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Neuromuscular > Dmd > Flashcards

Dmd Flashcards

1
Q

Incidence of dmd and BMD

A

1: 3500 DMD
1: 18000 BMD

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2
Q

Types of DMD mutations and BMD

A

60-65% out of frame deletions 1+exons
5% exon duplication
Rest nonsense or frameshift

BMD = in frame mutations (85%deletions)

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3
Q

Dmd onset and symptoms?

A 
Before 5 years 
Progressive muscular weakness-proximal 
Muscular pseudohyoertrophy (chunky calves)
Dilated cardiomyopathy 
Mean age of death 25
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4
Q

Symptoms BMD

A

Late learning to walk
Muscle weakness around 11
Loose ability t walk 40-50 yrs
No LD

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5
Q

Symptoms female carriers

A 
5-10% cramps 
Usually in 30s 
20% dilated cardiomyopathy -5yr echo/ecg 
Proximal weakness and asymmetric 
Carriers of BMD less affected
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6
Q

Management DMd?

A

Physio and splints to prevent contractures
Scoliosis - surgery
Cardiomyopathy- echo and ecg every 2 years until 10 - annually after

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7
Q

Management BMD

A

May require walking frames/ wheelchairs

Echo/ECG every 5 years

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8
Q

What percentage of mothers of affected are carriers?

A

60% carriers

But 10-20% gonadal mosaicism

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9
Q

Risk to future affected sons if mum NOT carrier?

A

10% affected son
10% risk carrier daughter
Based on results, pedigree and bayes
PND PGD

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10
Q

Mutation rate in dystrophin gene ?

A

~ 1/3 de novo

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11
Q

3 options for de novo mutations?

A

1) occur in egg at probands conception
2) after conception - mosaic
3) mutation present in mothers egg cells

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12
Q

Situation where female has classic dmd?

A

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

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13
Q

Location of DYstophin ?

A

Xp21.2

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14
Q

What is the DAPC and what does it do?

A

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)
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15
Q

Dystrophin domains?

A

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

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16
Q

Dystrophin levels is DMD and BMD?

A

Dmd- virtually absent

BMD- 10-40%

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17
Q

Pathogenesis of lack of dystrophin?

A
  • 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
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18
Q

What other DAPC members are implicated in muscle wasting disorders?

A

Laminin alpha2 causes MDC1A

Meridian deficient congenital muscular dystrophy

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19
Q

Size of dystrophin?

A

2.4 Mb - ink 0.3% of genomic sequence present in mature transcript
79 exons
14 kb mRNA

20
Q

How many promoters and how many tissue specific?

A

7 different promoters

3 tissue specific - brain, muscle purkinji(large to small) dif exon 1

21
Q

Hotspots for deletions?

A

Proximal - exons 2-20

Distal - exons 45-55

22
Q

Frameshift hypothesis?

A

Deletions that disrupt the translational reading frame = more severe
Deletions leaving frame intact =milder BMD
Correct for 92% of cases

23
Q

Exceptions to frameshift hypothesis?

A
  • Deletions in protein binding domain are severe even if in frame
  • deletion may affect splicing
  • deletions affecting central rod domain are milder
24
Q

What percentage of dmd/BMD are caused by duplications

A

5-10%

Difficult for frameshift mutation as orientation and position usually not known

25
Q

Percentage point mutations

A

Dmd 25-35% (usually premature termination codons)

BMD 10-20% ( Missense, splice site, nonsense at 3’ end that avoids nonsense mediated decay).

26
Q

What mutations exclusively cause DMD related cardiomyopathy? (DCM)

A

Mutations that disrupt a muscle specific isoform

Eg. Muscle specific promotor - compensated for in other

27
Q

CK levels for DMD, BMD, DCM, female carriers DMD, female carriers BMD

A 
DMD- 100% >10x normal Ck
BMD- 100% 5x
Dcm- most have increased CI
Carrier dmd -50% 2-10x
Carrier BMD- 30% 2-10x
28
Q

3 non genetic methods to test for DMD

A

1) cK levels
2) muscle biopsy
3) immunohistochemisty

29
Q

What to expect of dmd muscle biopsy

A

1) increase in variation of fibre size diameter
2) increase in fibrous connective tissue
3) large rounded hyaline fibres
4) foci of degeneration and regeneration

30
Q

Immunohistochemisty results with anti-dystrophin antibody

A

Dmd patients show absence of staining

BMD show reduction in staining

31
Q

Steps of MLpA

A

1) Denaturation
2) hybridisation of adjacent probes
3) ligation of adjacent probes
4) pcr of all lighted probes

32
Q

What are the MLPA kits and what is sensitivity?

A

P034 exons 1-10 21-30 41-50 61-70
P035 exons 11-20+ promoter, 31-40, 51-60, 71-79

Sensitivity 72%

33
Q

Benefit of array for dmd?

A

Loss or gain of sequence at intronic breakpoints

34
Q

What percentage of point mutations not detected by Sanger?

A

2% due to complex rearrangements

35
Q

Alternative to PB seq?

A

Sequence cDNA from muscle - detect rna mutations - try confirm with DNA but not always possible (i.e. Intronic)

36
Q

Risk of recombination across gene if using micro satellite markers?

A

10%

37
Q

Normal MLPA?

A

Only excludes 72%

If clinical diagnosis- can offer seq

38
Q

Pos MLPA?

A
  • If single exon- confirm by second method
  • Check whether in frame or out using Leiden muscular dystrophy site
  • if first or last exon deleted- could extend into neighbouring gene
39
Q

If familial mutation is unknown?

A

MLPA of woman in fam with highest risk. If not identified- linkage

40
Q

If mutation not found in mum?

A

If fam mutation known- mum gonadal?

If fam not known- carrier risk reduced- bayes

41
Q

Risk of carrier if mum or grandmother of affected (bayes)

A

2/3 for mum

1/3 for gran

42
Q

Recombination frequencies calculation?

A

If none seen- work out ave risk of double recombination between markers and multiplying by % of coding region between markers

43
Q

Antisense oligonucleotides

A

Alter splicing of dmd precursor mRNA by targeting exons affected by deletion/mutation
- cause skipping of targeted exon from mature mRNA = convert dmd to BMD

44
Q

What antisense rna molecule targeted in trial?

A

Exon 51 skipping in clinical trial (13% of dmd)

45
Q

Prob with antisense rna?

A

Only transient

Muscle tissue must be present - can’t reverse muscle loss

46
Q

How do read through drugs work?

A

Induce protein making machinery to read through premature stop codons

47
Q

2 types of read through drugs?

A

Aminoglycoside antibiotics (gentamicin) - can’t be administered orally
Ataburen (ptc124) non amnioglycoside
- orally and less toxic (phase 2)

Neuromuscular (2 decks)

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