OS 211 Dr. Mina N.

Astejada
Muscle Diseases Exam 3

Outline: • a neuromuscular disease in which the muscle fibers

I. Introduction do not function for any one of many reasons, resulting
in muscular weakness
II. Classification of Myopathies
• primary defect is within the muscle (vs. neuropathy)
A. Hereditary

1. Congenital Myopathy
II. Classification of Myopathies (Appendix A)
a. Central Core Disease

b. Centronuclear/Myotubular Myopathy

c. Nemaline Myopathy A. Hereditary Myopathies

d. Congenital Fiber Type Disproportion 1. Congenital Myopathy

2. Muscular Dystrophy  A clinically, genetically and pathologically

heterogeneous disorder defined by the presence
a. Congenital Muscular Dystrophy of particular histological features
b. Dystrophinopathies
 Onset is often at birth or early childhood (~7
c. Limb Girdle Muscular Dystrophy years old)

3. Myotonia Dystrophica  Floppy infant with variable hypotonia

4. Channelopathies  Long “myopathic” face is a common feature

a. Sodium Channel Disease  CNS and peripheral nerves are not usually
involved
b. Calcium channel Disease

c. Myotonia Congenita
 Normal intelligence

5. Mitochondrial Myopathy  Generally non-progressive

6. Metabolic Myopathy  Diaphragmatic involvement may be

disproportionate to overall muscle weakness
B. Acquired
 Inheritance: AR, AD or X-linked
1. Inflammatory Myopathies
 CK are usually normal or slightly elevated
a. Idiopathic

b. Infectious  Treatment: supportive

2. Toxic Myopathy

*Classification is based on histologic features (muscle biopsy

is therefore needed for diagnosis):

a. Central Core Disease

*Hi 2012! This trans was made from scratch because the 2011
supplementary CD doesn’t have a softcopy of this trans (they have the - Gene: Ryanodine receptor (RyR1)
filename but if u try to open it, different content)! But we are confident
about this trans. Medyo tinoxic namin ‘to! Happy reading! Swerte ng
- associated with malignant hyperthermia
Jolly B’s na magttrans nito! Hehe libre nyo kami. Haha!

I. Introduction b. Centronuclear/Myotubular Myopathy

Skeletal Muscle - Gene: Myotubularin (MTM1)  X-linked

 75% water Dynamin (DNM2)  AR

 20% protein
c. Nemaline Myopathy
 5% others: high-energy phosphates, urea, lactic acid,
Ca, Mg, P, enzymes, amino acids, lipids and - Gene: ACTA1*, nebulin, α-tropomyosin, β-
carbohydrates
tropomyosin, slow troponin T

Myopathies
d. Congenital Fiber Type Disproportion

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D Twilighters
 OS 211 Dr. Mina N. Astejada
Muscle Diseases Exam 3

- Gene: ACTA1*
Walker-Warburg Muscle Eye Fukuyam MDC1
* same gene but different location of mutation Brain a C

Agyria Pachygyria/ Agyria Focal Normal

Agyria brain

Figure 2. CNS Involvement in CMD. Take note that CNS involvement

A B is not an absolute characteristic of CMD.

b. Dystrophinopathies

Duchene Muscular Dystrophy (DMD)

C D • Most common

• Sex - linked recessive disorder (Xp21)

Figure 1. Different Types of Congenital Myopathy Based on Histology.
(A. Central Core Disease, B. Centronuclear Myopathy, C. Nemaline
Myopathy, D. Congenital Fiber Type Disproportion) • mutation in the gene coding for dystrophin (400kD)

• Clinical Features:
2. Muscular Dystrophy
1. Early signs - starts at age 3 to 5 years
 First described by Nattrass in 1954 - Pelvic girdle weakness (waddling gait,
frequent falls, difficulty climbing stairs, awkward
 It is a heterogeneous group of inherited primary running)
diseases of the muscle, clinically characterized
by progressive muscle weakness and wasting. - Pseudohypertrophy of calf muscles

 Histologically, it is unified by the presence of - (+) Gowers’ sign

necrotic and regenerating processes, often
associated with an increased amount of 2. Later signs - 10 to 14 yrs old
connective and adipose tissues
- relentless progression & involvement of
TYPES: shoulder girdle muscles

a. Congenital Muscular Dystrophy (CMD) - Scoliosis & thoracic deformity

 First described by Batten in 1903 - Inability to ambulate

 A group of clinically heterogeneous AR inherited - at 20 to 25 yrs old - respiratory failure  usual

muscle diseases endpoint in DMD; but because of advancement
in ventilation technology, cardiac failure is now
 Characterized by hypotonia at birth, generalized the common endpoint
muscle weakness, frequently multiple contractures

 Muscle Biopsy: necrotic and regenerating

process
• Diagnosis:

 The clinical spectrum ranges from a very severe 1. Genetic studies

form, often resulting in early infant death, to
- Multiplex PCR- detect dystrophin gene deletion
relatively mild conditions, where the patient
in 60 % of cases
survives into adulthood
- MLPA- detect deletion and duplication, more
 CK could range from normal to marked elevation
sensitive than multiplex PCR

2. Immunohistochemical stain for dystrophin –

negative

• Treatment:

1. NOT YET AVAILABLE

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 OS 211 Dr. Mina N. Astejada
Muscle Diseases Exam 3

2. Temporary stabilization with steroids DMD/BMD suspect

3. Gene therapy to date is not possible DNA

Multiplex PCR No gene deletion

Muscle biopsy
Becker Muscular Dystrophy (BMD)
Immunohistochemistry Normal
• Milder form of DMD (milder weakness) for dystrophin dystrophin staining
(+) Dystrophin gene
deletion
• Sex - linked recessive disorder (Xp21), allelic
No dystrophin Reduced dystrophin
staining staining
• 1 in 30,000 male births

• Partial deletion of the gene coding for dystrophin
(vs. complete deletion in DMD)
• Dystrophin is partially present , muscle
membrane is semi – functional
DMD/BMD
Non DMD/BMD
DMD BMD
Figure 4. Diagnostic Algorithm between DMD and BMD. Notice that
both DMD and BMD have dystrophin gene deletion but BMD has
partial deletion only (kaya may patches pa of dystrophin sa histo). So
that’s why you need muscle biopsy to differentiate the two (gets?)

• Clinical Features:

1. Later onset of muscle weakness at slower rate c. Limb Girdle Muscular Dystrophy

2. Ambulatory up to adult life  A group of phenotypically and genetically

heterogeneous disorder
3. Cardiac abnormality may be seen but mental
retardation is rare  Weakness of the proximal muscles in the upper and
lower extremities

 18 different gene locus identified:

Type 1- AD

Type 2- AR

LGMD 2A- Calpainopathy

Normal • fiber size variation

• endomysial fibrosis – increase

CT surrounding muscle cell

• lobulated fibers

LGMD 2B- Dysferlinopathy

DMD

• (-) dysferlin in diseased muscle

cells

* Tyoe 2 is most common. Calpainopathy can only be

diagnosed with genetic screening. Dysferlinopathy can now be
BMD diagnosed immunohistichemically by the absence of dysferlin
in diseased muscle cells

Figure 3. Immunohistochemical stain: important to differentiate DMD * Dysferlin is a protein linked with skeletal muscle repair.
and BMD. BMD has patches of dystrophin in the plasma membrane Absence is characterized with muscle weakness and wasting.
while DMD totally has no outline of dystrophin. Compare both with a
normal plasma membrane which has a clear outline of dystrophin.

3. Myotonia Dystrophica

• multisystem disease (muscle, heart, eye, endocrine

system & CNS)

• sustained muscle contraction; failure of relaxation

• close eyes or hands  see if he can open eyes or

hands immediately

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 OS 211 Dr. Mina N. Astejada
Muscle Diseases Exam 3

• Histo: lots of nuclei in center  indicates immature  During attack, areflexia,

fiber (normal: peripheral/subsarcomeral), chained
nuclei, pale peripheral region (ring binden fiber),  [K+] > 6mM, signs of hyperkalemia in ECG
type1 fiber hypotrophy (DARKER colored due to
lots of mitochondria)  mas maliit size ng fiber  Tx: acetazolamide and thiazide diuretics (excrete
excess K)
• Charcteristics:

Weakness
Paramyotonia Congenita:
Myotonia (sustained muscle contraction)
 Paradoxical myotonia, increasing muscle stiffness
Cataracts with physical exercise, worsening of myotonia by cold,
weakness after exposure to cold.
Cardiac arrhythmia
 Tx: acetazolamide, mexiletine and salbutamol
Frontal balding

Potassium-aggravated myotonia :
TYPES: (based on weakness pattern distribution)
 Muscle stiffness without weakness and cold
Type I sensitivity.

• Distal> proximal

• Facial muscle affected b. Calcium Channel Diseases (all are PRIMARY diseases-
genetic)
• CTG trinucleotide repeats in DMPK gene
(chromosome 19) Hypokalemic Periodic Paralysis

• AD  Characterized by prolonged (days/ weeks)and severe

bouts of weakness  weakness is due to the
decrease in serum K+ (hindi makalabas sa cell)
therefore there is a decrease in action potential

 Precipitated by rest after a period of exercise or stress

Type II

• Proximal > distal  Tx: oral potassium supplements, acetazolamide

• Facial muscle rarely involved

Malignant Hyperthermia
• CCTG repeat expansion in ZNF9 gene (Chromosome
3)
 Dramatic and often fatal condition characterized by
• AD rapid and sustained rise in Temp during generalized
anesthesia associated with generalized muscle
rigidity, tachycardia, tachypnea and cyanosis

4. Channelopathies  Severe respiratory and metabolic acidosis

• Mutations in the genes encoding the proteins of the  Extensive muscle necrosis with subsequent
ion channels of the sarcolemma, SR and T-tubules myoglobinuria and renal shutdown
disrupt the normal transport of ions, in particular,
Na+, K+, Cl- and Ca2+  CK =/>50,000IU/L with elevated serum K+

• Clinically falls into 2 groups: those with myotonia

and those with paralysis
QUESTION: Why is Hyper- and Hypo-kalemic Periodic
Paralysis under sodium and calcium channel diseases,
• Appendix 1: Ion Channel Disorders of the Skeletal respectively?
Muscle. REMEMBER: Becker Syndrome lang ang
AR! All the rest are AD! ANSWER: Kasi daw K+ can pass through those channels
made up of calcium and sodium. The problem is with calcium
and sodium. Ung K+ ay effect na lang of that disorder (thus,
the name hyper- and hypo-kalemic). According to ma’am din, it
TYPES: is not that well understood pa.
a. Sodium Channel Diseases:

Hyperkalemic Periodic Paralysis c. Myotonia Congenita

 Paralytic episodes usually at rest after physical
excercise. • Gene mutation (encoding chloride channel)

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D Twilighters
 OS 211 Dr. Mina N. Astejada
Muscle Diseases Exam 3

• Characteristics:

- Myotonia

- Muscle stiffness

- warm-up phenomenon- increased muscle

strength with decreased activity

- Muscle hypertrophy

“- herculean” appearance

TYPES:

Thomsen’s disease: AD inheritance, generalized

Becker’s disease: AR inheritance; more of lower ex Figure 5. Modified Trichrome Gomori stain: Ragged red fibers are the
small patches of red stain surrounding and inside the muscle fiber.

Mitochondrial Diseases
6. Metabolic Myopathy
 Maternally inherited
Glycogenosis
 Clinically heterogenous
 breakdown of glycogen is an important source
 Onset may vary from birth to adulthood of energy in muscle

 Course may be rapidly progressive, static or even  defect in any steps in the glycolytic pathway
reversible can cause muscle fatigue, cramps, or
rhabdomyolysis, which is an important
 Distribution of weakness may be generalized with indicator of several metabolic problems
respiratory failure or proximal more than distal, and
may involve facial muscles with associated ptosis and
progressive external ophthalmoplegia
Acid Maltase Deficiency
 Serum and CSF lactate level may be increased
• 3 main clinical types: severe infantile
(Pompe’s), juvenile and adult onset

5. Mitochondrial Myopathy  Pompe’s disease (most common): usually

 Mitochondrial myopathy, Lactic acid and stroke-like
symptoms (MELAS)
- can be a differential diagnosis for stroke
because of the ‘stroke-like’ symptoms: sudden
weakness in 1 side; normal labs
 Myoclonic epilepsy and ragged red fiber (MERRF)
- cereballar atrophy
fatal in infancy affecting the liver, heart,
skeletal muscles, CNS and kidneys
 Severe hypotonia
 Tx: enzyme replacements (Genzyme) 
ONLY metabolic disease with treatment!
 Patho: lots of vacuoles with basophilic
materials

 Chronic Progressive External Ophthalmoplegia  Tx effect could be toxic myopathy (but don’t
(CPEO) deny Tx) monitor CK level and glycogen

 Kearns Sayre Syndrome (KSS): retinitis B. Acquired Myopathies

pigmentosa, PEO and heart block
1. Inflammatory Myopathies

*RAGGED RED FIBER is present in all types of mitochondrial

myopathy! This indicates an abnormal mitochondria TYPES:

a. Idiopathic: (Appendix B)
o Dermatomyositis (DM)

- Gottrons papules; Heliotrope rash in the face

and/or eyelids

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 OS 211 Dr. Mina N. Astejada
Muscle Diseases Exam 3

- Perifascicular atrophy: muscle fibers at

periphery of fascicles are atrophied
(secondary to ischemia; blood vessels o Overlap syndromes with CTD
involved); natitira ung nucleus tapos
nakakain ung membrane o Sarcoidosis

- Perivascular inf;ammation: lymphocytes o Behcet’s Syndrome

surround muscle fiber

Severe quadriceps atrophy

o Polymyositis (PM)
b. Infectious Myopathies
- fiber size variation
- atrophy not just peripheral A. Bacterial: Staphylococci, Streptococci, Yersinia,
- marked inflammation Legionella, Borrelia burgdoferi (Lyme’s dse),
Clostridium welchii (gas gangrene), Leprous myositis

o Inclusion Body Myositis (IBM) B. Parasitic: Trichinosis, Cysticercosis,

- most common acquired muscle disease >50
y/o
- Prevalence of 5-10/million
- Affects men > women at 2-3:1
Trypanosomiasis, Toxoplasmosis
C. Fungal: Candida, cyptococcus, sporotrichosis,
actinomycosis, Histoplasmosis
D. Viral: Adenovirus, Coxsackie, CMV, Influenza, EBV,
HIV, Parainfluenza, HTLV-1, Hepatitis B & C

- Average time from symptom onset to

diagnosis is ~ 6 yrs

- Scooped out forearm; finger flexor atrophy

2. Toxic Myopathy (Appendix C)
(more distal dominant than polymyositis);
quadriceps atrophy

- DOES NOT RESPOND TO STEROIDS!

 END OF TRANS 

Appendx A. Classification of Myopathies

Based on age of onset:

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 OS 211 Dr. Mina N. Astejada
Muscle Diseases Exam 3

Based on etiology:

Hereditary Acquired

Channelopathies Drug-induced myopathies

Congenital myopathies Endocrine myopathies

Metabolic myopathies Inflammatory myopathies

Mitochondrial myopathies Myopathies associated with

systemic diseases
Muscular myopathies
Toxic myopathies
myotonias

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 OS 211 Dr. Mina N. Astejada
Muscle Diseases Exam 3

Appendix B. Clinical Features of Major Inflammatory Myopathies

Myopathy Gender Ageof Weakness CK Levels Histologic Response

Onset pattern Findings to Steroids

DM F >M Childto Proximal > 50X↑ Perimysial & Yes

Adult Distal perivasular
inflammation ;
perifascicular
atrophy
PM F >M Adult Proximal > 50X↑ Endomysial Yes
Distal inflammatiion

IBM M>F Elderly Proximal = 10X↑ Endomysial No

(>50yrs) Distal inflammation ;
Rimmed
vacuoles,
tubofilaments
on EM

Edward’s Troop: Nonette’s Gang:

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D Twilighters
 OS 211 Dr. Mina N. Astejada
Muscle Diseases Exam 3

Nonette’s Mob:

Edward: Merry Christmas Jelly A’s & Jolly B’s!!! Enjoy the break!

Nonette: Hi phinoms, Conquis, & 4play! This trans is dedicated

to my Block B sisses dahil miss ko na kayo! Wag kayong
masyadong ma-toxic. Chillax! After renal, super benign nyo na!
Kami nmn ang toxic. Ultimate bonding soon, girls! Mwah! Hi
mahjong girls! Tanx sa mga pagkain. Kaya ako tumataba dhil sa
inyo! Haha! Go Duquerendribles! To my Singapore groupies,
sana makuha ko tlga on time ang passport ko. Baka hndi ako
makasama! Oh no! Wag nmn!!! Good luck Jelly A’s. Last stretch
for neuro. We can do this!!!

Appendix C. Features of Glycogenoses That Affect Muscles

Drug Clinical features Histology Comments

1. Statins (Cholesterol Myalgia,

Myalgia, weakness or Atrophy, inflammation, Fibrates &niacin also implicated in
loweringmyopath thyor
yor even rhabdomyolysis Occasional necrosis causing
causingCLAM
CLAM) CK elevation – 1%
1%
2. Ste
Steroids Insidious onset after weeks or months of Type II atrophy Regular exercise may redu ce this
reduce
use , Flourinatedform
Flourinatedforms are more myotoxic
Painless proximal weakness &atrophy, (eg.
eg. Dexamethasone,
ethasone, triamcinolon
cinolonee))
Normal CK levels
3. Zidovudine Proximal weakness, myalgia,
yalgia, elevated Mitochondrial proliferation,
CK levels Ragged Red Population

4. Chloroquine Painless proximal weakness, elevated CK Curvelinear bodies on EM Cardiac muscles &PN may be
involved

5. Colchicine Muscle pain &weakness Acid phosphase (+) PN involvement

Vacuoles

6. Amiodarone Muscle pain &weakness Vacuolar myopathyw

yopathywith inclusion
inclusion PN involvement
bodies

7. D- penicillamine
icillam Poximal pain and weakness Inflammation
(Seen in 1%
1%of treated patients)

8. Cyclosporine Muscle pain &weakness, Atrophy, accumulation of

Occasional CK elevation mitochondria, lipid vacuoles

9. Valp
alproic Acid Muscle weakness Mitochondria abnormalities, lipid Can improve with carnitine
accumulation supplementation

PALARONG MED IS THE BEST! CONGRATS 2012 PLAYERS! (Photos by Joanne Lucero )

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 OS 211 Dr. Mina N. Astejada
Muscle Diseases Exam 3

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