A Beginners Guide to Duchenne Muscular Dystrophy

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:

In order to work, our muscle cells need a protein called dystrophin. 

Dystrophin has two functions: 

Firstly, 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.  Without dystrophin the cell wall disintegrates.  Secondly, dystrophin is like a shock absorber.  It is long and 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 a chemical ‘instruction book’ called DNA.  The chemicals of DNA 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.  Each DNA ‘word’ is three ‘letters’ or chemicals long.

DNA has twenty two ‘chapters’, or chromosomes.  Each person has two copies of each of these chromosomes in every cell.  There are also two further chromosomes, called X and Y.  Women have two copies of the X chromosome and no Y chromosome.  Men have one X chromosome and one Y chromosome. 

The DNA instruction for dystrophin is in the X chromosome.

The instruction for making dystrophin (or any other protein) is a bit like the instruction for building a tower out of Lego bricks.  You can imagine it like this:

            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.

No problem.  But sometimes there is a ‘mistake’ or mutation, and the instruction is unreadable.  Letters or words can be repeated, or missed out, as in this example:

            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.

Here, two letters have been missed out.  The other letters have shunted up, in the place of the missing letters.  The result is gobbledegook.

Sometimes there can be a full stop before the instruction has finished, as in this example:

            Start with blue brick then green brick then blue brick then

            red.

 The body reads up to the full stop, and the result is a truncated protein which won’t work.

If the body can’t read the instruction and can’t make dystrophin, the muscle cell dies.  Over time that means progressive loss of muscle tissue.  Muscle is replaced by scarring and fatty tissue.

 What I have outlined here are the kinds of mutation that can occur in DNA instructions.  In about 85 – 90% of DNA mutations, letters are missed out or added.  In about 10 – 15% of mistakes, full stops are put in before the end of the instruction.  .

Mutations 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 mutations.

The body does have a back-up plan.  Every cell contains two full copies of 22 chromosomes.  Girls also get two X chromosomes.  If there is a mutation on one, the body can use the other.  However, boys only get one copy of the X chromosome.  The Y chromosome 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 treat Duchenne muscular dystrophy and turn it into a manageable condition.  There are four main approaches to tackling the condition.  The four approaches are outlined here, along with the main lines of research which use each approach.  The examples are not exhaustive

Correct the body’s reading of the DNA mutation

Exon skipping:  this 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 given earlier, 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.

If you cut these letters you would not get full dystrophin, but it would work.  Duchenne muscular dystrophy would become a milder condition called Becker muscular dystrophy:  there would still be some loss of muscle, but Becker is usually much less severe and life-shortening than DMD.  

Translarna:  this 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.  Translarna could potentially restore full-length dystrophin.  

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 muscle cell. 

A difficulty here is that dystrophin is very big indeed, 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.  So researchers are looking at two solutions: dividing the dystrophin into three parts, each transported by a virus; and using ‘micro-dystrophin’ – finding the optimal version of dystrophin which has all the essential parts but some of the middle ‘springy’ bits left out, a version which would produce the mildest possible symptoms of Becker muscular dystrophy.

Replace dystrophin with another protein/ways to hold the cell wall together

Utrophin is a protein which does the same job as dystrophin at the foetal stage and shortly after birth.  The body then switches it off.   Researchers are developing a drug to enable the body to keep utrophin switched on and boosted up, to replace the missing dystrophin.

Ways to prolong strength or build up muscle to compensate for muscle loss

Steroids are currently used to help prolong muscle strength.  They do have some effect, on average prolonging ambulation by an average of 2 to 4.5 years depending on when they are started and the dose.  However, they can’t boost up muscle strength to anywhere near the level needed and they have a lot of adverse 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. 

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.