Duchenne Muscular Dystrophy Flashcards
What is DMD?
-Genetic muscle condition
-Affects 2500 boys UK
-100 boys diagnosed in UK per year
-Causes progressive muscle weakness
-Wheelchair bound in teens & death mid 30s
Statistics for DMD?
What is the pathology of DMD?
*Caused by mutated dystrophin gene
-One of biggest genes in body
-Normal function = producing dystrophin protein
—> so mutation = impairs production of dystrophin in muscles
—> muscles become fibrosed & replaced by fat & muscle breaks down
*Severe phenotype = DMD
*Milder phenotype = Becker MD
Role of dystrophin protein (normal production)?
Gives muscle membrane stability - between cell membrane & muscle fibre
-Causes damage - causes inflammation
-Get death of muscle tissues
-Muscle replaced by fat/adipose tissue
Structure of the dystrophin gene?
79 exons - pieced together in specific order = gives code to produce dystrophin protein
How can dystrophin gene be mutated?
By interrupting the code - by various ways
-Out of frame mutation (= if reading frame is fully disrupted - so no dystrophin protein can be made)
What is an ‘in frame mutation’ that can occur to the dystrophin gene?
An exon is deleted by ‘puzzle’ still fits together - so gives shorter protein - but some dystrophin can still be produced
What does an ‘in frame mutation’ of dystrophin gene cause?
Becker’s muscular dystrophy
What is an ‘out of frame mutation’ that can occur to the dystrophin gene?
An exon is deleted in a way that means ‘puzzle’ can no longer fit together meaning no dystrophin can be produced in muscles
What does an ‘out of frame mutation’ of dystrophin gene cause?
DMD
How do people get DMD - describe genetics?
-X-linked condition
-Dystrophin gene = on X chromosome Xp21.2
-Girls carry DMD & boys are affected
*2/3 cases gene inherited from mum
*1/3 cases is a spontaneous mutation
What are some typical presenting features of DMD in toddler years?
-Delayed motor milestones (late to sit, stand, walk)
-Poor head control
-Frequent falling
-Waddling gait (as have poor/no proximal muscle strength to lift legs up)
-Wide placed gait when stood
What are some of the typical presenting features of DMD in school age children?
-Difficulty climbing steps
-Waddling gait
-Difficulty jumping & running
-Gower’s sign = how child moves to stand from sitting on floor - shown in image - sign of proximal muscle weakness
–> stand by “walking” hands progressively up shins, knees & thighs
What are some associated features to do with DMD?
-Speech delay
-Beh difficulties
-Calf hypertrophy
What are the clinical manifestations of DMD?
How does DMD progress with time?
How is DMD diagnosed?
-Clinical diagnosis = Gower’s sign
-Blood test:
*Creatine Kinase in 1000s (should be 200) = elevated
*Deranged liver enzymes
*DNA analysis - look for mutation & which exon is affected
-Muscle biopsy
What is meant by DMD being a progressive condition?
Muscles weaken as age - muscle fibroses & then replaced by fat/adipose tissue & then breaks down
What is the MUSCLE mnemonic for DMD?
What are some of the different therapeutic approaches for DMD?
What is exon skipping (DMD treatment)?
-Skip over faulty exon - so is ‘ignored’ in protein production
-Faulty exon ‘hidden’ under molecular patch called an antisense oligionucleotide (AON)
-AON = small RNA molecules - bind to specific exon sequences
—> causes splicing of dystrophin gene - can restore reading frame so some dystrophin can be made
-Can turn DMD into Becker’s MD
Role of eteplirsen?
Role of translarna?
What are the 2 new types of steroids for DMD?
& why are they better?
-No side-effects:
*Less impact on weight gain
*Better for bones & heart
How is gene therapy carried out for DMD?
-Replace faulty gene
-Use vector to carry healthy dystrophin gene into cells e.g., AV virus (as is big so fits dystrophin gene)
-AV carries shortened dystrophin gene
