Flashcards in DMD - L4 Deck (25)
classification of muscular dystrophies
limb-girdle muscular dystrophies
facioscapulohumeral muscular dystrophy
Classification of muscular dystrophies?
age of onset
pattern of weakness
pattern of inheritance
involvement of other system
Why make a diagnosis?
to know the disease course
monitor for complications
autosomal dominant (1/8000)
Consequences of DM1?
proximal and distal weakness and wasting
smooth muscle involvement: constipation, uterine
excessive somnolence, personality changes
endocrine dysfunction: diabetes, infertility
Types of 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
babies often die of respiratory failure
myotonia (what is it?)
Histology of DM1?
ringbinden (what is it?)
increased central nuclei
DM1 molecular pathogenesis?
expanded CTG trinucleotide repeat in the gene DMPK
normal 5-35 repeats
pre-mutation 35 - 49 (asymptomatic)
fully penetrant >50
Anticipation of DM1?
DM1 RNA gain of function?
RNA CUG expansions fold into hairpin-like secondary structures which sequester specific proteins resulting in their depletion
What proteins bind to CUG repeats?
MBNL1 - sequestered
CUGBP1 - up-regulated
Describe MBNL1 & CUGBP1 normal and DM1
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
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)
LGMD type 1 - dominant
LGMD type 2 - recessive
third most common MD
affects 1/20,000 people
most symptomatic by age 20
proximal arm weakness
leg weakness usually less prominent
FSHD genetics info?
FSHD1 - 95%
FSHD2 - 5%
FSHD1 genetic basis?
D4Z4 repeat sequence on Ch4q
normal: 11-100 D4Z4 repeats
FSHD1: 1-10 (smaller = more severe)
What does D4Z4 encode for and what does it do?
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
DUX4 in FSHD1?
less repressive chromatin structure, DUX4 expressed in skeletal muscle
normal D4Z4 repeats
mutations in SMCHD1
What does SMCHD1 do?
keeps D4Z4 repressed in somatic cells by modifying the chromatin