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Genetics Of Neuromuscular Disorders > DMD/BMD > Flashcards

DMD/BMD Flashcards

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1
Q

What is the incidence for DMD and BMD?

A
  • DMD: 1/3500 males

- BMD: 1/18000 males

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2
Q

DMD and BMD are caused by mutations in what gene?

A

Dystrophin gene (Xp21.2)

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3
Q

What is the mode of inheritance for DMD/BMD?

A

X-linked recessive (100% penetrance in males)

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4
Q

Is there a high mutation rate in the dystrophin gene?

A
  • Yes: approx 1/3 of mutations are de novo
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5
Q

What are the three ways de novo mutations can arise in the context of DMD/BMD?

A
  1. Mut may occur in egg at time of proband’s conception (Mut in every cell of proband’s body, mother does not carry Mut so no recurrence risk)
  2. Mut may occur after conception and not present in all cells of proband (proband = somatic mosaic, mother doesn’t carry Mut so no recurrence risk)
  3. Mut present in mother of the proband’s egg cells (Mut not detected in DNA extracted from blood, mother = germline mosaic - risk to further children)
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6
Q

What are the five ways in which females can manifest with classical DMD?

A
  1. X:autosome translocation affecting inactivation resulting in no active dystrophin gene
  2. Turner syndrome - only one X, if it has mutation they have DMD
  3. UPD - daughter inherits two copies of the X with the mut and therefore has no normal dystrophin
  4. Skewed X-inactivation - X containing the Mut remains active in disproportionate number of cells
  5. Father affected with BMD and mother a carrier - daughter inherits Mut on both X chromosomes
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7
Q

What is the difference between levels of dystrophin protein in DMD vs BMD individuals?

A
  • DMD: dystrophin virtually absent

- BMD: dystrophin levels 10-40% of normal OR protein present but with reduced function

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8
Q

What is the effect of dystrophin deficiency in DMD/BMD?

A
  • Affects formation of dystrophin associated protein complex (DAPC)
  • disruption of link between cytoskeletal actin and extracellular matrix
  • Cell membrane more fragile and can be mechanically damaged during eccentric muscle contraction
  • Looseness of sarcolema permits calcium channels to open
  • increase in calcium ions activates proteases that digest contractile proteins resulting in much weaker muscle
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9
Q

Provide some details on the dystrophin gene

A
  • Largest known human gene
  • 2.4Mb but only 0.3% of genomic sequence is present in mature transcript
  • 79 exons
  • at least 7 different promoters : produce tissue specific transcripts of differing sizes
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10
Q

What percentage of DMD/BMD cases are caused by deletions/dups of one or more exons?

A 
Dels
- DMD = 65%
- BMD = 85%
Dups
- 5-10% for both
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11
Q

What are the deletion hotspots in the dystrophin gene?

A
  • Proximal = exons 2-20

- Distal = exons 45-55

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12
Q

What is the Frameshift hypothesis for DMD/BMD?

A
  • Deletions which disrupt translational reading frame generally cause severe DMD phenotype: premature termination codon leads to nonsense mediated decay = no protein
  • Deletions leaving reading frame intact cause milder BMD: abnormal version of dystrophin but retains some function
  • Consistent in approx 90% of cases
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13
Q

What are some things to be cautious about with regards to the Frameshift hypothesis in DMD/BMD?

A
  • Prediction based on assessment at DNA level: may be different at RNA level (e.g. may affect splicing)
  • Deletions in protein binding domains may severely affect dystrophin function even if in frame
  • Dystrophin can retain significant function even when missing large portions of amino acid sequence: e.g. Dels affecting central rod domain may be associated with mild/no manifestations
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14
Q

What proportion of DMD/BMD cases are caused by dystrophin point mutations?

A
  • DMD: 25-35% (usually result in premature termination codon)
  • BMD: 10-20%
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15
Q

What is the major non-genetic testing method for DMD/BMD?

A
  • Measuring serum creatine kinase (CK) levels (non specific screening test)
  • Enzyme mainly found in muscle and brain
  • Elevated levels indicate muscle damage
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16
Q

What are the expected levels of serum CK in DMD/BMD?

A
  • DMD males: more than 10x normal level
  • BMD males: more than 5x normal level
  • Males with DMD-related cardiomyopathy tend to have increased levels
  • DMD/BMD carrier females: ~50%/30% have more than 2-10 times normal level
17
Q

What are two important points to remember surrounding serum CK levels in DMD/BMD?

A
  • Levels can decrease with advancing age due to progressive elimination of dystrophic muscle fibres
  • Levels can be taken into account for Bayes
18
Q

Aside from serum CK levels, what is another non-genetic test employed for DMD/BMD?

A
  • Muscle biopsy
  • characterisation of muscle fibres using number of chemical stains or IHC with anti-dystrophin antibody
  • IHC = absence (DMD)/reduction (BMD) of stain
19
Q

What is the main genetic testing method for DMD/BMD?

A
  • MLPA: detects dels and dups
  • Two probe sets needed to cover gene (P034 and P035)
  • Sensitivity approx. 72% as can’t detect point mutations
20
Q

What aspect of MLPA should be approached with caution in the context of DMD/BMD?

A
  • Variants under probe hybridisation site can cause reduction in peak height = false positives
  • All single exon deletions should be confirmed by another technique (e.g. Multiplex PCR or sequencing)
21
Q

What were three previous genetic testing methods employed for DMD/BMD?

A
  • Southern blotting (time consuming, laborious, can’t detect small changes)
  • Multiplex PCR: amplify exons known to be most commonly deleted
  • Fluorescent quantitative dosage PCR: limited number of exons included
22
Q

What is the future method for genetic testing of DMD/BMD?

A

NGS - when copy number analysis routinely available using NGS then will be able to detect dels/dups/point mutations

23
Q

Provide details on linkage analysis in the context of DMD/BMD testing

A
  • Required when mutation in family not known
  • microsatellite Markers near and within dystrophin gene are genotyped in number of family members to determine haplotype associated with DMD/BMD
  • Can enable prenatal diagnosis to be performed
24
Q

What are the limitations of linkage analysis for DMD/BMD?

A
  • Risk of recombination between markers: 10% for dystrophin gene
  • Markers may be uninformative
  • Assumes affected family member has DMD/BMD
  • Need appropriate family members to identify high risk haplotype: ideally affected males are required but may be possible to perform exclusion testing based on presence of unaffected males in pedigree
25
Q

When reporting diagnostic male DMD/BMD results, what does it mean if you have a normal MLPA result?

A
  • Does not exclude diagnosis as dels/dups only account for approx 72% of dystrophin mutations
  • If clinical diagnosis confirmed (CK levels or muscle biopsy) then can offer point mutation analysis/linkage studies
26
Q

When reporting diagnostic male DMD/BMD results, what does it mean if you have a positive deletion or duplication identified by MLPA?

A
  • Single exon deletion must be confirmed by another method
  • Need to check if predicted to be in frame or out of frame using Leiden Muscular Dystrophy site
  • Result confirms diagnosis of DMD/BMD
  • If first/last exon deleted then could extend into neighbouring genes and alter phenotype
  • If individual has children all daughters are obligate carriers
27
Q

When reporting diagnostic female DMD/BMD results, what does it mean if you find a duplication or deletion in your MLPA result?

A
  • If the female has symptoms of DMD/BMD then this result is consistent with clinical phenotype of a manifesting DMD/BMD carrier
  • Further testing should be offered such as cytogenetic analysis to detect if translocation/Turner syndrome
  • X inactivation studies may be appropriate
28
Q

What does it mean if you do not identify a mutation in DMD/BMD carrier testing?

A
  • If familial mutation is known then (1) if individual is not mother of affected child they are unlikely to be a carrier but (2) if they are mother then still risk of germline mosaicism
  • If familial mutation is not known then carrier risk is reduced depending on detection rate of the test performed (can perform a Bayes)
29
Q

What are some of the prior risks involved in Bayes calculation for DMD/BMD?

A
  • 4u (mutation rate) is risk that a female is carrier of DMD when no other info taken into account (prior population risk)
  • this is 18u for BMD (due to biological fitness)
  • risk for mother of sporadic case = 2/3
  • risk for grandmother of sporadic case =1/3
30
Q

Provide details on prenatal diagnosis for DMD/BMD

A
  • Usually only test male foetus as females not usually affected and ethical issues surround identification of carrier female prior to age of onset
  • Can sex free fetal DNA prior to prenatal diagnosis
  • MCC will need to be ruled out
  • If mutation is unknown then PND may be performed by linkage analysis
  • PGD now available for DMD
31
Q

Can prenatal diagnosis be performed for DMD/BMD when mother is not known to be carrier?

A

Yes - due to the risk of germline mosaicism

32
Q

What are the common clinical features of DMD?

A
  • Onset before 5yrs
  • Dev delay and LD (30-50%)
  • Progressive muscular weakness
  • Dilated cardiomyopathy
  • Loss of ambulation before 12 years
  • Mean age of death 25 years due to cardiomyopathy and respiratory insufficiency
33
Q

What are the common clinical features of BMD?

A
  • May be late learning to walk
  • Muscle weakness around 11 years
  • Muscle cramps
  • Lose ability to walk around 40-50 years
  • No LD
  • Survive into middle age and beyond
34
Q

What are the common clinical symptoms for female carrier of DMD/BMD?

A
  • Approx 5-10% have cramps or mild muscle weakness (proximal and asymmetric)
  • Usually noticed in 30s
  • Carriers of BMD are less affected than DMD
  • 20% have evidence of dilated cardiomyopathy
35
Q

What are the reproductive risks for a mother not found to be carrying the mutation of her affected son?

A
  • 10% risk of having affected future son due to gonadal mosaicism
  • 10% carrier risk for future daughter for same reason
36
Q

What is germline mosaicism and what is the prevalence of this in DMD/BMD?

A
  • More than one set of genetic information is found specifically within the gamete cells
  • In DMD/BMD = approx 7-10%

Genetics Of Neuromuscular Disorders (7 decks)

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