Dystrophy, Duchenne, Becker, Genetic predisposition

1. 2014-03-09 ۱۳۹۲-۱۲-۱۹
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2. ARRANGED BY: KALIMULLAH (WARDAK)
INSTRUCTOR PROF: DR. RAFIQI
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3. MYOPATHY AND DYSTROPHY
• Myopathy is a term applied to an acquired or developmental
defect in certain muscles. It is not a neurological disease, and
should be distinguished from neuropathic conditions such as
MOTOR NEURONE DISEASE (MND), which tend to affect the
distal limb muscles. The main subdivisions are:
1. genetically determined
2. Congenital
3. Metabolic
4. drug-induced
5. and myopathy (often inflammatory) secondary to a distant
carcinoma.
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MYOPATHY &DYSTROPHY

4. • Progressive muscular dystrophy is characterized by
symmetrical wasting and weakness, the muscle fibers
being largely replaced by fatty and fibrous tissue, with no
sensory loss. Inheritance may take several forms, thus
affecting the sex and age of victims.
• The commonest type is DUCHENNE MUSCULAR
DYSTROPHY, which is inherited as a sex-linked disorder. It
nearly always occurs in boys.
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MYOPATHY &DYSTROPHY

5. APPROACH TO MYOPATHY
• Hereditary
• acquired
MYOPATHY &DYSTROPHY
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6. HISTORY
• Onset age
• distribution
• Course
• Myalgia
• Cramp
• Contracture
• Dark urine
• Myotonia ,Stiffness
• Aggravating: exercise /diet/temperature/drug
MYOPATHY &DYSTROPHY
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7. EXAM
• Limb girdle
• Scapuloperoneal
• Distal
• Ocular or pharyngeal
• Neck extensor
• Atrophy or hypertrophy
• Myotonia
MYOPATHY &DYSTROPHY
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8. HEREDITARY MYOPATHY
Heriditaary MYOPATHY
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9. • Structural
• functional
Heriditaary MYOPATHY
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10. CLASSIFICATION
• Dystrophy
• Congenital myopathy
• Channelopathies & myotonia
• Metabolic (fatty acid/ glycogensis/mitochondrial)
Heriditaary MYOPATHY
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11. MUSCULAR DYSTROPHY
• are inherited myopathy characterized by progressive
muscles weakness &degeneration &subsequent
replacement by fibrous & fatty connective tissue
• Historically were categorized by their:
• Age onset /distribution of weakness& pattern of
inheritance
• The genetic mutation &abnormal gene product were
defined for many of them
MUSCULARDYSTROPHY
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12. MD
MUSCULARDYSTROPHY
protein
age
inheritance
disease
dystrophin
2y
X linked
duchenne
..
5-15
X linked
beckers
emerin
childh
X linked
Emery-dreifuss
sacroglycan
AD/AR
LGD
birth
AR
Cong/CNS
merosin
..
AR
Cong/noCNS
AD/AR
Distal MD
AD
bethlen
Child&
adult
AD
FSH
5th dec
AD
oculodystrophy
2th,3th
decade
AD
Myotonic type1
AD
Myotonic type 2
desmmin
AD
myofibrillar
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13. DUCHENNE MD
• Incidence: 1/3500 male birth
• 1/3 new mutation
• Age of onset: as early as 2-3y with delay milestones
• Progressive limb girdle pattern
• Fall 5-6y/difficult climb stair 8y, confined to wheelchair 12y
MUSCULARDYSTROPHY
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14. • Joint contractures 6-10y
• Calf hypertrophy is early
• Muscles atrophy late
• Progressive kyphoscliosis due to Paraspinal muscles weakness
• Reflex: biceps/knee/lost by age 10y
• ankle preserved late in disease
• Respiratory distress after age 10
MUSCULARDYSTROPHY
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15. • Cardiac: generally asymptomatic
• CHF, arrhythmia late
• 90% abnormal ECG :tall R wave,deep Q wave
• Echo: hypokinesia ,dilatation of ventricular wall
• GI: intestinal pseudo obstruction
• IQ: one SD below N
MUSCULARDYSTROPHY
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16. LAB
• A dystrophin gene deletion can be detected by:
• DNA analyses from leukocytes by PCR in 2/3 patient or DNA
muscles
• The other 1/3 diagnosed by… muscles biopsy( dystrophin
defferentiade by stain, typical features of MD)
• EMG:myopathic &fibrillation
• Note :if DNA study +ve no need for EMG &muscles biopsy
MUSCULARDYSTROPHY
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17. BECKERS MD
• Is milder form
• 5/100,000
• Age :5-15y
• Wheelchair at 30y
• Cardiac similar to duchenne
• Death by age 40
• Dx: DNA, muscle biopsy decrease in dystrophin
• CK:moderatly elevated
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18. TREATMENT
• No treatment prevent the progression
corticosteroid :controlled trial with predinsone 0,75mg/kg
demonstrate moderate improvement in strength &delay
progression to wheel chair& respiratory compromise
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19. EMERY-DREIFUSS
• X linked
• onset :childhood
• Triad of:
1-early contracture elbow, ankle &posterior cervical
2-progressive scapulohumroperoneal
3-cardiomyopathy with atrial conduction defect
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20. • CK :normal to or only moderate elevated
• The muscle biopsy :myopathic &fewer dystrophic
• DNA:mutation gene in Xq28 code for protien emerin
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21. LIMB GIRDLE DYSTROPHY
• AR majority
• Onset: adolescence or late
childhood: sever child recessive muscular dystrophy
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22. • AR: defect in sacroglycan component of the DGC(
sacroglycanopathy(
• Alpha sacrglycan adhelin is account for 20%
• Onset:childhood& variable
• No intellectual impairment or cardiac
• Muscle biopsy :immune stain absent or diminished for
sacroglycan 22

23. • AD: onset: second and third decades
• Protein defect:caveolin-3
• There are multiple subtypes
• AD type 1:1A,1B …
• AR type 2:
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24. CONGENITAL MUSCULAR DYSTROPHY
• AR
Perinatal onset
• c/p:hypotonia &proximal weakness,arthrogryposis
• Two types
• CNS involvement: sever mental retardation ,visual, seizure
..cerebrocular dysplasia, progressive death by age 10-12
• No CNS :classic type MRI (hypomyelination), benign outcome,
non progressive
• Muscle biopsy :dystrophy…
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25. FSH
• Inheritance: AD
• Variable expression within the families
• Age: childhood or adult life
• C/P: weakness early facial then descending
to scapula stabilizer muscles &muscles of the upper limb& distal weakness ..peroneal ,the rate
of progression to forearm &pelvic girdle
• Asymmetrical/ deltoid preserved / joint contracture are uncommon
• Popeye hand/ winging scapula/ no muscle hypertrophy
• Early onset worse prognosis
• 20% require wheelchair
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26. WORK UP
• CK:N or mild elevation
• Muscles biopsy: myopathic dystrophic& occasionally prominent
mononuclear infiltrate
• Gene: ch 4q35 gene deletion
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27. MYOTONIC DYSTROPHY
• AD, CTG repeat
• Affect : skeletal,cardiac,
smooth muscles, eye,endocrine &brain
• Onset :at any age ,usually at late 2nd decade
• Some individual can be symptoms free their entire
life
• Sever form :congenital myotonic dystrophy
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28. • C/P:weakness: (facial,temporalis wasting,ptosis,neck
flexor,distal weakness progress to involve limb girdle)
• Weakness >myotonia
• May be areflexic
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29. SYSTEMIC
• Posterior sub scapular cataract
• Testicular atrophy& impotence
• Intellectual impairment
• Hypersomnia (central & obstructive)
• Respiratory failure
• Elevation of serum glu, rarely frank DM
• GI: dysphagea, pseudo obstruction
• Cardiac conduction defect sudden death
• Fetal loss in female
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30. PROMM
• AD
• Proximal weakness, no distal weakness
• Myotonia &myalgia
• Less cardiac &other organ involvement except cataract
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31. WORK UP
• CK:N or mild elevation
• EMG: myopathic & myotonia
• Muscle biopsy: atrophic, non specific
• Gene :CTG repeat >50 in ch19q13.2
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32. TTT
• Myotonia rarely sever to require tt: phenytoin is the only safe
drug
• Annual ECG ..pacemaker may required
• Positive pressure ventilation support
• High risk in surgery (cardiac &respiratory)
• Sedation & opiod use with caution
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33. DISTAL DYSTROPHY
• Types
• AD:4th &6th decade
• AR:in early adult onset/late second or early 3rd
• CK :elevated 200xN AR
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34. OCULOPHARENGEAL
• AD
• Onset:5th &6th decade
• Ptosis &dysphagea later all extra ocular muscles
&extremities affected (limb girdle) but distal can be
significant in some variant
• Slow progressive ,death from aspiration pneumonia or
starvation
• Ck:n or mild elevated
• Muscle biopsy :rim vacuoles
• Genetic GCG repeat in ch14 34

35. 35

36. CONGENITAL MYOPATHY
• Are distinguished from dystrophy in three respect:
• Characteristic morphologic alteration
• At birth
• Non progressive
• However there are exception to all these generalization
• Inheritance: are variable
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37. • c/p: hypotonia with subsequent developmental delay
• Reduce muscles bulk, slender body build &long narrow face
• Skeletal abnormalities: high arched palate ,pectus exacavitum, kyphscliosis,
dislocated hip, pes cavus)
• Absent or reduced muscle stretch reflex
• Weakness: limb girdle mostly, but distal weakness exist
• CK &EMG may be normal
• Muscle biopsy: the diagnostic method
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38. CENTRAL CORE MYOPATHY
• Characterized by discrete zones of myofibrillar disruption in
the center of muscles fiber
• AD but can be sporadic
• Mutation ch 19,similar to malignant hyperthermia patient
• So anesthesia precaution are necessary
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39. NEMALINE MYOPATHY
• Pathology: the presence of rods or melamine bodies within
muscles fiber
• AD or AR
• c/p:
• Sever neonatal form which is fatal in the first year of life
• Mild static
• Slowly progressive from birth or early childhood
• Note :rods can present in HIV related myopathy ,some
inflammatory
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40. CENTRO NUCLEAR (MYOTUBULAR)
• Pathology: large central nuclei in the muscle fiber
• X linked/AD/AR
• sever neonatal/static or slowly progressive
• c/p: ptosis & opthalmoparesis
• Genetic defect: mutation in myotubularin gene Xp28
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41. METABOLIC MYOPATHY
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42. METABOLIC MYOPATHY
• Glucose/glycogen metabolism
• Fattay acid metabolism
• Purine nucleotide
• mitochondrial
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43. METABOLIC MYOPATHY
• Clues to hereditary metabolic myopathy
• Excersize induce weakness &myoglobinuria…glycogen &lipid
• Part of diffuse neurological syndrome…mitochondrial
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44. GLUCOSE/GLYCOGEN
• Glucose &its storage is essential for the short term anaerobic energy
(glycogensis)
• Two clinical presentation:
• 1-dynamic:type V/V11/V111/1X//XX1
• 2-static:fix weakness
1/111/1V
• Inheritance:AR except for phosphoglycerate kinase
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45. GLYCOGENSIS WITH EXERCISE INTOLERANCE
• C/P: exercise intolerance in the childhood followed by
excertional induced muscle pain &myoglobinurea in sec or 3rd
decade..
• (Second wind phenomena)
• work up: CK/EMG normal
between the attack in early stage but after attack( myopathic
&fibrillation)
• Forearm exercise test
• Enzyme assay
• Muscle biopsy
• Genetic for mutation 45

46. GLYCOGENSIS WITH FIXED WEAKNESS
• Acid maltase deficiency:
• Enzyme convert glycogen to glucose
• Three clinical variant:
• Infantile: pompes: progressive weakness ,enlargement of
heart, tongue &liver death by age 2
• Juvenile type: proximal weakness, may calf hypertrophy
death by age 20 from respiratory failure
• Adult type:2&7th progressive limb girdle or
scapuloperoneal .no liver ,no heart involvement
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47. WORK UP
• CK :moderately increased
• EMG: myopathic changes &myotonic discharge in paraspinus
• Enzyme assay:
• Muscle biopsy: a vacuolar myopathy with high glycogen content
• Genetic: mutation in ch 17
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48. FATTY ACID METABOLISM
• Lipids are essential for aerobic metabolism
• Dynamic & static
• CPT:carnitine palmitoyl transeferase deficiency
• Carnitine deficiency
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49. CPT
• Type 1:infancy &child hood with hepatic dysfunction
• Type 2:exertional myalgia &myoglobinurea,
it is the most frequently definable metabolic defect presenting
with myoglobinurea
• AR ,gene 1p32
• The attacks occur after prolonged exercise, fasting, febrile
illness
• Unlike mecardle disease the patient can tolerate brief exercise
,no second wind phenomena
• Muscle strength are normal at rest 49

50. LAB
• CK:n at rest
• Forearm exercise test :N
• EMG: n at rest ,&myopathic during the attack
• Muscle biopsy: usually N ,except of myopathic changes after
rhabdomylsis
• Enzyme assay
• ttt &meal frequency: increase CHO intake
&education about fasting &exercise
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51. MITOCHONDRIAL
• Kearns-sayer: opthalmoplegia, retinitis pigmentosa, heart block, hearing
loss, short stature, ataxia, delayed 2nd sexual characteristic, PN, respiratory
• MERF: myoclonic epilepsy, generalized seizure, ataxia, dementia, hearing
loss, optic atrophy ,PN, cardiomyopathy &cutenous lipoma
• MNGLE: mitochondrial neurogastrointestinal encephalomyopathy
• POLIP :polyneuropathy,opthalmoplasia,leukoencephalopathy& intestinal
pseudo obstruction
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52. CHANNELOPATHY
• Non dystrophic myotonia
• Periodic paralysis
• It due to mutation in different channels gene leading to :
• Hyper excitability :myotonia
• In excitability: paralysis
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53. CHLORIDE CHANNELOPATHY
• Mutation in CL channel..hyperexcitability after depolarization
• Myotonia congenita:
• AD..thomsen /AR:becker
• C/P: muscle hypertrophy,
myotonia/becker type has fluctuating limb girdle weakness
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54. SODIUM CHANNLEOPATHY
• AD
• Onset: first decade
• Phenotypic types:
• Paramyotonia congenita
• Hyperkalemic periodic paralysis
• myotonia :Potassium sensitive disorder : myotonia
fluctuant
myotonia permanent
acetazolamide responsive myotonia
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55. CALCIUM CHANNELOPATHY
• Hypokalemic
• malignant hyperthermia
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56. C/P OF CHANNELOPATHY
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57. PARAMYTONIA CONGENITA
• AD
• Onset :1st decade
• Paradoxical myotonia (Aggravated by warm as well cold)
• Face ,neck,forearm
• After several attempt of eye closure the patient can not open
the eye
• ttt: Na channels blocker mexiletine
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58. HYPERKALAMIC PERIODIC PARALYSIS
• K sensitive periodic paralysis
• Onset :1st decade
• Attack last:1-2 h
• During attack: areflexic with no ocular or respiratory muscles
weakness
• Strength is n between the attack, but some patient has
interictal limb girdle weakness
• Some families have myotonia &paramyotonia
• Aggravated: fasting/cold, shortly after exercise, K load, early
AM
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59. • Episodes are rarely serous enough to require acute ttt
• ttt:
• oral CHO
• Prevention: thiazide,B agonist, low K,high CHO
• Avoid fasting, strenuous exercise/
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60. MYOTONIA
• No weakness
• Aggravated by K diet/ excretion
• Can response to acetazolamide
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61. HYPOKALEMIA
• AD:
• It is the most frequent form of periodic paralysis
• Common in male
• Age: adolescence
• The attacks 3-24h/vague prodorme of stiffness
&heaviness& rarely ocular, bulbar, respiratory involved
• Early Myotonia of eyelid & late interictal proximal
weakness
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62. • Aggravated: CHO meal, cold,hrs post exercise, sleep
• Work up:K level q 30min /TFT/
• R/O 2nd causes of hypokalemia
• Tttt:
• Acute: oral K Q30min ,if symptoms sever iv K
• Prevention:
• Low CHO, low sodium diet ,spirnolactone,
trimetrine
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