Duchenne Muscular Dystrophy

Question 1

what is DMD

Answer 1

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

Question 2

pathology of DMD

Answer 2

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

Question 3

severe phenotype

Answer 3

DMD

Question 4

milder phenotype

Answer 4

Becker muscular dystrophy

Question 5

what does the image show

Answer 5

normal muscle compared to DMD muscle

Question 6

Duchenne gene

Answer 6

79 exons
arranged in specific order to code for dystrophin

Question 7

in frame mutation

Answer 7

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

Question 8

what is the difference between Becker and Duchenne

Answer 8

in Duchenne dystrophin gene isn’t present
in Becker the dystrophin is present but in smaller amounts so not complete normal muscle function

Question 9

what occurs in Duchenne

Answer 9

deletion of an exon
disrupts the reading frame
results in non functional protein and absence of dystrophin in muscles

Question 10

out of frame mutation

Answer 10

deletion of an exon which will then disrupt the reading frame

Question 11

how do you get DMD

Answer 11

X linked
located on Xp21.2 chromosome

Question 12

carriers of DMD

Answer 12

girls
boys are most often affected
2/3 cases gene inherited from the mother
1/3 cases there is a spontaneous mutation

Question 13

presenting features of DMD in toddler years

Answer 13

delayed motor milestones
poor head control
frequent falling
waddling gait

Question 14

presenting features of DMD in school aged child

Answer 14

difficulty climbing steps
waddling gait
difficulty jumping and running
gower’s sign

Question 15

what does the image show

Answer 15

Gower’s sign

Question 16

associated features of the clinical presentation of DMD

Answer 16

speech delay
behavioural difficulties
calf hypertrophy

Question 17

clinical manifestations of DMD

Answer 17

onset age 3-6
progressive weakness
pseudo hypertrophy of calf muscles
spinal deformity
cardiomyopathy
respiratory
30% mild to moderate MR

Question 18

typical progression of symptoms in DM D

Answer 18

Question 19

clinical diagnosis of DMD

Answer 19

Gower sign

Question 20

blood test result DMD

Answer 20

creatine kinase, elevated in 1000’s
deranged liver enzymes
DNA analysis to look for mutation and which exon is affected

Question 21

diagnosing DMD

Answer 21

gower sing
blood test
muscle biopsy

Question 22

management of DMD

Answer 22

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

Question 23

drug prescription in DMD

Answer 23

steroids

Question 24

steroids in DMD

Answer 24

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

Question 25

life expectancy in DMD

Answer 25

early 30s

Question 26

DMD age of diagnosis

Answer 26

4.7 years long delay between first parental concerns and diagnosis

Question 27

why does the diagnosis of DMD remain delayed

Answer 27

lack of training in child development no formal motor skills assessments in HCP pressure on primary care

Question 28

DMD progression

Answer 28

Question 29

what is the mnemonic used to help diagnose DMD in boys

Answer 29

MUSCLE

Question 30

what does MUSCLE stand for

Answer 30

motor milestone delay unusual gait speech delay creatine kinase asap leads to early diagnosis of DMD

Question 31

motor milestone delay

Answer 31

unable to walk by 18 months unable to jump by 2.5 years unable to run by 3 years

Question 32

unusual gait

Answer 32

tiptoe walking frequent falling difficulty climbing steps

Question 33

speech delay

Answer 33

no words spoken in first 18 months unable to speak sentences by age 3 any input from speech services SALT

Question 34

what would you do if you have more than 3 symptoms over 2 or more categories in diagnosis

Answer 34

creatine kinase ASAP for early diagnosis

Question 35

new therapies for DMD

Answer 35

modifcation of the mutation (exon skipping, stop codon suppression) new corticosteroids gene transfer cell therapies up reg of alternative proteins increase in muscle bulk

Question 36

exon skipping

Answer 36

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

Question 37

exon skipping illustrated

Answer 37

Question 38

first treatment for DMD

Answer 38

Question 39

first treatment approved in the UK

Answer 39

Question 40

new types of steroids

Answer 40

VBP15 VISION-DMD

Question 41

VBP15

Answer 41

vamorolone anti-inflammatory dissociative steroid promising results

Question 42

VISION-DMD

Answer 42

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

Question 43

gene therapy

Answer 43

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