DMD - L4 Flashcards
Topics?
classification of muscular dystrophies
myotonic dystrophy
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
appropriate treatment
genetic counselling
About DM1?
autosomal dominant (1/8000) Ch19
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
Types of DM1?
congenital
classic
mild
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
Mild DM1?
cataract
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?
> 35 unstable
maternal transmission
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