TRANS Muscle Disease

Muscle Diseases

OS 211 Dr. Mina N. Astejada

Exam 3

November 28, 2008 | Friday Page 1 of 6D Twilighters

Outline:I. IntroductionII. Classification of Myopathies

A. Hereditary1.Congenital Myopathy

a. Central Core Diseaseb. Centronuclear/Myotubular Myopathyc. Nemaline Myopathyd. Congenital Fiber Type Disproportion

2.Muscular Dystrophya. Congenital Muscular Dystrophyb. Dystrophinopathiesc. Limb Girdle Muscular Dystrophy

3.Myotonia Dystrophica4.Channelopathies

a. Sodium Channel Diseaseb. Calcium channel Diseasec. Myotonia Congenita

5.Mitochondrial Myopathy6.Metabolic Myopathy

B. Acquired1. Inflammatory Myopathies

a. Idiopathicb. Infectious

2. Toxic Myopathy

*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. IntroductionSkeletal Muscle

75% water 20% protein 5% others: high-energy phosphates, urea, lactic acid,

Ca, Mg, P, enzymes, amino acids, lipids and carbohydrates

Myopathies 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)

II. Classification of Myopathies (Appendix A)

A. Hereditary Myopathies1. 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)

Floppy infant with variable hypotonia Long “myopathic” face is a common feature CNS and peripheral nerves are not usually

involved Normal intelligence Generally non-progressive Diaphragmatic involvement may be

disproportionate to overall muscle weakness Inheritance: AR, AD or X-linked CK are usually normal or slightly elevated Treatment: supportive

*Classification is based on histologic features (muscle biopsy is therefore needed for diagnosis): 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, a-tropomyosin, b-

tropomyosin, slow troponin T

d. Congenital Fiber Type Disproportion- Gene: ACTA1*

* same gene but different location of mutation

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)

2. Muscular Dystrophy First described by Nattrass in 1954 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

TYPES:a. Congenital Muscular Dystrophy (CMD)

First described by Batten in 1903 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

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 could range from normal to marked elevation

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

b. DystrophinopathiesDuchene Muscular Dystrophy (DMD)

Most common Sex - linked recessive disorder (Xp21) mutation in the gene coding for dystrophin (400kD) Clinical Features:

A

C

B

D

FukuyamaMuscle Eye Brain MDC1C

Agyria Pachygyria/ Agyria Normal brain

Walker-Warburg

Focal Agyria

Muscle Diseases

OS 211 Dr. Mina N. Astejada

Exam 3

November 28, 2008 | Friday Page 2 of 6D Twilighters

1. Early signs - starts at age 3 to 5 years - Pelvic girdle weakness (waddling gait, frequent falls, difficulty climbing stairs, awkward running)

- Pseudohypertrophy of calf muscles - (+) Gowers’ sign2. Later signs - 10 to 14 yrs old

- relentless progression & involvement of shoulder girdle muscles

- Scoliosis & thoracic deformity- Inability to ambulate- 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

Diagnosis: 1. Genetic studies - Multiplex PCR- detect dystrophin gene deletion in 60 % of cases - MLPA- detect deletion and duplication, more sensitive than multiplex PCR 2. Immunohistochemical stain for dystrophin – negative

Treatment: 1. NOT YET AVAILABLE 2. Temporary stabilization with steroids 3. Gene therapy to date is not possible

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

Normal

DMD

BMD

Normal

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.

DMD/BMD suspect

Multiplex PCR

(+) Dystrophin gene deletion

DMD/BMD

No gene deletion

DNA

Muscle biopsy

Immunohistochemistryfor dystrophin

No dystrophinstaining

Reduced dystrophinstaining

Normal dystrophin staining

Non DMD/BMD

DMD BMD

DMD/BMD suspect

Multiplex PCR

(+) Dystrophin gene deletion

DMD/BMD

No gene deletion

DNA

Muscle biopsy

Immunohistochemistryfor dystrophin

No dystrophinstaining

Reduced dystrophinstaining

Normal dystrophin staining

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?)

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 fiber size variation endomysial fibrosis – increase CT

surrounding muscle cell lobulated fibers

LGMD 2B- Dysferlinopathy (-) 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 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 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

Charcteristics:WeaknessMyotonia (sustained muscle contraction)CataractsCardiac arrhythmia Frontal balding

TYPES: (based on weakness pattern distribution) Type I

• Distal> proximal• Facial muscle affected• CTG trinucleotide repeats in DMPK gene

(chromosome 19)• AD

Type II

Muscle Diseases

OS 211 Dr. Mina N. Astejada

Exam 3

November 28, 2008 | Friday Page 3 of 6D Twilighters

• Proximal > distal• Facial muscle rarely involved• CCTG repeat expansion in ZNF9 gene (Chromosome

3)• 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:a. Sodium Channel Diseases:

Hyperkalemic Periodic Paralysis Paralytic episodes usually at rest after physical

excercise. During attack, areflexia, [K+] > 6mM, signs of hyperkalemia in ECG Tx: acetazolamide and thiazide diuretics (excrete

excess K)

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

Potassium-aggravated myotonia : Muscle stiffness without weakness and cold

sensitivity.

b. Calcium Channel Diseases (all are PRIMARY diseases- genetic)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

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 subsequent

myoglobinuria and renal shutdown CK =/>50,000IU/L with elevated serum K+

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.

c. Myotonia Congenita Gene mutation (encoding chloride channel) Characteristics:

- Myotonia - Muscle stiffness- warm-up phenomenon- increased muscle

strength with decreased activity- Muscle hypertrophy

“- herculean” appearanceTYPES:

Thomsen’s disease: AD inheritance, generalized Becker’s disease: AR inheritance; more of lower ex

Mitochondrial Diseases Maternally inherited Clinically heterogenous Onset may vary from birth to adulthood Course may be rapidly progressive, static or even

reversible 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

Serum and CSF lactate level may be increased

5. Mitochondrial Myopathy 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 Chronic Progressive External

Ophthalmoplegia (CPEO) Kearns Sayre Syndrome (KSS): retinitis

pigmentosa, PEO and heart block

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

Figure 5. Modified Trichrome Gomori stain: Ragged red fibers are the small patches of red stain surrounding and inside the muscle fiber.

6. Metabolic MyopathyGlycogenosis

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

Acid Maltase Deficiency 3 main clinical types: severe infantile

(Pompe’s), juvenile and adult onset Pompe’s disease (most common): usually 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 Tx effect could be toxic myopathy (but don’t

deny Tx) monitor CK level and glycogen

Muscle Diseases

OS 211 Dr. Mina N. Astejada

Exam 3

November 28, 2008 | Friday Page 4 of 6D Twilighters

B. Acquired Myopathies1. Inflammatory Myopathies

TYPES:a. Idiopathic: (Appendix B)

o Dermatomyositis (DM) - Gottrons papules; Heliotrope rash in the face

and/or eyelids- Perifascicular atrophy: muscle fibers at

periphery of fascicles are atrophied (secondary to ischemia; blood vessels involved); natitira ung nucleus tapos nakakain ung membrane

- Perivascular inf;ammation: lymphocytes surround muscle fiber

o Polymyositis (PM) - fiber size variation- atrophy not just peripheral- marked inflammation

o 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!

o Overlap syndromes with CTD o Sarcoidosis o Behcet’s Syndrome

b. Infectious MyopathiesA. Bacterial: Staphylococci, Streptococci, Yersinia,

Legionella, Borrelia burgdoferi (Lyme’s dse), Clostridium welchii (gas gangrene), Leprous myositis

B. Parasitic: Trichinosis, Cysticercosis, Trypanosomiasis, Toxoplasmosis

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:

Severe quadriceps atrophy

Muscle Diseases

OS 211 Dr. Mina N. Astejada

Exam 3

November 28, 2008 | Friday Page 5 of 6D Twilighters

Based on etiology:

Hereditary Acquired

ChannelopathiesCongenital myopathiesMetabolic myopathiesMitochondrial myopathiesMuscular myopathiesmyotonias

Drug-induced myopathiesEndocrine myopathiesInflammatory myopathiesMyopathies associated with systemic diseasesToxic myopathies

Appendix B. Clinical Features of Major Inflammatory Myopathies

MyopathyMyopathy GenderGender Age of Age of OnsetOnset

Weakness Weakness patternpattern

CK LevelsCK Levels HistologicHistologicFindingsFindings

Response Response to Steroidsto Steroids

DMDM F > MF > M Child to Child to AdultAdult

Proximal > Proximal > DistalDistal

50 X 50 X PerimysialPerimysial & & perivasularperivasularinflammation ; inflammation ; perifascicularperifascicularatrophyatrophy

YesYes

PMPM F > MF > M AdultAdult Proximal > Proximal > DistalDistal

50 X 50 X EndomysialEndomysialinflammatiioninflammatiion

YesYes

IBMIBM M > FM > F Elderly Elderly

(> 50 yrs) (> 50 yrs) Proximal = Proximal =

DistalDistal10 X 10 X EndomysialEndomysial

inflammation ; inflammation ; Rimmed Rimmed vacuoles, vacuoles, tubofilamentstubofilamentson EMon EM

NoNo

MyopathyMyopathy GenderGender Age of Age of OnsetOnset

Weakness Weakness patternpattern

CK LevelsCK Levels HistologicHistologicFindingsFindings

Response Response to Steroidsto Steroids

DMDM F > MF > M Child to Child to AdultAdult

Proximal > Proximal > DistalDistal

50 X 50 X PerimysialPerimysial & & perivasularperivasularinflammation ; inflammation ; perifascicularperifascicularatrophyatrophy

YesYes

PMPM F > MF > M AdultAdult Proximal > Proximal > DistalDistal

50 X 50 X EndomysialEndomysialinflammatiioninflammatiion

YesYes

IBMIBM M > FM > F Elderly Elderly

(> 50 yrs) (> 50 yrs) Proximal = Proximal =

DistalDistal10 X 10 X EndomysialEndomysial

inflammation ; inflammation ; Rimmed Rimmed vacuoles, vacuoles, tubofilamentstubofilamentson EMon EM

NoNo

Edward’s Troop: Nonette’s Gang:

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!!!

Muscle Diseases

OS 211 Dr. Mina N. Astejada

Exam 3

November 28, 2008 | Friday Page 6 of 6D Twilighters

Appendix C. Features of Glycogenoses That Affect Muscles

PN involvementPN involvementVacuolar Vacuolar myopathymyopathy with inclusion with inclusion bodiesbodies

Muscle pain & weaknessMuscle pain & weakness6. 6. AmiodaroneAmiodarone

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

7. D7. D-- penicillaminepenicillamine

Atrophy, accumulation of Atrophy, accumulation of mitochondria, lipid vacuolesmitochondria, lipid vacuoles

Muscle pain & weakness,Muscle pain & weakness,Occasional CK elevationOccasional CK elevation

8. Cyclosporine8. Cyclosporine

Can improve with Can improve with carnitinecarnitinesupplementationsupplementation

Mitochondria abnormalities, lipid Mitochondria abnormalities, lipid accumulationaccumulation

Muscle weaknessMuscle weakness9. 9. ValproicValproic AcidAcid

PN involvementPN involvementAcid Acid phosphasephosphase (+)(+)VacuolesVacuoles

Muscle pain & weaknessMuscle pain & weakness5. 5. ColchicineColchicine

Cardiac muscles & PN may be Cardiac muscles & PN may be involvedinvolved

CurvelinearCurvelinear bodies on EMbodies on EMPainless proximal weakness, elevated CKPainless proximal weakness, elevated CK4. 4. ChloroquineChloroquine

DrugDrug Clinical featuresClinical features HistologyHistology CommentsComments

1. 1. StatinsStatins (Cholesterol (Cholesterol lowering lowering myopathymyopathy or or CLAM)CLAM)

MyalgiaMyalgia, weakness or , weakness or even even rhabdomyolysisrhabdomyolysisCK elevation CK elevation –– 1%1%

Atrophy, inflammation,Atrophy, inflammation,Occasional necrosisOccasional necrosis

FibratesFibrates & niacin also implicated in & niacin also implicated in causing CLAMcausing CLAM

2. Steroids2. Steroids Insidious onset after weeks or months of Insidious onset after weeks or months of use , use , Painless proximal weakness & atrophy, Painless proximal weakness & atrophy, Normal CK levelsNormal CK levels

Type II atrophyType II atrophy Regular exercise may reduce thisRegular exercise may reduce thisFlourinatedFlourinated forms are more forms are more myotoxicmyotoxic((egeg. . DexamethasoneDexamethasone, , triamcinolonetriamcinolone))

3. 3. ZidovudineZidovudine Proximal weakness, Proximal weakness, myalgiamyalgia, elevated , elevated CK levelsCK levels

Mitochondrial proliferation, Mitochondrial proliferation, Ragged Red PopulationRagged Red Population

PN involvementPN involvementVacuolar Vacuolar myopathymyopathy with inclusion with inclusion bodiesbodies

Muscle pain & weaknessMuscle pain & weakness6. 6. AmiodaroneAmiodarone

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

7. D7. D-- penicillaminepenicillamine

Atrophy, accumulation of Atrophy, accumulation of mitochondria, lipid vacuolesmitochondria, lipid vacuoles

Muscle pain & weakness,Muscle pain & weakness,Occasional CK elevationOccasional CK elevation

8. Cyclosporine8. Cyclosporine

Can improve with Can improve with carnitinecarnitinesupplementationsupplementation

Mitochondria abnormalities, lipid Mitochondria abnormalities, lipid accumulationaccumulation

Muscle weaknessMuscle weakness9. 9. ValproicValproic AcidAcid

PN involvementPN involvementAcid Acid phosphasephosphase (+)(+)VacuolesVacuoles

Muscle pain & weaknessMuscle pain & weakness5. 5. ColchicineColchicine

Cardiac muscles & PN may be Cardiac muscles & PN may be involvedinvolved

CurvelinearCurvelinear bodies on EMbodies on EMPainless proximal weakness, elevated CKPainless proximal weakness, elevated CK4. 4. ChloroquineChloroquine

DrugDrug Clinical featuresClinical features HistologyHistology CommentsComments

1. 1. StatinsStatins (Cholesterol (Cholesterol lowering lowering myopathymyopathy or or CLAM)CLAM)

MyalgiaMyalgia, weakness or , weakness or even even rhabdomyolysisrhabdomyolysisCK elevation CK elevation –– 1%1%

Atrophy, inflammation,Atrophy, inflammation,Occasional necrosisOccasional necrosis

FibratesFibrates & niacin also implicated in & niacin also implicated in causing CLAMcausing CLAM

2. Steroids2. Steroids Insidious onset after weeks or months of Insidious onset after weeks or months of use , use , Painless proximal weakness & atrophy, Painless proximal weakness & atrophy, Normal CK levelsNormal CK levels

Type II atrophyType II atrophy Regular exercise may reduce thisRegular exercise may reduce thisFlourinatedFlourinated forms are more forms are more myotoxicmyotoxic((egeg. . DexamethasoneDexamethasone, , triamcinolonetriamcinolone))

3. 3. ZidovudineZidovudine Proximal weakness, Proximal weakness, myalgiamyalgia, elevated , elevated CK levelsCK levels

Mitochondrial proliferation, Mitochondrial proliferation, Ragged Red PopulationRagged Red Population

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