DMD - L4 Flashcards Preview

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Flashcards in DMD - L4 Deck (25):
1

Topics?

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

2

Classification of muscular dystrophies?

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

3

Why make a diagnosis?

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

4

About DM1?

autosomal dominant (1/8000)
Ch19

5

Consequences of DM1?

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

6

Types of DM1?

congenital
classic
mild

7

Congenital DM1?

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

8

Mild DM1?

cataract
myotonia (what is it?)

9

Histology of DM1?

ringbinden (what is it?)
increased central nuclei

10

DM1 molecular pathogenesis?

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

11

Anticipation of DM1?

>35 unstable
maternal transmission

12

DM1 RNA gain of function?

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

13

What proteins bind to CUG repeats?

MBNL1 - sequestered
CUGBP1 - up-regulated

14

Describe MBNL1 & CUGBP1 normal and DM1

-

15

Possible therapeutic strategies for DM1?

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

16

About LGMD?

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)

17

LGMD inheritance?

LGMD type 1 - dominant
LGMD type 2 - recessive

18

About FSHD?

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

19

FSHD genetics info?

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

20

FSHD1 genetic basis?

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

21

What does D4Z4 encode for and what does it do?

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

22

DUX4 in FSHD1?

less repressive chromatin structure, DUX4 expressed in skeletal muscle

23

FSHD2?

normal D4Z4 repeats
mutations in SMCHD1

24

What does SMCHD1 do?

keeps D4Z4 repressed in somatic cells by modifying the chromatin

25

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

10q
nothing