DMD/BMD Flashcards
Clinical features of DMD
Gower manouvere dev del/LD muscle pseudohypertrophy Increased CK cardiomyopathy
Clinical features of BMD
motor delay
muscle weakness and cramps
What proportion of females are manifesting carriers
5-10%
Causes of manifesting carrier females
- Turner syndrome
- homozygous for DMD/BMD variant
- deletion on other allele; or other structural rearrangement
- skewed X inactivation
- X UPD
Cause of DMD
Dystrophin gene at Xp21.2
Out of frame deletions = 60-65%
Out of frame duplications = 5-10%
Point mutations = 25-35%
Cause of BMD
Dystrophin gene at Xp21.2
In frame deletions = 85%
In frame duplications = 5-10%
Point mutations = 10-20%
Hotspot exons in dystrophin gene
2-20
45-55
In what proportion of cases is the frameshift hypothesis true
~90%
What proportion of dystrophin mutations are de novo
1/3
What is the risk of gonadal mosacism?
10%
When might de novo mutation occur?
- in egg at probands conception - germline, no recurrence risk for mother
- after conception - proband mosaic
- mutation occurs in mothers egg cells pre conception; mother is germline mosaic, recurrence risl!
Normal function of dytrophin
Forms part of dystrophin-associated protein complex (DAPC)
DAPC forms link between actin exoskeletion and extracellular component
-stabilises plasma membrane in muscle during repeated rounds of contraction and relaxation –> key in maintaining muscle integrity
Testing strategy in DMD/BMD
MLPA, array, NGS/Sanger
Limitation of linkage analysis in DMD
10% chance of recombination across dystrophin gene because it is so large
Therapy options in DMD
- Gene therapy - introduction of dystrophin gene
- Antisense oligonucleotides - cause exon skipping in DMD to bring back in frame
- Read through drugs - promote read through of STOP codons
