Myopathies Flashcards
Muscular dystrophies
Characterized by muscle degeneration and regeneration that is progressive
Leads to weakness and often loss of ambulation
Dystrophinopathies:
Duchenne muscular dystrophy
1/3,500 boys
Onset 2-4 years
Wheelchair before 13 yr of age
Lifespan into 4th decade
Dystrophinopathies:
Becker muscular dystrophy
Milder end of the spectrum 1/30,000 males Onset variable: childhood to adulthood Wheelchair >16 yrs Can remain ambulatory throughout life Lifespan very variable, related to level of cardiac involvement
Dystrophinopathy phenotypes
DMD
BMD
Intermediate dystrophinopathy: loss of ambulation 13-16 years of age
Isolated cardiomyopathy
Exercise induced myalgias, muscle cramping
DMD symptoms
Generalized weakness and muscle wasting
Generally affects hips, pelvic muscles and thighs first
First presenting sign may be difficulty climbing stairs or rising from floor (gowers maneuver):
-delayed motor milestones: 42%
-abnormal gait (toe walking): 30%
-speech delay and LD: 8%
Some degree of static Cognitive impairment seen in 25-30% with specific cognitive profile:
- deficits in short term/ working memory - limited capacity for verbal span
- deficits in executive function which take some time to emerge
DMD and BMD progression
Proximal to distal
- trunk, pelvic girdle, and shoulder girdle are lost first
- hands and feet are usually maintained the longest
- facial muscles are usually spared
Scoliosis develops in most after loss of ambulation (can be decreased by being put on steroids during ambulation phase)
Eventually heart and lungs are also affected leading to respiratory and cardiac failure (due to cardiomyopathy)
Diagnosis of DMD and BMD
Dystrophin acts as a shock absorber and interacts with actin and plasma membrane
Clinical phenotype and elevated CK
Could do EMG but not specific
Molecular Genetic testing: tier 1: test for exonic del dups, tier 2: full sequencing
Carrier testing: 2/3 of moms are carriers
Muscle biopsy is gold standard but not routinely done
Immunofluorescent staining with dystrophin
-dystrophin protein identification by Western blot immunohistochemistry (Duchenne absent dystrophin, Becker reduced)
-rtPCR to look for rare intronic mutations
DMD/BMD inheritance and carrier risks
X linked
Mom is carrier: 25% chance to have a boy with DMD and a 25% chance to have a girl who is carrier
Most carrier are asymptomatic
Symptomatic carriers ( skewed X inactivation)
- less than 5% of carriers can have some weakness
-cardiac function is the biggest concern, and may be independent of X inactivation
->DMD carriers have a 5-8% lifetime risk for DCM, up to 20% lifetime risk of LVD
->BMD carriers: <1% risk of DCM, up to 15% lifetime risk of LVD
Baseline cardiac echo when carrier status is found and when pregnant repeat every 5 years
Dystrophin mutations
- entire gene deleted (rare, contiguous)
- exonic deletions or duplication
- > 60% of DMD and 85-90% BMD
- > hot spots at exons 2-19 and 45-55
- > PCR detects 26/79 exons, MLPA or dystrophin specific CGH detects all
- intragenic mutations
- > small indels
- > premature STOP codons -15% in DMD
- > missense mutations rare, some deep intronic mutations
Out of frame exonic deletions-> DMD
In frame exonic deletions -> BMD
Holds true 92% of the time
Prospective Treatments for DMD
Unregulated utrophin (fetal form of dystrophin) expression
Myoblast transfer - unsuccessful so far
Myostatin inhibition
Exon skipping for frame shift deletions to bring back in frame (DMD to BMD) - in process, promising
Premature STOP codon read through: ataluren (aminoglycoside derivative that allows for read through of the early stop codon): some success among low dose study group
Gene therapy hasn’t worked due to vector not being able to hold large dystrophin gene
Limb girdle muscular dystrophies
Purely descriptive diagnosis with many subtypes that cannot be easily distinguished clinically: used to differentiate from X linked dystrophinopathy
-progressive weakness that begins in proximal limb muscles
-onset from childhood to adulthood
-elevated CK levels
-dystrophic changes on muscle biopsy
-involvement of other organ systems: cardiac (cardiomyopathy), respiratory (nocturnal hypoventilation), absence of bulbar symptoms
Inheritance: AD (type 1, A to H) or AR (type 2A-2Q)
LGMD type 2C-2F
Sarcoglycanopathies
Initial muscle involvement reminiscent of DMD/BMD
-age 3-15 years, elevated CK, somewhat more scapular involvement early on
Differences from DMD/BMD: Intellect normal, AR with equal male:female
4 separate genetic causes- cannot be distinguished clinically: muscle biopsy and IF staining. Genetic testing for SGCA (2D), SGCB (2E), SGCG (2C), SGCD (2F)
Genotype- phen correlation minimal
Marked phenotypic variability; some remain ambulatory >15yrs
Myotonic dystrophy 1
DM1
Multi system disorder: skeletal and smooth muscle: myotonia (delayed relaxation of voluntary contraction), slowly progressive weakness (distal>proximal)
Eye: early cataracts
Heart: arrhythmias, cardiomyopathy
Endocrine: diabetes, hypothyroidism, decreased fertility in males
CNS: full spectrum from LD to sever ID
Clinically subdivided: mild, classic (extra muscular involvement and spectrum of muscle), congenital (neuromuscular symptoms from birth/infancy)
DM1 repeats
Normal 5-37 repeats
Premutations 38-~49
Mild 50 - ~150, onset 20-70 yrs
Classic ~100-~1000, onset 10-30yr, avg age at death 48-55
Congenital ~>1000, onset birth to 10 yr, avg death 45 yrs
Congenital myotonic dystrophy
Polyhydramnios, decreased fetal movement
Severe generalized hypotonia
Multiple joint contractures/ arthrogryposis at birth in some
Significant facial diplegia
Respiratory insufficiency: some requiring mechanical ventilation
Surviving patients show: gradual improvement in motor function, usually able to walk, myopathy, all have mild to moderate ID
