Dmd Flashcards
(47 cards)
Incidence of dmd and BMD
1: 3500 DMD
1: 18000 BMD
Types of DMD mutations and BMD
60-65% out of frame deletions 1+exons
5% exon duplication
Rest nonsense or frameshift
BMD = in frame mutations (85%deletions)
Dmd onset and symptoms?
Before 5 years Progressive muscular weakness-proximal Muscular pseudohyoertrophy (chunky calves) Dilated cardiomyopathy Mean age of death 25
Symptoms BMD
Late learning to walk
Muscle weakness around 11
Loose ability t walk 40-50 yrs
No LD
Symptoms female carriers
5-10% cramps Usually in 30s 20% dilated cardiomyopathy -5yr echo/ecg Proximal weakness and asymmetric Carriers of BMD less affected
Management DMd?
Physio and splints to prevent contractures
Scoliosis - surgery
Cardiomyopathy- echo and ecg every 2 years until 10 - annually after
Management BMD
May require walking frames/ wheelchairs
Echo/ECG every 5 years
What percentage of mothers of affected are carriers?
60% carriers
But 10-20% gonadal mosaicism
Risk to future affected sons if mum NOT carrier?
10% affected son
10% risk carrier daughter
Based on results, pedigree and bayes
PND PGD
Mutation rate in dystrophin gene ?
~ 1/3 de novo
3 options for de novo mutations?
1) occur in egg at probands conception
2) after conception - mosaic
3) mutation present in mothers egg cells
Situation where female has classic dmd?
1) an x-autosome translocation alters normal x inactivation
2) Turner syndrome
3) uniparental disomy (2 from ma)
4) skewed x-inactivation
5) father has BMD and mother a carrier
Location of DYstophin ?
Xp21.2
What is the DAPC and what does it do?
Dystrophin associated protein complex
- Forms links between actin cytoskeleton and the extra cellular matrix
- stabilises sarcolema during repeated rounds of contraction and relaxation (nb. Muscle integrity)
Dystrophin domains?
FOUR
1) amino terminal (binds actin filaments)
2) rod like domain- 24 spectrin-like triple helical coiled coils (much dispensable)
3) cysteine rich domain
4) carboxy terminal - interacts with membrane proteins sarcoglycan and day
Dystrophin levels is DMD and BMD?
Dmd- virtually absent
BMD- 10-40%
Pathogenesis of lack of dystrophin?
- disruption of link between cytoskeleton actin and extracellular matrix
- cell membrane is fragile and can be mechanically damaged
- deficiency disrupts subsarcolenmal mitochondria localisation, promotes inefficiency, restricts atp generating capacity
What other DAPC members are implicated in muscle wasting disorders?
Laminin alpha2 causes MDC1A
Meridian deficient congenital muscular dystrophy
Size of dystrophin?
2.4 Mb - ink 0.3% of genomic sequence present in mature transcript
79 exons
14 kb mRNA
How many promoters and how many tissue specific?
7 different promoters
3 tissue specific - brain, muscle purkinji(large to small) dif exon 1
Hotspots for deletions?
Proximal - exons 2-20
Distal - exons 45-55
Frameshift hypothesis?
Deletions that disrupt the translational reading frame = more severe
Deletions leaving frame intact =milder BMD
Correct for 92% of cases
Exceptions to frameshift hypothesis?
- Deletions in protein binding domain are severe even if in frame
- deletion may affect splicing
- deletions affecting central rod domain are milder
What percentage of dmd/BMD are caused by duplications
5-10%
Difficult for frameshift mutation as orientation and position usually not known
