportion
o Gene: ACTA1 (same gene but different
location of mutation)
B. Muscular Dystrophy
 First described by Nattrass in 1954
 Definition: It is a heterogeneous group of inherited primary
diseases of the muscle, clinically characterized by progressive
muscle weakness and wasting.
 Histologically, it is unified by the presence of necrotic and
regenerating processes, often associated with an increased
amount of connective and adipose tissues (“malambot sobra”)
 Types:
o Congenital muscular dystrophy (CMD)
o Dystrophinopathies (DMD and BMD)
o Limb-Girdle Muscular Dystrophy (LGMD)
o Emery-Dreifuss muscular dystrophy (EDMD)
o Fascio-scapulo humeral dystrophy (FSHD)
CONGENITAL MUSCULAR DYSTROPHY (CMD)
 Onset at birth – congenital; floppy infant syndrome
 First described by Batten in 1903
 Require MRI; usually with IQ abN
 High CK (vs. congenital myopathy) because of problem w/
membrane of skeletal muscle
 A group of clinically heterogeneous autosomal recessive
inherited muscle diseases
 Characterized by hypotonia at birth, generalized muscle
weakness, frequently multiple contractures
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 Associated with retardation (CNS involvement in CMD), have
worse prognosis compared with Congenital Myopathy
 Muscle Biopsy: necrotic and regenerating process must be seen
which means that muscle membrane is affected
 Variable: The clinical spectrum ranges from a very severe form,
often resulting in early infant death, to relatively mild conditions,
where the patient survives into adulthood
 CK: range from normal to marked elevation (thousands) due to
necrotic and regenerating processes(muscular dystrophy until
thousands because muscular membrane is destroyed and the
enzymes leak out)
 Merosin deficient CMD: most common in Europe due to
absence of Lamina alpha2 (MC in Europe)
 Fukuyama CMD: most common in Japan (MC in Asia: Japan)
B. BECKER MUSCULAR DYSTROPHY
 Milder form of DMD that can have a later onset (can actually
survive until adulthood)
 Sex - linked recessive disorder (Xp21)
 CNS involvement is more rare
 Still has cardiovascular involvement
 Life span up to 30 years old (compared to Duchenne who only
reach their 20s).
 1 in 30,000 male births
 Partial deletion of the gene coding for dystrophin
 Dystrophin is partially present , muscle membrane is semi –
functional
 H&E: Necrotic: pinkish in color, acidic because being destroyed,
regenerating is basophilic because of the increase in protein
 Dystrophin: normally brown, in Duchenne none, in Becker
patchy

CLINICAL FEATURES
1. Later onset of muscle weakness at slower rate
2. Ambulatory up to adult life
3. Cardiac abnormality may be seen but mental retardation is rare

Figure 4. CNS Involvement (Top) and Alpha Dystroglycanopathis DIAGNOSIS

(Bottom) in Congenital Muscular Dystrophy  Same as DMD (MPCR before biopsy)

DYSTROPHINOPATHIES (DMD, BMD)– abnormality in dystrophin

A. DUCHENNE MUSCULAR DYSTROPHY
 Most common; only males present symptoms; females may be
carriers and also present few sx but not so common
 Sex - linked recessive disorder (Xp21)
 mutation in the gene coding for dystrophin (400kD)
 Total absence of dystrophin (vs. just a reduction of dystrophin in
Becker MD) (“Becker is more benign”)
 Cardiac and CNS involvement is evident with cardiomyopathy
(megaly) and low IQ in some cases
 Psychomotor retardation (start of standing and walking is
delayed [1 yr 6 months]) with mental retardation

CLINICAL FEATURES Figure 5.Diagnostic algorithm of DMD and BMD.Perform Multiplex

Early signs (3-5 years) Later signs (10-14 years) PCR first because it is non-invasive
o Pelvic girdle weakness o Relentless progression &
o (waddling gait, involvement of shoulder girdle
o frequent falls, muscles
o difficulty climbing stairs,
o awkward running)
o Pseudohypertrophy of o Scoliosis & thoracic deformity
calf muscles
o (+) Gowers’ sign o Inability to ambulate, delayed
walking
o At 20 to 25 yrs old - respiratory
failure*
o Cardiac + CNS involvement: low
IQ and Cardiomyopathy in some
cases Figure 6.Immunohistochemical stain: DMD and BMD. Note complete
absence of cell membrane in DMD, and partial absence (patchy) in
* Respiratory failure: the usual endpoint in DMD; but because of
BMD. (Antibodies would usually target dystrophin at the level of the
advancement in ventilation technology, cardiac failure is now the
sarcolemma)
most common “mode of exit” /cause of death
* Progression of weakness  wheelchair bound
LIMB-GIRDLE MUSCULAR DYSTROPHY (LGMD)
DIAGNOSIS  Variable age of onset: childhood to adulthood
1. Genetic studies  The term "limb-girdle" is used to describe these disorders
a. Multiplex PCR - detect dystrophin gene deletion in 60 % of because the muscles most severely affected are generally those
cases of the hips and shoulders -- the limb girdle muscles.
b. MPLA- detect deletion and duplication, more sensitive than  A group of phenotypically and genetically heterogeneous
multiplex PCR; if negative, perform muscle biopsy disorder
2. Immunohistochemical stain for dystrophin – negative (then  Weakness of the proximal muscles in the upper and lower
already diagnostic of Duchenne, if patchy – Becker) extremities (shoulder and pelvic muscles), some have scapular
winging and (+) Gowers’
TREATMENT  Symmetric, proximal and slowly progressive
1. Definitive treatment NOT YET AVAILABLE; supportive only  18 different gene locus identified:
2. Temporary stabilization with steroids o Type 1- Autosomal dominant (7 examples); PCR: 60% of
3. Gene therapy to date is not possible; only in animal studies certain exons

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o Type 2- Autosomal recessive (11 examples, adult onset,  Type I fiber: DARK staining on oxidative stain
more common); (-) dystrophin- DMD; patchy-Beckers; 2A  Type I is smaller ccompared to type II
and 2B are most common, seen in older Pt(clinical
presentation might be the same).
LGMD 2A - Calpainopathy LGMD 2B - Dysferlinopathy
Fiber size variation (+)dysferlin in normal
Endomysial fibrosis: may be muscle
replaced with fat: adipose (-)dysferlin in diseased
deposition muscle
Lobulated fibers; fiber is round and
not polygonal anymore due to
replacement of connective tissue
Necrotic and regenerative process
in histology
Myofibrils are deranged (loculation)
*only staining for dysferlin is available

Figure 9. Changes seen in Myotonic Dystrophy

D. Channelopathies

Figure 7. L to R. Fiber size variation, Endomysial fibrosis, Lobulated

and disorganized muscle fibers in LGMD 2A (Calpainopathy) stained
blue because of the mitochondria

Figure 10. Ion Channels in cell membrane.

 Mutations in the genes encoding the proteins of the ion channels

of the sarcolemma, SR and T-tubules disrupt the normal
+ + - 2+
transport of ions, in particular, Na , K , Cl and Ca
 Episodic weakness; Exercise intolerance
 Clinically fall into 2 groups: those with myotonia and those with
Figure 8. Immunohistochemistry. Left: (+) dysferlin in normal
paralysis
muscle, Right: (-) dysferlin in muscle with LGMD 2B (Dysferlinopathy)
 Most common:
Note: Only LGMD 2B has an available commercial antibody
o Myotonia Congenita (Autosomal dominant; due to
abnormality in Cl channel)
C. Myotonica Dystrophica
o Hypokalemic Periodic Paralysis (abnormality mainly in Ca
 Multisystem disease (muscle, heart, eye, endocrine system &
and sometimes Na channels)
CNS)
Table 1.Ion channel disorders of skeletal muscles. Just focus on
SYMPTOMS MyotoniaCongenita and Hypokalemic Periodic Paralysis.
 Weakness Locu
 Can be associated with insulin deficiency Syndrome Ion Channel Gene Inh.
s
 Myotonia (sustained muscle contraction; grip is sustained and Myotonia Congenita Chloride
cannot relax) CLCN1 7q35 AR
(Becker) channel
 Cataracts Myotonia Congenita Chloride
 DM CLCN1 7q35 AD
(Thomsen) channel
 Cardiac arrhythmia Potassium aggravated Sodium 17q2
SCN4A AD
 Frontal balding – more commonly seen even in younger patients myotonia Channel 3
Paramyotonia Sodium 17q2
TYPES (BASED ON PATTERN OF WEAKNESS) SCN4A AD
congenital Channel 3
TYPE 1 TYPE 2 Hyperkalemic Periodic Sodium 17q2
SCN4A AD
Distal> proximal Proximal> distal Paralysis Channel 3
Facial muscle affected Facial muscle rarely involved Calcium
CACNA1 1q32
CTG trinucleotide repeats in CCTG repeat expansion in ZNF9 Hypokalemic Periodic Channel
S 17q2 AD
DMPK gene (chromosome 19) gene (Chromosome 3) *Paralysis* Sodium
SCN4A 3
AD inheritance AD inheritance channel
Potassium
Andersen’s syndrome KCN12 17q AD
Channel
CHANGES SEEN IN MYOTONIC DYSTROPHY
Malignant
 Fiber size variation hyperthermia RyR1 19q1
 Centrally placed nuclei (normal muscle fiber has nucleus in the Calcium
(an allelic form of CACNA1 3 AD
periphery) Channel
central core disease in S 1q32
 Chained nuclei: dikit-dikit ng nucleus Congenital Myopathy )
 Ring binden fiber: peripheral lightly staining fiber surrounding  Becker: only one with AR inheritance (inh.)
muscle edge  Andersen’s: only one with K+ channel
 Sarcoplasmic mass (accumulation of Abn Sarcoplasmic
reticulum) MYOTONIA CONGENITA
 Type I fiber hypotrophy (reduction in caliber of fibers)

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 Etiology: Gene mutation (encoding Cl channel )
 Thomsen’s disease: AD inheritance
 Becker’s disease: AR inheritance
 Characterized by:
o Myotonia (persistent contraction)
o Muscle stiffness (relieved upon exercise)
o Warm-up phenomenon (stiffness and weakness is decreased
with physical activity)
o Muscle hypertrophy (“herculean” appearance) – diffuse
hypertrophy of muscles
o EMG: dive-bomber pattern (upon injection of needle 
sudden burst of high frequency and high amplitude waves
that slowly die down)
SODIUM CHANNEL DISEASES
 Hyperkalemic periodic paralysis: Most Important
o Paralytic episodes usually at rest after physical exercise
o During attack, areflexia,
o [K+] > 6mM, signs of hyperkalemia in ECG
o Tx: acetazolamide and thiazide diuretics
From Wikipedia:
o Mutations altering the usual structure and function of this sodium channel disrupt
regulation of muscle contraction, leading to episodes of severe muscle weakness or
paralysis. The condition is hyperkalemic because a high extracellular potassium ion
concentration will make it even more unfavourable for potassium to leave the cell
in order to repolarise it to the resting potential, and this further prolongs the
sodium conductance and keeps the muscle contracted. Hence, the severity would
be reduced if extracellular (serum) potassium ion concentrations are kept low.
Pathomechanism of Hyperkalemic periodic paralysis
Figure 11. Sodium channels are gated by changes in the membrane potential, switching between the
closed, activated and inactivated states according to membrane potential variations (Figure 1A). The
activation of NavChs by membrane depolarization causes Na+ influx responsible for the sudden
membrane depolarization in the initial phase of the action potential. In response, there is a
compensatory outward K+ current that perpetuates the process along the membrane. The fast
inactivation (within milliseconds) of NavChs is essential for membrane repolarization. Like all members
of the NavChs family, Nav1.4 is made up of a principal pore-forming α subunit, associated with an
accessory β subunit. The α subunit consists of four domains, each comprising six transmembrane
segments which form the ion-selective pore and confer the voltage dependence of the protein,
whereas the intracellular loop between the domains III and IV is involved in the inactivation process.
Most of the SCN4A mutations causing HyperPP are located in the inner part of transmembrane
segments or in the intracellular loops (Figure 1B), where they affect the fast inactivation of the
channel. As compared to wildtype channels, mutant channels show incomplete inactivation resulting in
an increased level of persistent Na+ current (gain of function) that causes a sustained membrane
depolarization. In turn, the sustained depolarization will favour K+ release from the cells, causing
hyperkalaemia, and inactivate the majority of NavChs, causing electrical inexcitability of skeletal
muscles.
From powerpoint:
 The mutation in Na channel causes inactivation of the Na gate
hence allowing increased Na influx. As a compensatory
mechanism, K+ efflux occurs (exits the cell) causing an increased K
(hyperkalemia).
 SCN4A mutations located in the inner part of transmembrane
loops affect the fast inactivation of the sodium channel
 Incomplete Na+ channel inactivation result to an ↑ level of
persistent Na+ current (gain of function) that causing sustained
membrane depolarization
 In turn, the sustained depolarization will favour K+ release from
the cells, causing hyperkalaemia, and inactivate the majority of
NavChs, causing electrical inexcitability of skeletal muscles
 Paramyotonia congenita:
o Paradoxical myotonia, increasing muscle stiffness with
physical exercise, worsening of myotonia after exposure to
cold temperature
o The more they exert effort, the more they get stiff (vs.
myotoniacongenital with its warm up phenomenon)
o Tx: acetazolamide, mexiletine and salbutamol
 Potassium-aggravated myotonia :
JOM, CARLO, CHRIS
o Muscle stiffness without weakness and cold sensitivity
CALCIUM CHANNEL DISEASES
 Hypokalemic Periodic Paralysis: Most Important
o Characterized by prolonged (days/ weeks)and severe bouts of
weakness
o Most common Ca channel disease, primary (genetic mutation)
o Precipitated by rest after a period of exercise or stress
o Weakness induced by: rest, alcohol intake, carbohydrate
loading (excess glucose in the body cause K to go inside muscle
fibershyperpolarizationunexcitableweakness)
o Tx: oral potassium supplements, acetazolamide (stabilize
potassium levels)
o Pathogenesis
Figure 12. An aberrant current permeable to protons could stimulate the NHE and NBC transporters
with a resultant increase in intracellular sodium ions. Stimulation of the monocarboxylate transporter
would result in increased lactate efflux from the cell which has been proposed as contributory to
vacuolar formation. MCT, monocarboxylate transporter; NHE, sodium-hydrogen anti-port exchanger;
NBC, sodium-dependent bicarbonate transporter; CA, carbonic anhydrase.
From wikipedia:
The channel involves 4 domains with 6 helical proteins in each domain.
Mutation occurs mostly/usually at the 4th domain. Mutations altering the usual
structure and function of these channels therefore disrupts regulation of muscle
contraction, leading to episodes of severe muscle weakness or paralysis. Mutations have
been identified in arginine residues making up the voltage sensor of Nav1.4. This voltage
sensor comprises the S4 alpha helix of each of the four transmembrane domains (I-IV) of
the protein, and contains basic residues that only allow entry of the positive sodium ions
at appropriate membrane voltages by blocking or opening the channel pore. In Ca v1.1,
mutations have also been found in domains II and IV. These mutations are loss-of-
function, such that the channels cannot open normally.
In patients with mutations in SCN4A or CACNA1S, therefore, the channel has a
reduced excitability and signals from the central nervous system are unable to
depolarise the muscle. As a result, the muscle cannot contract efficiently (paralysis). The
condition is hypokalemic because a low extracellular potassium ion concentration will
cause the muscle to repolarise to the resting potential more quickly, so even if calcium
conductance does occur it cannot be sustained. It becomes more difficult to reach the
calcium threshold at which the muscle can contract, and even if this is reached then the
muscle is more likely to relax. Because of this, the severity would be reduced if
potassium ion concentrations are kept high.
o In treatment, replace K+ in Plain NSS and not with D5W
(dextrose 5% water). Restrict carbohydrate intake. Increase K.
 Malignant Hyperthermia
o Dramatic and often fatal condition characterized by rapid and
sustained rise in temperature during generalized anesthesia
associated with generalized muscle rigidity, tachycardia,
tachypnea and cyanosis, leading to rhabdomyolysis
o Mutation in RyR1 is a predisposing factor
o Severe respiratory and metabolic acidosis
o Extensive muscle necrosis with subsequent myoglobinuria and
renal shutdown
o CK =/>50,000IU/L with elevated serum K+
o Tx: dantrolenesodiumASAP! (not available in the Philippines)
o Central core disease: may also develop malignant hyperthermia
because they have the same gene mutation.
E. Mitochondrial Myopathy
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Figure 13.Ragged Red Fibers.(mitochondria) These are small patches myoglobinuria

of red stain surrounding and inside the muscle fiber.

MITOCHONDRIAL DISEASES Exercise

Phosphoglycerate intolerance,
 Mitochondria: powerhouse of the cells – generates ATP X
mutase cramps, fatigue,
 Clinically heterogenous
myoglobinuria
 Onset may vary from birth to adulthood
Exercise
 Course may be rapidly progressive, static or even reversible
Lactate intolerance,
 Distribution of weakness may be generalized with respiratory XI
dehydrogenase cramps, fatigue,
failure or proximal more than distal, and may involve facial myoglobinuria
muscles with associated ptosis and progressive external
ophthalmoplegia
ACID MALTASE DEFICIENCY
 Serum and CSF lactate level may be increased: so check lactate
pyruvate ratio  Acid maltase is needed to breakdown glycogen
 Dx: muscle biopsy  Glycogen accumulates in muscle fiber and becomes toxic since
acid maltase is deficient
MITOCHONDRIAL MYOPATHY  3 main clinical types: severe infantile (Pompe’s), juvenile and
adult onset
 Mitochondrial myopathy, Lactic acid and stroke-like symptoms
 Pompe’s disease: usually fatal in infancy affecting the liver, heart,
(MELAS); sudden onset
skeletal muscles, CNS and kidneys
 Myoclonic epilepsy and ragged red fiber (MERRF) in Modified
 Severe hypotonia, floppy infant syndrome
Trichome Gomori stain; ragged blue fiber in Succinic
 Histo: (+) large vacuoles;
Dehydrogenase stain
 Tx: enzyme replacements (Genzyme available in Taiwan and US
 Chronic Progressive External Ophthalmoplegia (CPEO)
only)
 Kearns Sayre Syndrome (KSS): retinitis pigmentosa, PEO and
heart block
 Most common: MELAS and MERRF
 Mitochondria stained RED and located peripherally -abnormal
 Chronic sx: ptosis, diplopia
 Treatment: supportive

F. Metabolic Myopathy
GLYCOGENOSES
 The breakdown of glycogen is an important source of energy in
Figure 14. Acid Maltase Deficiency. Vacuolated fibers with basophilic
muscle (eg. failure of breakdown due to enzyme deficiency)
(glycogen) materials) – undigested glycogen become toxins causing
 Defect in any steps in the glycolytic pathway can cause muscle
harm, contained inside large vacuoles
fatigue, cramps, or rhabdomyolysis, which is an important
indicator of several metabolic problems
 Episodic weakness precipitated by strenous exercise, IV. ACQUIRED MYOPATHIES
 Affects the liver; tea-colored urine (myoglobinuria) A. Inflammatory Myopathy
 Type II most common
IDIOPATHIC
Table 2. Features of Glycogenoses that affect muscle:  Dermatomyositis, Polymyositis , Inclusion Body Myositis, most
Other common- see table below
T Enzyme def. AKA Clinical Features  Overlap syndromes with CTD, Sarcoidosis, Behcet’s syndrome
systems
a) Severe: Heart, CNS,
-1,4- Table 3. Clinical features of major inflammatory myopathies
Pompe’s resembles SMA leukocytes,
II Glucosidase M Sex Age WP CK Histologic findings St
disease b) Milder: liver,
(acid maltase) DM F>M Child P>D 50X Inflammation: Yes
resemble LGMD kidneys
Hepatic to Perimysial +
Amylo-1,6- Forbes’ adult perivasular;
Infantile hypoglycemi
glucosidase disease perifascicular atrophy
III hypotonia a, ketosis,
(debrancher Cori’s Yes
Mild weakness leukocytes, PM F>M Adult P>D 50X Endomysial
enzyme) Disease
heart  inflammation,
Amylo (1,41,6) Usually no lymphocytic infiltration
transglucosidase amylopect muscle sxs, in entire muscle fiber
IV Liver, heart
(branching inosis muscle wasting in IBM M>F Elderly P=D 10X Endomysial No
enzyme) some (>50) inflammation; Rimmed
Exercise vacuoles, tubofilaments
Myophosphorylas McArdle’s intolerance, on EM
V None
e Disease cramps, fatigue, * M = myopathy (DM = Dermatomyositis, PM = Polymyositis, IBM =
myoglobinuria Inclusion Body Myositis); Sex = predominant gender, Age = age of
Exercise onset, WP = weakness pattern, CK = CK levels(increased because of
VI Phosphofructokin Tarui’s intolerance, Hemolytican inflammation) ,St = responds to steroid
I ase disease cramps, fatigue, emia
myoglobinuria A. DERMATOMYOSITIS
Exercise  Gottrons papules
VI Phosphorylase B intolerance,  Heliotrope rash over the cheeks or eyelids
Liver heart
II kinase muscle stiffness,  Perifascicular atrophy (Hallmark of Dermatomyositis; due to
muscle weakness ischemia) – blood vessel with surrounding epithelial cells
Exercise  Perivascular inflammation
Phosphoglycerate Hemolytican
IX
kinase
intolerance,  Perimysial inflammation
emia, CNS
cramps, fatigue,  Whole muscle is involved (plus the skin, hence the name)
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 Childhood onset; Females more affected INFECTIOUS

o Staphylococci
A B C o Streptococci
o Yersinia
Bacterial o Legionella
o Borreliaburgdoferi (Lyme’s disease)
o Clostridium welchii (gas gangrene)
D E F o Leprous myositis
o Trichinosis
o Cysticercosis
Parasitic o Trypanosomiasis
o Toxoplasmosis
Figure 15. Signs and Histology of Dermatomyositis: (A) Gottrons o Ex. Trichinella (+ eosinophils)
papules, (B) Heliotrope rash in the face, (C) Heliotrope rash in the o Candida
eyelid, (D) Perifascicular atrophy, (E) Perivascular inflammation, (F) o Cyptococcus
Perimysial inflammation Fungal o Sporotrichosis
B. POLYMYOSITIS o Actinomycosis
 Similar to dermatomyositis, except for the lack of cutaneous o Histoplasmosis
involvement and its occurrence mainly in adults (Robbins) o Adenovirus
 Histological Characteristics: o Coxsackie
o No perifascicular atrophy or vascular injury o CMV
o Both necrotic and regenerating muscle fibers are scattered o Influenza
throughout the fascicle Viral
o eBV
o Presence of perimysial inflammation o HIV Parainfluenza
o HTLV-1
o Hepatitis B & C

B. Toxic Myopathy
See Appendix II: Toxic myopathies
* Statins are also known as Cholesterol lowering myopathy or CLAM

END OF TRANSCRIPTION

REVIEW TIME!
1. The following are true about Duchenne Muscular dystrophy
Polymyositis except:
A. Multiple PCR will identify 80% of gene mutation
Figure 16. Histology of Polymyositis
B. Immunostaining show total absence of dystrophin in the
sarcolemma
C. INCLUSION BODY MYOSITIS
C. It is associated with mental retardation and
 Most common acquired muscle disease > 50 y/o cardiomyopathies
 Prevalence of 5-10/million D. Psychomotor delay is seen during the development
 Affects men > women at 2-3:1, 50 years old E. This is a sex-linked recessive disorder
 Average time from symptom onset to diagnosis is ~ 6 yrs
 Characteristics: Scooped out forearm, finger flexor atrophy, 2. Perifascicular atrophy is a pathologic hallmark of this disease:
quadriceps atrophy(involves the distal muscles) A. Polymyositis
 Histological features: endomysial inflammation, inclusion bodies, B. Congenital muscular dystrophy
rimmed vacuoles inside muscle fibers (contains basophilic C. Dermatomyositis
substances: accumulated abnormal proteins) D. Myotonic dystrophy
 Unresponsive to steroids E. LGMD 2a

3. This term refers to failure of muscle relaxation

A. Myokimia
B. Myoedema
C. Myotonia
D. Dystonia
E. Rhabdomyolysis

Figure 17. Histology of Inclusion Body Myositis. L to R: Endomysial 4. The following is/are true about inclusion body myositis :
inflammation, Inclusion bodies, Rimmed vacuoles A. The pathological hallmark is the presence of rimmed
vacuoles
B. Mode of treatment includes steroid
C. There are preferential involvement of the finger flexors and
quadriceps
D. All are true
E. A and C

5. The following is/are differential diagnosis for an infant who

presents with general hypotonia:
A. Congenital muscular dystrophy
Figure 18. MRI at mid-thigh level presenting severe quadriceps B. Central core disease
atrophy C. Pompe’s disease
D. All of the above
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E. A and C

Answers:
A, C, C, E, D Source: Scott’s

Appendix II. TOXIC MYOPATHIES

Drug Clinical features Histology Comments
Myalgia, weakness or
Atrophy, inflammation, Fibrates & niacin also implicated in
Statins* even rhabdomyolysis
Occasional necrosis causing CLAM
CK elevation – 1%
Regular exercise may reduce this
Insidious onset after weeks or months of use ,
Flourinated forms are more
Steroids Painless proximal weakness & atrophy, Normal Type II atrophy
myotoxic (eg. Dexamethasone,
CK levels
triamcinolone)
Zidovudine Mitochondrial proliferation,
Proximal weakness, myalgia, elevated CK levels
(anti-HIV) Ragged Red Population
Chloroquine Cardiac muscles & PN may be
Painless proximal weakness, elevated CK Curvelinear bodies on EM
(anti-malaria) involved
Acid phosphase (+)
Colchicine Muscle pain & weakness PN involvement
Vacuoles
Vacuolar myopathy w/ inclusion
Amiodarone Muscle pain & weakness PN involvement
bodies
Poximal pain and weakness
D-penicillamine Inflammation
(Seen in 1% of treated patients)
Muscle pain & weakness, Atrophy, accumulation of
Cyclosporine
Occasional CK elevation mitochondria, lipid vacuoles
Valproic Acid
Mitochondria abnormalities, Can improve with carnitine
(Anti- Muscle weakness
lipid accumulation supplementation
convulsants)

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