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Duchenne Muscular Dystrophy
A clinical and molecular overview
This PowerPoint file contains a number of slides that may be useful for teaching of
genetics concepts.
You may use these slides and their contents for non-commercial educational purposes.
© 2009 NHS National Genetics Education and Development Centre
Genetics and Genomics for Healthcare
www.geneticseducation.nhs.uk
Duchenne Muscular Dystrophy
This presentation includes:
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Clinical features and Inheritance
Pedigrees showing X-linked inheritance pattern
Clinical photographs showing Gower’s manoeuvre
Muscle histology slides showing staining in normal and affected tissue samples
Deletion of dystrophin gene, and PCR images
Image of the dystrophin molecule
Case scenario.
© 2009 NHS National Genetics Education and Development Centre
Genetics and Genomics for Healthcare
www.geneticseducation.nhs.uk
Duchenne Muscular Dystrophy
(DMD)
Clinical Features:
• Progressive muscle weakness.
• Mainly in a wheelchair by early teens.
• Respiratory muscles eventually involved.
• Death usually in late teens, early twenties.
Inheritance:
• X linked recessive condition, hence males affected and females are carriers (see
pedigree on next slide).
© 2009 NHS National Genetics Education and Development Centre
Genetics and Genomics for Healthcare
www.geneticseducation.nhs.uk
DMD Pedigree
The X chromosome carrying the disease-causing mutation can be tracked through the family. Note: Shaded
squares = affected males: dots in circles = carrier females.
© 2009 NHS National Genetics Education and Development Centre
Genetics and Genomics for Healthcare
www.geneticseducation.nhs.uk
Pedigree of Martin Davies’s family
Assuming this is X-linked muscular dystrophy, the women marked with dots are obligate carriers of the disease
gene – that is, they must be carriers because they have offspring who are affected or carriers.
Fig. 1.10 ©Scion Publishing Ltd
© 2009 NHS National Genetics Education and Development Centre
Genetics and Genomics for Healthcare
www.geneticseducation.nhs.uk
Duchenne muscular dystrophy
(a) Affected boys stand up by bracing their arms against their legs (Gower’s manoeuvre) because their proximal
muscles are weak.
(b) and (c) Muscle histology (Gomori trichrome stain). Normal muscle (b) shows a regular architecture of cells
with dystrophin (brown stain) on all the outer membranes. (c) Shows muscle from a 10-year-old affected boy.
Note the disorganisation, invasion by fibrous tissue and complete absence of dystrophin.
Histology photos courtesy of Dr Richard Charlton, Newcastle upon Tyne.
Fig. 1.4 ©Scion Publishing Ltd
Histology photos courtesy of Dr Richard Charlton.
© 2009 NHS National Genetics Education and Development Centre
Genetics and Genomics for Healthcare
www.geneticseducation.nhs.uk
A muscle biopsy from a female carrier of Duchenne muscular dystrophy stained with
an antibody against dystrophin
Note the patchy distribution of staining around the outer membranes of cells (compare with the sections from
an affected boy and a normal control in next slide).
Fig. 7.11 ©Scion Publishing Ltd
Photo. courtesy of Dr Richard Charlton
© 2009 NHS National Genetics Education and Development Centre
Genetics and Genomics for Healthcare
www.geneticseducation.nhs.uk
Immunolabeling of Muscle Biopsy Sections
Dystrophin
antibody staining of
muscle cells
Normal Control
© 2009 NHS National Genetics Education and Development Centre
4 year old boy with DMD – No detectable
dystrophin
Genetics and Genomics for Healthcare
www.geneticseducation.nhs.uk
A deletion of part of the dystrophin gene
This figure shows a 500 kb region containing exons 41-50. These exons are all 100-200 bp long, and so if drawn to
scale each exon would be represented by a line occupying less than 0.05% of the width of the figure. Random
deletion breakpoints therefore almost always fall in introns. Their effect is to remove one or more complete
exons from the mature mRNA. The deletion shown removes exons 45-47 from the mature mRNA, while leaving
all the other exons intact.
Fig. 3.9 ©Scion Publishing Ltd
© 2009 NHS National Genetics Education and Development Centre
Genetics and Genomics for Healthcare
www.geneticseducation.nhs.uk
The dystrophin molecule anchors
the cytoskeleton of muscle cells
to the extracellular matrix, via the
dystrophin glycoprotein complex.
This includes the sarcoglycans
(mutations in which cause limbgirdle muscular dystrophies) and
dystroglycans.
Muscle cells that lack dystrophin
are mechanically fragile, and fail
after a few years, hence
progressive muscle weakness.
Fig. 6.4 ©Scion Publishing Ltd
© 2009 NHS National Genetics Education and Development Centre
Genetics and Genomics for Healthcare
www.geneticseducation.nhs.uk
PCR deletion screen in Duchenne muscular dystrophy
Nine selected exons of the dystrophin gene have been amplified from the DNA of a panel of 20 affected boys.
When the product is run on an electrophoretic gel each exon gives a band of a characteristic size. Because a boy
has only a single X chromosome, any deletion shows up as missing bands. Different exon deletions can be seen
in lanes 1, 5, 11, 12, 19 and 20. Lane 3 may be a large deletion or a technical failure. The boys with no deletion on
this gel may have others of the 79 dystrophin exons deleted, or may have point mutations or duplications to
cause loss of function of the gene.
Fig. 4.17 ©Scion Publishing Ltd
© 2009 NHS National Genetics Education and Development Centre
Genetics and Genomics for Healthcare
www.geneticseducation.nhs.uk
18-exon Multiplex PCR Assay DMD
Reaction 1
NC
1
2
Reaction 2
3
NC 1
2
Reaction 3
3
NC
1
2
3
Patient 2 deleted for exons 47, 48 and 50
© 2009 NHS National Genetics Education and Development Centre
Genetics and Genomics for Healthcare
www.geneticseducation.nhs.uk
Jason’s family tree
Jason, aged 3 yrs referred to a paediatrician by his GP
•Later walking than older siblings
Rachel
14.3.74
Tony
26.9.73
•Difficulty running and riding tricycle
•Always climbs up stairs on all fours.
Susie
3.6.95
© 2009 NHS National Genetics Education and Development Centre
Fay
7.1.98
Jason
15.11.99
Genetics and Genomics for Healthcare
www.geneticseducation.nhs.uk