I could plunge in the deep end, and tell you about the multiple things I'm dealing with today: chasing up the neuromuscular consultant to rebook an appointment for T; replying to the contractor who has just sent us an estimate for making adaptations to our kitchen to make it wheelchair accessible; preparing for the meeting with T's special school tomorrow; negotiating with T on whether he wears pants today.... These are all posts in their own right, and I'll get to them all in turn in the next days and weeks.
But first, to introduce us: I'm in my late forties and live in the UK with my husband B and our ten year old son. Let's call him Tom. I'm keeping the blog anonymous, partly to protect our son, but also because I want to be able to be completely honest and tell it like I experience it. Tom was diagnosed with Duchenne muscular dystrophy five and a half years ago, when he was four and a half. We have been on a Duchenne journey ever since. Of course, having Duchenne is just one thing about Tom. He's also a sparky, imaginative, sociable, loving kid who's got loads of ideas and interest in the world, and is out there living life to the full.
Over the years of the Duchenne journey so far, I've written a number of things about Duchenne for a wider audience. To kick off this blog, here is the one that sets the scene of what Duchenne muscular dystrophy is: a beginner's guide to Duchenne, its causes and potential treatments.
Duchenne
Muscular Dystrophy:
a beginner’s
guide to its cause and potential treatments
What is Duchenne muscular
dystrophy?
Duchenne muscular dystrophy (DMD) is a progressive muscle
wasting condition. It is relatively rare
- roughly one in seven thousand births – and affects mainly boys.
People with DMD gradually lose strength in the skeletal
muscles. Later the heart and respiratory
muscles are involved. DMD does not
affect continence, speech, or eye movements.
On average boys with DMD begin to need a wheelchair full time
between the ages of eight and twelve.
Life expectancy when DMD is untreated is around nineteen
years. With specialist care management
life expectancy can rise into the thirties and even forties. Work being done on potential new treatments gives
realistic hope of even longer lives for the current generation of boys growing
up with DMD – the hope that DMD might become a long-term manageable condition.
What causes Duchenne
muscular dystrophy?
Lack
of a crucial protein called dystrophin:
To work, our muscle cells need a protein called
dystrophin. Dystrophin is crucial for
holding muscle cell walls together. It
is like scaffolding for the cell wall.
It holds in place a number of other proteins which all help the cell
wall work properly. Dystrophin is also
like a shock absorber. It is
springy. This enables muscle cells to
absorb impact without getting damaged.
People with DMD do not have any dystrophin in their muscle
cells.
Why
do people with DMD lack dystrophin?
In every cell of the body there is an instruction book called
DNA. It is made up of chemicals and
those chemicals act just like letters and words. DNA contains instructions for the body to
make everything it needs to grow and to maintain itself, including dystrophin
and thousands of other proteins.
DNA has twenty two chapters plus a chapter called X. The scientific name for these chapters is
chromosomes. In chapter X there is a
paragraph giving the instruction for dystrophin.
Imagine that you are in a muscle cell. In this imaginary cell you are going to use
the DNA instruction to make dystrophin out of Lego bricks. You turn to the paragraph in Chapter X and
you read this instruction:
Start with
blue brick then green brick then blue brick then
red brick yellow brick red
brick yellow brick red brick yellow brick
red brick yellow brick red
brick yellow brick red brick yellow brick
red brick yellow brick red
brick yellow brick red brick yellow brick
blue brick green brick blue
brick.
Fine: you make
dystrophin. But imagine that you turn to
the dystrophin paragraph and instead get this instruction:
Start with
blue brick then green brick then blue brick then
rbr ickye
llowbr ickre dbr ickye llowbr ickre dbr ickye llowbr ickre
dbr ickye llowbr ickre dbr
ickye llowbr ickre dbr ickye llowbr ickre
dbr ickye llowbr ickre dbr ickye llowbr ickre dbr
ickye llowbr ickbl
uebr ickgr eenbr ickbl uebr
ick.
The instruction is unreadable. You can’t make dystrophin. Two letters have been missed out. The words are all of the right length. The other letters have shunted up, in the
place of the missing letters. The result
is gobbledegook.
Now imagine that you turn to the dystrophin paragraph and instead
of the previous examples you get this instruction:
Start with blue
brick then green brick then blue brick then
red.
There is a full stop before the instruction has finished. You can’t make dystrophin.
If the body can’t make dystrophin, the muscle cell dies. The long term effect of this is that muscle
fibre degenerates and is replaced by fatty tissue.
What I have outlined
here are the two kinds of mistake that can occur in DNA instructions. In about 85 – 90% of DNA mistakes, letters are
missed out or added. In about 10 – 15%
of mistakes, full stops are put in before the end of the instruction. When these mistakes happen, the body can’t
follow the instruction and can’t make the protein.
These two kinds of mistake can happen anywhere in the DNA
instruction book. Depending on where
they are they cause different conditions.
Haemophilia, cystic fibrosis, some forms of sight loss, and predisposition
to certain cancers are all examples of conditions caused by DNA mistakes.
The body does have a back-up plan. Girls get a full copy of the twenty-two
chapters plus chapter X. Every cell
contains two full copies of DNA. If
there is a mistake on one copy, the body can use the other copy. Boys get a copy of the twenty-two chapters,
but instead of a second chapter X they get chapter Y. Chapter Y contains instructions for making
testicles, but it doesn’t contain the instructions that are in chapter X for
making dystrophin and some other crucial proteins. That is why it is usually only boys who get
Duchenne muscular dystrophy.
How are scientists tackling
Duchenne muscular dystrophy?
Scientists are exploring a number of ways to tackle Duchenne
muscular dystrophy and turn it into a manageable condition. The main approaches are listed below. Different research projects are at different
stages of development. We are looking at
a time scale of five to ten years for research to produce the first treatments.
Target
the DNA mistake
Exon skipping targets DNA instructions which have been turned into gobbledegook. It cuts letters out of the faulty instruction
so that the letters get back in the right place. In the example here, you could cut the
underlined letters to restore a readable instruction:
Start with blue brick then
green brick then blue brick then
rbr ickye
llowbr ickre dbr ickye llowbr ickre dbr ickye llowbr ickre
dbr ickye llowbr ickre dbr
ickye llowbr ickre dbr ickye llowbr ickre
dbr ickye llowbr ickre dbr ickye llowbr ickre dbr
ickye llowbr ickbl
uebr ickgr eenbr ickbl uebr
ick.
You would not get full dystrophin but it would work. Duchenne muscular dystrophy would become a
milder condition called Becker muscular dystrophy: still muscle degeneration, but usually much
less severe and life-shortening than DMD. A number of scientists are working on exon
skipping, including Matthew Wood at Oxford University in the UK and Steve
Wilton in Perth, Western Australia.
Ataluren is a drug which targets premature full stops. It aims to enable the body to ‘read through’
the premature full stop. In cases of
premature full stops, the rest of the instruction is there, but the body does
not read it because it stops at the full stop.
Ataluren could potentially restore full-length dystrophin. It is being trialled by an American
pharmaceutical company called PTC Therapeutics.
Bring
in dystrophin from outside the body
Adeno-associated virus vectors (AAV): this approach uses empty virus ‘shells’ to
bring dystrophin into the body and transport it to every cell. There are two main difficulties which need to
be overcome here. The first is that
dystrophin is very big, as you would expect of a protein which is a cell wall
scaffolding and shock absorber – too big to fit into viruses without being
modified. The second is the problem of
immune responses by the body to incoming viruses. AAV is being explored by Keith Foster at
Reading University in the UK.
Replace
dystrophin with another protein
Utrophin is a protein which does the same job as dystrophin at
the foetal stage and shortly after birth.
It is then switched off. Kaye
Davies and her team at Oxford University are working to develop a drug which
would keep utrophin switched on and boosted up to replace dystrophin.
Build
up muscle to compensate
Steroids are currently used to help prolong muscle
strength. While they do have some effect,
they can’t boost up muscle strength to anywhere near the level needed and they
have a lot of side effects.
Myostatin inhibitors: myostatin is a substance in the body which
stops it from making too much muscle. If
myostatin could be switched off or inhibited, the body would make more muscle, potentially
enough to compensate for the continuous muscle loss in DMD. George Dickson at Royal Holloway College,
University of London, is working on this approach.
Stem cells: these are
cells in the body with the potential to turn into any kind of cell. It might be possible to direct stem cells to
turn into muscle cells. Research into
stem cell use for Duchenne muscular dystrophy is being done by Jenny Morgan at
University College, University of London.
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