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MBOD Week 15 > Duchenne and Becker Muscular Dystrophy > Flashcards

Duchenne and Becker Muscular Dystrophy Flashcards

1
Q

Duchenne Muscular Dystrophy (DMD)

  • Inheritance
  • Prevalence
  • Presentation
  • Survival
A
  • X-linked recessive
  • Affects 1/3500 males
  • Delayed motor milestones, progressive weakness and muscle loss; hypertrophic calf muscles; Cardiac and respiratory complications
  • Patients usually only live into their early 20s
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2
Q

How does Becker Muscular Dystrophy (BMD) compare to Duchenne Muscular Dystrophy (DMD)?

A
  • BMD is a milder allelic variant with later age of wheelchair dependency
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3
Q

Dystrophan in Duchenne Muscular Dystrophy (DMD)

  • Quantity
  • Immunohistochemistry
  • Protein Quality
A

Quantity:
- 0% - 5% present

Immunohistochemistry:
- Complete/almost complete absence (muscle tissue)

Protein Quality:
- Most often severely TRUNCATED Protein is unstable and degraded

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4
Q

Dystrophan in Becker Muscular Dystrophy (BMD)

  • Quantity
  • Immunohistochemistry
  • Protein Quality
A

Quantity:
- 20%-100%

Immunohistochemistry:
- Normal appearing or reduced ± patchy staining

Protein Quality:

  • Reduced levels of altered protein
  • NORMAL terminal domains with SHORTENED internal domains
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5
Q

What is the overarching difference that leads to the different manifestations of Duchenne and Becker Muscular Dystrophy?

A

The functionality and general presence of dystrophan

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6
Q

Why is the DMD gene so susceptible to errors and mutation?

A
  • Its the largest known gene
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7
Q

Why does the size of the DMD gene play a role in it being frequently mutated?

A
  • 79 exons
  • Spans MULTIPLE recombination HOTSPOTS
  • multiple REPETITIVE sequence elements
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8
Q

What percentage of simplex cases are the result of a new mutation in muscular dystrophy ?
- Remember why this is the case

A
  • 1/3 or simplex males are new mutations

NOTE: this is the general rule with severely debilitating X-linked recessive:

  • 1/3 of X gene pool is in males
  • The affected X gene is lost from affected DMD patients
  • Prevalence of the disease stays the same overtime so 1/3 of affected people came from new mutation

**otherwise disease prevalence would decline steady as mutated X chromosomes were lost in affected individuals

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9
Q

How often do the following mutations occur in the DMD gene:

  • Large Deletions (spanning 1 or more exons)
  • Large Duplications
  • Small insertions/Deletions or point mutations
A
  • 65% large deletions spanning one or more exons
  • 10% large duplications
  • 25% small insertions/deletions or point mutations
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10
Q

Where do breakpoints tend to occur in the DMD gene (5’-UTR, Exon, Intron, 3’-UTR)?

A

Introns - these breaks usually span 1 or more exons

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11
Q

What are the consequences of deleting an exon that is a multiple of 3?

A
  • Fairly small because this does NOT lead to a frameshift mutation
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12
Q

What are the risks associated with deleting an exon that is not a multiple of 3? (2 possible outcomes)

A
  1. Frameshift
  2. Frame Neutral (no frameshift)
    - this is only the case if you had a (3)n+2 exon and a (3)n+1 exon being ligated the overhang of 2 and 1 would come together to make a readable codon (otherwise its framshift)
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13
Q

See Slide 7 or Dr. Park’s DMD/BMD lecture

A

See Slide 7 or Dr. Park’s DMD/BMD lecture

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14
Q

If Frame neutral deletion of an exon in the DMD gene occurred, what disease would you expect the patient to have?

A
  • You would expect the patient to have Becker’s MD because the deletion occurred in a multiple of 3
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15
Q

T or F: SIZE of mutation is more important than changes in reading frame

A

FALSE, a change in the reading frame will certainly lead to a truncated protein

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16
Q

What happens to proteins that have a frameshift mutation?

- patient

A
  • Protein is truncated then degraded

- Patient will have full blown DMD

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17
Q

T or F: duplications follow the same rules as deletions (aka multiples of 3 are less harmful than frameshifts)

A

True

18
Q

Is it possible to determine the kind of muscular dystrophy someone has without doing a muscle biopsy to look at the dystrophan protein?

A

Yes, blood samples can be taken where we can just look at the GENE SEQUENCE to see if the mutation was FRAMESHIFT (DMD) or FRAME NEUTRAL (BMD)

  • This is 90% accurate
19
Q

What 4 types of point mutations can occur at the DMD gene?

*Note: these combined account for 25% of DMD cases

A
  1. Nonsense
  2. Splice Site
  3. Small Insertions/deletions
  4. Missense (rare)
20
Q

What is the result of nonsense mutations in the DMD gene?

DMD point mutation

A

Truncating - so they more commonly lead to DMD than BMD

21
Q

What are the outcomes of a splice site mutation in the DMD gene?

(DMD point mutation)

A
  • Could be Neutral (BMD) or Truncating (DMD) depending on the exon taken out
22
Q

What is the outcome of small insertions and deletions in the DMD gene?

(close in size to DMD point mutation)

A
  • Depends on whether these occur in multiples of 3

**Note: these are too small to be detected with an array

23
Q

What is the outcome of RARE missense mutations in the DMD gene?

(DMD point mutation)

A
  • Not usually disease causing
24
Q

What type of tests are commonly used in DMD/BMD testing?

A
  1. Scanning Tests (most common)

2. Targeted tests (way less common)

25
Q

What are 2 good reasons that we use a scanning approach to DMD diagnosis?

A
  1. Lots of Allelic Heterogeneity
  2. High Mutation Rates

Therefore, we need to look through the ENTIRE GENE

26
Q

Why is there lots of Allelic Heterogeneity in individuals with the DMD phenotype?

A

many different mutations possible so many affected individuals may have different mutations on each chromosome giving rise to the DMD phenotype

27
Q

When is it okay to use a targeted DMD test?

A

To test for the Presence or Absence of a KNOWN FAMILIAL mutation

28
Q

What type of test would you use if a female had an affected child and wanted to know her chances of having another affected child?

A
  • Targeted, you would see if her genes had the same mutation that is seen in her affected son
29
Q

When you do an array to for DMD testing what genes are included in the array?

A

DMD genes ONLY

30
Q

Which of the following will a DMD custom array test for?

  • Exon deletions and Duplications
  • Gene mutations elsewhere on Chromosome
  • Insertions and deletions
A

Yes:
- exon deletions and duplications (75% of cases)

NO:

  • gene mutations in other genes
  • Insertions or deletions
31
Q

See slide 6 from second part of DMD/BMD lectures

A

See slide 6 from second part of DMD/BMD lectures

32
Q

What do you do if you’re pretty sure a patient has DMD but they’re array test comes back negative?

A

Scan the Gene again and SEQUENCE specific parts

33
Q

What parts of the DMD would you sequence if an array test came back negative?

A
  • Intron/Exon Junctions (splice junctions)
  • Promoter Regions
  • A few know intronic mutation points
34
Q

Suppose you find a mutation deep in an intron, what do you do with this information?

A
  • Compare it to a database and see if its Pathogenic or not

NOTE: few of these are documented so often its hard to say whether or not the small mutation is pathogenic

35
Q

Where do breakpoints in the DMD gene typically occur?

- what accompanies this deletion?

A
  • INTRONS, these deletions are usually accompanied by the deletion of at least 1 exon
36
Q

What are the two most important domains in Dystrophin protein that is encoded by the DMD gene?

A
  • Two Globular Terminal Domains
37
Q

You take a muscle biopsy and no dystrophin is detected. What is the diagnosis?

A
  • DMD, if it were Becker’s you would expect to see some dystrophin
38
Q

T or F: although much less common insertions/deletions or point mutations still make up a large portion of mutations leading to DMD or BMD.

A

True

39
Q

You use a DMD array test to see if a patient has DMD or BMD and no mutations are detected. What’s your next move?

A

Next you’ll want to do another SCANNING test that SEQUENCES the entire DMD gene to look for the point mutations etc.

40
Q

A woman had uncle with DMD and has a Child with DMD, but nothing shows up on either DMD test. What can you assume?

A

She’s the 1% whose results don’t show up. We know she has the disease because she is an obligate carrier

41
Q

T or F: a chromosomal microarray and a DMD array are the same thing.

A

False, the DMD array only does the test on one gene

MBOD Week 15 (7 decks)

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