DMD - L4 Flashcards

1
Q

Topics?

A

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

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2
Q

Classification of muscular dystrophies?

A

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

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3
Q

Why make a diagnosis?

A

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

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4
Q

About DM1?

A
autosomal dominant (1/8000)
Ch19
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5
Q

Consequences of DM1?

A

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

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6
Q

Types of DM1?

A

congenital
classic
mild

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7
Q

Congenital DM1?

A

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

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8
Q

Mild DM1?

A

cataract

myotonia (what is it?)

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9
Q

Histology of DM1?

A

ringbinden (what is it?)

increased central nuclei

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10
Q

DM1 molecular pathogenesis?

A

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

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11
Q

Anticipation of DM1?

A

> 35 unstable

maternal transmission

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12
Q

DM1 RNA gain of function?

A

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

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13
Q

What proteins bind to CUG repeats?

A

MBNL1 - sequestered

CUGBP1 - up-regulated

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14
Q

Describe MBNL1 & CUGBP1 normal and DM1

A

-

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15
Q

Possible therapeutic strategies for DM1?

A

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
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16
Q

About LGMD?

A

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
Q

LGMD inheritance?

A

LGMD type 1 - dominant

LGMD type 2 - recessive

18
Q

About FSHD?

A
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
Q

FSHD genetics info?

A
FSHD1 - 95%
FSHD2 - 5%
autosomal dominant
penetrance incomplete
germline mosaicism
20
Q

FSHD1 genetic basis?

A

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

21
Q

What does D4Z4 encode for and what does it do?

A

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
Q

DUX4 in FSHD1?

A

less repressive chromatin structure, DUX4 expressed in skeletal muscle

23
Q

FSHD2?

A

normal D4Z4 repeats

mutations in SMCHD1

24
Q

What does SMCHD1 do?

A

keeps D4Z4 repressed in somatic cells by modifying the chromatin

25
Q

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

A

10q

nothing