Trans Muscle Disease

OS 211

Dr. Mina N. Astejada Exam 3

Muscle Diseases

Outline: I.

Introduction

II.

Classification of Myopathies A.

•

a neuromuscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness

•

primary defect is within the muscle (vs. neuropathy)

Hereditary 1.

Congenital Myopathy

2.

a.

Central Core Disease

b.

Centronuclear/Myotubular Myopathy

c.

Nemaline Myopathy

d.

Congenital Fiber Type Disproportion

Muscular Dystrophy a.

Congenital Muscular Dystrophy

b.

Dystrophinopathies

c.

Limb Girdle Muscular Dystrophy

II. Classification of Myopathies (Appendix A)

A. Hereditary Myopathies 1. Congenital Myopathy 

A clinically, genetically and pathologically heterogeneous disorder defined by the presence of particular histological features

 Onset is often at birth or early childhood (~7 years old)

3.

Myotonia Dystrophica



Floppy infant with variable hypotonia

4.

Channelopathies



Long “myopathic” face is a common feature



CNS and peripheral nerves are not usually involved



Normal intelligence

a.

Sodium Channel Disease

b.

Calcium channel Disease

c.

Myotonia Congenita

5.

Mitochondrial Myopathy



Generally non-progressive

6.

Metabolic Myopathy



Diaphragmatic involvement may be disproportionate to overall muscle weakness



Inheritance: AR, AD or X-linked



CK are usually normal or slightly elevated



Treatment: supportive

B.

Acquired 1.

2.

Inflammatory Myopathies a.

Idiopathic

b.

Infectious

Toxic Myopathy

*Classification is based on histologic features (muscle biopsy is therefore needed for diagnosis): *Hi 2012! This trans was made from scratch because the 2011 supplementary CD doesn’t have a softcopy of this trans (they have the 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 Jolly B’s na magttrans nito! Hehe libre nyo kami. Haha!

I. Introduction Skeletal Muscle 

75% water



20% protein

 5% others: high-energy phosphates, urea, lactic acid, Ca, Mg, P, enzymes, amino acids, lipids and carbohydrates

Myopathies

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a. Central Core Disease - Gene: Ryanodine receptor (RyR1) - associated with malignant hyperthermia

b. Centronuclear/Myotubular Myopathy - Gene: Myotubularin (MTM1)  X-linked Dynamin (DNM2)  AR

c. Nemaline Myopathy - Gene: ACTA1*, nebulin, α-tropomyosin, βtropomyosin, slow troponin T

d. Congenital Fiber Type Disproportion

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- Gene: ACTA1* Walker-Warburg Muscle Eye Brain

* same gene but different location of mutation

Agyria

A

B

Pachygyria/ Agyria

Fukuyam a

Focal Agyria

MDC1 C

Normal brain

Figure 2. CNS Involvement in CMD. Take note that CNS involvement is not an absolute characteristic of CMD.

b. Dystrophinopathies Duchene Muscular Dystrophy (DMD)

C

D

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)

•

Most common

•

Sex - linked recessive disorder (Xp21)

•

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 running)

 It is a heterogeneous group of inherited primary diseases of the muscle, clinically characterized by progressive muscle weakness and wasting. 

- Pseudohypertrophy of calf muscles

Histologically, it is unified by the presence of necrotic and regenerating processes, often associated with an increased amount of connective and adipose tissues

- (+) Gowers’ sign 2. Later signs - 10 to 14 yrs old - relentless progression & involvement of shoulder girdle muscles

TYPES:

- Scoliosis & thoracic deformity

a. Congenital Muscular Dystrophy (CMD) 

- Inability to ambulate

First described by Batten in 1903

- at 20 to 25 yrs old - respiratory failure  usual endpoint in DMD; but because of advancement in ventilation technology, cardiac failure is now the common endpoint

 A group of clinically heterogeneous AR inherited muscle diseases 

Characterized by hypotonia at birth, generalized muscle weakness, frequently multiple contractures

 Muscle Biopsy: necrotic and regenerating process 



•

Diagnosis: 1. Genetic studies

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

- Multiplex PCR- detect dystrophin gene deletion in 60 % of cases - MLPA- detect deletion and duplication, more sensitive than multiplex PCR

CK could range from normal to marked elevation

2. Immunohistochemical stain for dystrophin – negative

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Treatment: 1. NOT YET AVAILABLE

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Muscle Diseases

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)

•

Milder form of DMD (milder weakness)

•

Sex - linked recessive disorder (Xp21), allelic

•

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

•

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

(+) Dystrophin gene deletion

Immunohistochemistry for dystrophin

Normal dystrophin staining

No dystrophin staining

Reduced dystrophin staining

DMD

BMD

DMD/BMD

Non 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?)

c. Limb Girdle Muscular Dystrophy 

A group of phenotypically and genetically heterogeneous disorder



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

•

BMD

Figure 3. Immunohistochemical stain: important to differentiate DMD and BMD. BMD has patches of dystrophin in the plasma membrane while DMD totally has no outline of dystrophin. Compare both with a normal plasma membrane which has a clear outline of dystrophin.

(-) dysferlin in diseased muscle cells

* Tyoe 2 is most common. Calpainopathy can only be diagnosed with genetic screening. Dysferlinopathy can now be diagnosed immunohistichemically by the absence of dysferlin in diseased muscle cells * Dysferlin is a protein linked with skeletal muscle repair. Absence is characterized with muscle weakness and wasting.

3. Myotonia Dystrophica

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•

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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•

•

Histo: lots of nuclei in center  indicates immature fiber (normal: peripheral/subsarcomeral), chained nuclei, pale peripheral region (ring binden fiber), type1 fiber hypotrophy (DARKER colored due to lots of mitochondria)  mas maliit size ng fiber



During attack, areflexia,



[K+] > 6mM, signs of hyperkalemia in ECG

 Tx: acetazolamide and thiazide diuretics (excrete excess K)

Charcteristics: Weakness Myotonia (sustained muscle contraction)

Paramyotonia Congenita: 

Paradoxical myotonia, increasing muscle stiffness with physical exercise, worsening of myotonia by cold, weakness after exposure to cold.



Tx: acetazolamide, mexiletine and salbutamol

Cataracts Cardiac arrhythmia Frontal balding

Potassium-aggravated myotonia : TYPES: (based on weakness pattern distribution) 

Type I •

Distal> proximal

•

Facial muscle affected

•

CTG trinucleotide repeats in DMPK gene (chromosome 19)

•

AD

Muscle stiffness sensitivity.

without

weakness

and

cold

b. Calcium Channel Diseases (all are PRIMARY diseasesgenetic) Hypokalemic Periodic Paralysis

 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

Type II •

Proximal > distal

•

Facial muscle rarely involved

•

CCTG repeat expansion in ZNF9 gene (Chromosome 3)

•



Precipitated by rest after a period of exercise or stress



Tx: oral potassium supplements, acetazolamide

Malignant Hyperthermia 

Dramatic and often fatal condition characterized by rapid and sustained rise in Temp during generalized anesthesia associated with generalized muscle rigidity, tachycardia, tachypnea and cyanosis



Severe respiratory and metabolic acidosis



Extensive muscle necrosis with myoglobinuria and renal shutdown



CK =/>50,000IU/L with elevated serum K+

AD

4. Channelopathies •

• •

Mutations in the genes encoding the proteins of the ion channels of the sarcolemma, SR and T-tubules disrupt the normal transport of ions, in particular, Na+, K+, Cl- and Ca2+ Clinically falls into 2 groups: those with myotonia and those with paralysis Appendix 1: Ion Channel Disorders of the Skeletal Muscle. REMEMBER: Becker Syndrome lang ang AR! All the rest are AD!

TYPES:

subsequent

QUESTION: Why is Hyper- and Hypo-kalemic Periodic Paralysis under sodium and calcium channel diseases, respectively? 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 is not that well understood pa.

a. Sodium Channel Diseases: Hyperkalemic Periodic Paralysis 

Paralytic episodes usually at rest after physical excercise.

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c. Myotonia Congenita

•

Gene mutation (encoding chloride channel)

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Muscle Diseases

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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



Clinically heterogenous



Onset may vary from birth to adulthood



Course may be rapidly progressive, static or even reversible

Glycogenosis 

breakdown of glycogen is an important source of energy in muscle

 defect in any steps in the glycolytic pathway can cause muscle fatigue, cramps, or rhabdomyolysis, which is an important indicator of several metabolic problems

 Distribution of weakness may be generalized with 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

•

5. Mitochondrial Myopathy 

 Pompe’s disease (most common): usually fatal in infancy affecting the liver, heart, skeletal muscles, CNS and kidneys

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 

3 main clinical types: severe infantile (Pompe’s), juvenile and adult onset

 Tx: enzyme replacements (Genzyme)  ONLY metabolic disease with treatment!

Myoclonic epilepsy and ragged red fiber (MERRF)



- cereballar atrophy 



Chronic Progressive (CPEO)

External

Patho: lots of vacuoles with basophilic materials

 Tx effect could be toxic myopathy (but don’t

Ophthalmoplegia

Kearns Sayre Syndrome (KSS): pigmentosa, PEO and heart block

Severe hypotonia

deny Tx) monitor CK level and glycogen retinitis

*RAGGED RED FIBER is present in all types of mitochondrial myopathy! This indicates an abnormal mitochondria

B. Acquired Myopathies 1. Inflammatory Myopathies

TYPES:

a. Idiopathic: (Appendix B) o

Dermatomyositis (DM)

-

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Gottrons papules; Heliotrope rash in the face and/or eyelids

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Muscle Diseases

-

-

o

Perivascular inf;ammation: lymphocytes surround muscle fiber

o

Overlap syndromes with CTD

o

Sarcoidosis

o

Behcet’s Syndrome

Severe quadriceps atrophy

Polymyositis (PM) -

o

Perifascicular atrophy: muscle fibers at periphery of fascicles are atrophied (secondary to ischemia; blood vessels involved); natitira ung nucleus tapos nakakain ung membrane

b. Infectious Myopathies

fiber size variation atrophy not just peripheral marked inflammation

A. Bacterial: Staphylococci, Streptococci, Yersinia, Legionella, Borrelia burgdoferi (Lyme’s dse), Clostridium welchii (gas gangrene), Leprous myositis B. Parasitic: Trichinosis, Cysticercosis, Trypanosomiasis, Toxoplasmosis

Inclusion Body Myositis (IBM) -

most common acquired muscle disease >50 y/o

-

Prevalence of 5-10/million

-

Affects men > women at 2-3:1

-

Average time from symptom onset to diagnosis is ~ 6 yrs

-

Scooped out forearm; finger flexor atrophy (more distal dominant than polymyositis); quadriceps atrophy

-

DOES NOT RESPOND TO STEROIDS!

C. Fungal: Candida, cyptococcus, sporotrichosis, actinomycosis, Histoplasmosis D. Viral: Adenovirus, Coxsackie, CMV, Influenza, EBV, HIV, Parainfluenza, HTLV-1, Hepatitis B & C

2. Toxic Myopathy (Appendix C)

 END OF TRANS 

Appendx A. Classification of Myopathies

Based on age of onset:

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Muscle Diseases

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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Appendix B. Clinical Features of Major Inflammatory Myopathies

Myopathy

Gender

Ageof Onset

Weakness pattern

CK Levels

DM

F >M

Childto Adult

Proximal > Distal

50X↑

Perimysial & perivasular inflammation ; perifascicular atrophy

Yes

PM

F >M

Adult

Proximal > Distal

50X↑

Endomysial inflammatiion

Yes

IBM

M>F

Elderly (>50yrs)

Proximal = Distal

10X↑

Endomysial inflammation ; Rimmed vacuoles, tubofilaments on EM

No

Edward’s Troop:

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Histologic Findings

Response to Steroids

Nonette’s Gang:

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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 loweringmyopath thyor yor CLAM)

Myalgia, Myalgia, weakness or even rhabdomyolysis CK elevation – 1% 1%

Atrophy, inflammation, Occasional necrosis

Fibrates &niacin also implicated in causing causingCLAM

2. Ste Steroids

Insidious onset after weeks or months of use , Painless proximal weakness &atrophy, Normal CK levels

Type II atrophy

Regular exercise may redu ce this reduce Flourinatedform Flourinatedforms are more myotoxic (eg. e)) eg. Dexamethasone, ethasone, triamcinolon cinolone

3. Zidovudine

Proximal weakness, myalgia, yalgia, elevated CK levels

Mitochondrial proliferation, Ragged Red Population

4. Chloroquine

Painless proximal weakness, elevated CK

Curvelinear bodies on EM

Cardiac muscles &PN may be involved

Acid phosphase (+) Vacuoles

PN involvement PN involvement

5. Colchicine

Muscle pain &weakness

6. Amiodarone

Muscle pain &weakness

Vacuolar myopathyw clusion yopathywith in inclusion bodies

7. D- penicilla mine icillam

Poximal pain and weakness (Seen in 1% 1%of treated patients)

Inflammation

8. Cyclosporine

Muscle pain &weakness, Occasional CK elevation

Atrophy, accumulation of mitochondria, lipid vacuoles

9. Valp alproic Acid

Muscle weakness

Mitochondria abnormalities, lipid accumulation

Can improve with carnitine supplementation

PALARONG MED IS THE BEST! CONGRATS 2012 PLAYERS! (Photos by Joanne Lucero ) November 28, 2008 | Friday

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OS 211 Muscle Diseases

November 28, 2008 | Friday

Dr. Mina N. Astejada Exam 3

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