Duchenne Muscular Dystrophy Flashcards
what is DMD
most common genetic muscle condition in children
2500 boys n UK
100 diangosed per year
progressive muscle weakness
wheelchair bound in teens and death mid thirties
pathology of DMD
mutation in the dystrophin gene
impairs the production of dystrophin protein in muscles
doesn’t become fibroses and is replaced by fat and eventually breaks down
severe phenotype
DMD
milder phenotype
Becker muscular dystrophy
what does the image show
normal muscle compared to DMD muscle
Duchenne gene
79 exons
arranged in specific order to code for dystrophin
in frame mutation
part of the gene is missing but the exon can still join up
results in a shorter protein but still able to produce some dystrophin
what is the difference between Becker and Duchenne
in Duchenne dystrophin gene isn’t present
in Becker the dystrophin is present but in smaller amounts so not complete normal muscle function
what occurs in Duchenne
deletion of an exon
disrupts the reading frame
results in non functional protein and absence of dystrophin in muscles
out of frame mutation
deletion of an exon which will then disrupt the reading frame
how do you get DMD
X linked
located on Xp21.2 chromosome
carriers of DMD
girls
boys are most often affected
2/3 cases gene inherited from the mother
1/3 cases there is a spontaneous mutation
presenting features of DMD in toddler years
delayed motor milestones
poor head control
frequent falling
waddling gait
presenting features of DMD in school aged child
difficulty climbing steps
waddling gait
difficulty jumping and running
gower’s sign
what does the image show
Gower’s sign
associated features of the clinical presentation of DMD
speech delay
behavioural difficulties
calf hypertrophy
clinical manifestations of DMD
onset age 3-6
progressive weakness
pseudo hypertrophy of calf muscles
spinal deformity
cardiomyopathy
respiratory
30% mild to moderate MR
typical progression of symptoms in DM D
clinical diagnosis of DMD
Gower sign
blood test result DMD
creatine kinase, elevated in 1000’s
deranged liver enzymes
DNA analysis to look for mutation and which exon is affected
diagnosing DMD
gower sing
blood test
muscle biopsy
management of DMD
standards of care including corticosteroids
prolong ability to walk independently for 2-5 years
delay respiratory and cardiac complications
prolonged survival
access to ventilatory support
proactive cardiac intervention
drug prescription in DMD
steroids
steroids in DMD
started around age 4-5
around the plateau phase of motor function
uses prednisolone 0.75mg/kg/day
or can use deflazacort 0.9mg/kg/day
life expectancy in DMD
early 30s
DMD age of diagnosis
4.7 years
long delay between first parental concerns and diagnosis
why does the diagnosis of DMD remain delayed
lack of training in child development
no formal motor skills assessments in HCP
pressure on primary care
DMD progression
what is the mnemonic used to help diagnose DMD in boys
MUSCLE
what does MUSCLE stand for
motor milestone delay
unusual gait
speech delay
creatine kinase asap
leads to
early diagnosis of DMD
motor milestone delay
unable to walk by 18 months
unable to jump by 2.5 years
unable to run by 3 years
unusual gait
tiptoe walking
frequent falling
difficulty climbing steps
speech delay
no words spoken in first 18 months
unable to speak sentences by age 3
any input from speech services SALT
what would you do if you have more than 3 symptoms over 2 or more categories in diagnosis
creatine kinase ASAP for early diagnosis
new therapies for DMD
modifcation of the mutation (exon skipping, stop codon suppression)
new corticosteroids
gene transfer
cell therapies
up reg of alternative proteins
increase in muscle bulk
exon skipping
technique designed to skip over faulty exon so it is ignored in protein production
faulty exon hidden by molecule patch called antisense oligonucleotide AON
which are small RNA molecules that can bind specific internal exon sequences
causes splicing of dystrophin gene
can restore reding frame and produce some dystrophin
DMD to Becker
exon skipping illustrated
first treatment for DMD
first treatment approved in the UK
new types of steroids
VBP15
VISION-DMD
VBP15
vamorolone
anti-inflammatory
dissociative steroid
promising results
VISION-DMD
phase 2b of study
now enrolling patients
led byJWMDRC Newcastle
120 boys in 10 countries
randomised, double blind parallel group placebo and active controlled study
gene therapy
replace faulty gene
use vector to carry healthy gene into the cells
adenovirus carrying shortened version of dystrophin
patients treated have had an increase in dystrophin in all muscles and significant reduction in CK
significant concern
