DMD - L4

Question 1

Topics?

Answer 1

classification of muscular dystrophies
myotonic dystrophy
limb-girdle muscular dystrophies
facioscapulohumeral muscular dystrophy

Question 2

Classification of muscular dystrophies?

Answer 2

age of onset
pattern of weakness
pattern of inheritance
involvement of other system

Question 3

Why make a diagnosis?

Answer 3

to know the disease course
monitor for complications
appropriate treatment
genetic counselling

Question 4

About DM1?

Answer 4

autosomal dominant (1/8000)
Ch19

Question 5

Consequences of DM1?

Answer 5

proximal and distal weakness and wasting
smooth muscle involvement: constipation, uterine
cognitive deficits
excessive somnolence, personality changes
cataracts
endocrine dysfunction: diabetes, infertility

Question 6

Types of DM1?

Answer 6

congenital
classic
mild

Question 7

Congenital DM1?

Answer 7

most severe, presents in first 4 weeks of life
respiratory failure, feeding difficulties and early death common
hypotonia (floppy baby)
facial & proximal weakness
delayed motor development
respiratory insufficiency
babies often die of respiratory failure

Question 8

Mild DM1?

Answer 8

cataract

myotonia (what is it?)

Question 9

Histology of DM1?

Answer 9

ringbinden (what is it?)

increased central nuclei

Question 10

DM1 molecular pathogenesis?

Answer 10

expanded CTG trinucleotide repeat in the gene DMPK
normal 5-35 repeats
pre-mutation 35 - 49 (asymptomatic)
fully penetrant >50

Question 11

Anticipation of DM1?

Answer 11

> 35 unstable

maternal transmission

Question 12

DM1 RNA gain of function?

Answer 12

RNA CUG expansions fold into hairpin-like secondary structures which sequester specific proteins resulting in their depletion

Question 13

What proteins bind to CUG repeats?

Answer 13

MBNL1 - sequestered

CUGBP1 - up-regulated

Question 14

Describe MBNL1 & CUGBP1 normal and DM1

Answer 14

-

Question 15

Possible therapeutic strategies for DM1?

Answer 15

RNA-based mechanism to inhibit toxic CUG expanded RNA species

small-molecule inhibitors such as pentamidine-like compounds
RNA interface (RNAi)-mediated suppression of mutated DMPK transcripts
antisense oligonucleotide (AO)-mediated knockdown of DMPK

Question 16

About LGMD?

Answer 16

progressive
onset 2nd - 6th decade
muscle weakness and hypertrophy (pelvic girdle then shoulder)
respiratory and cardiac involvement (no nervous)
affects sarcoglycans (pathology cytoskeletal, rather than contractile)

Question 17

LGMD inheritance?

Answer 17

LGMD type 1 - dominant

LGMD type 2 - recessive

Question 18

About FSHD?

Answer 18

dominantly inherited
third most common MD
affects 1/20,000 people
most symptomatic by age 20
facial weakness
scapular winging
proximal arm weakness
leg weakness usually less prominent

Question 19

FSHD genetics info?

Answer 19

FSHD1 - 95%
FSHD2 - 5%
autosomal dominant
penetrance incomplete
germline mosaicism

Question 20

FSHD1 genetic basis?

Answer 20

D4Z4 repeat sequence on Ch4q
normal: 11-100 D4Z4 repeats
FSHD1: 1-10 (smaller = more severe)

Question 21

What does D4Z4 encode for and what does it do?

Answer 21

DUX4 gene
germline transcription factor that gets silenced in somatic cells
can only be expressed if D4Z4 have a polyadenylation signal
long D4Z4 arrays have a repressive chromatin structure –> very little DUX4 expression observed

Question 22

DUX4 in FSHD1?

Answer 22

less repressive chromatin structure, DUX4 expressed in skeletal muscle

Question 23

FSHD2?

Answer 23

normal D4Z4 repeats

mutations in SMCHD1

Question 24

What does SMCHD1 do?

Answer 24

keeps D4Z4 repressed in somatic cells by modifying the chromatin

Question 25

Where else is there D4Z4 repeat array and what happens if its shortened?

Answer 25

10q

nothing