muscular dystrophies

Question 1

by what mechanisms can muscular dystrophies occur?

Answer 1

loss of structural proteins

defective enzymes

disruption of sarcolemma-repair mechanisms

loss of signaling molecules

non coding region mutations

defective post translational modifications

Question 2

what are muscular dystrophies?

Answer 2

inherited diseases

causing progressive weakness and wasting of muscles

replacement of muscle tissue with fibrous connective tissue

cardiac involvement, respiratory involvement seen in some

CNS tissue not usually affected

Question 3

muscular dystrophes can be classified either by

Answer 3

historical classification ie duchenne muscular dystrophe

clinical phenotype

inheritance ( Gene) / x linked

underlying genetic cause eg DMD-dystrophinopathy

Question 4

what is duchenne muscular dsystrophy?

Answer 4

x linked muscular dystrophe Xp21

dystrophic localised at the sarcolemma- dystrophinopathy

depending on mutation may get a milder becker phenotype

Question 5

when does the Becker phenotype of DMD occur?

Answer 5

when dystrophin is produced in frame deletions

Question 6

what causes DMD

Answer 6

large deletions, duplications and point mutations that disrupt the reading frame and tend to cause the absense of dystrophin and DMD phenotype

Question 7

how does Duchenne Muscular Dystrophe present ?

Answer 7

usually with delayed milestones

wheelchair by 13 years old

cardiac involvement (100% after 18)

respiratory involvement
survival beyond 30 is unusual

Question 8

how does becker muscular dystrophe present?

Answer 8

later onset than DMD and ambulant in to 20s

worse cardiac involvement

mean age of death mid 40s

Question 9

what is DMD- associated DCM?

Answer 9

mutations in the promoter or exon 1
No dystrophin in cardiac muscle
little or no skeletal muscle involvement

Question 10

what treatment is available for DMD?

Answer 10

Supportive
Scoliosis corrective surgery as children
Manage congestive cardiac failure and arrythmias
beta blocker, ACE inhibitor, transplantation
NIV for respiratory failure
Steroids
Gene therapy

Question 11

how do steroids work in DMD?

Answer 11

mechanisms unclear as other immunosuppressants do not have similar effect

slows down disease progression

start when motor functions plateau stop when non-ambulant

Question 12

how can gene therapy improve outcome for DMD

Answer 12

anti sense oligonucleotides - weekly s/c injectons

• PTC 124 (Ataluren) oral drug that promotes ribosomal read-through of nonsense (stop) mutations

Question 13

what is myotonic dystrophy

Answer 13

commonest type of muscular dystrophy

onset in adulthood
congenital
late onset
oligosymptomatic

Question 14

how does adult onset Myotonic dystrophe present

Answer 14

muscle weakness
myotonia
cataracts
cardiac conduction defects
cognitive changes
GI disturbances
diabetes
male hypogonadism

Question 15

how can myotonic dystrophe be treaed

Answer 15

supportive

cardiac complications

experimental AON knockdown of expansions?

fleicanide or mexilitine for symptom relief of myotonia

Question 16

what is FSH dystrophy?

Answer 16

facialscapulohumeral muscular dystrophy

typically presents before 20 years of age

scapular fixators and ankle dorsiflexor weakness

can lead to retinal telangectasia and sensorineural hearing loss

20% need wheelchair

normal life expectancy