Duchenne and Becker muscular dystrophy (MD) are caused by an abnormality (mutation) of the dystrophin gene, which is on the X chromosome. The dystrophin gene is responsible for telling the body how to make the protein dystrophin, which is essential for normal muscle function; dystrophin is also present in the heart and in the brain. The exact nature of the mutation determines whether the result is a male with Duchenne MD, or the milder condition of Becker MD.
Females have two X chromosomes, whereas males have one X and one Y. Males therefore only have one copy of the dystrophin gene, and if it is not working properly (mutated) they can not produce any normal dystrophin and have either DMD or BMD. Typically, such a male inherits the abnormal gene from his mother, who has a normal dystrophin gene on one of her X chromosomes, but “carries” the mutated gene on her other X chromosome.
Every cell in a woman’s body has the two X chromosomes, but nature doesn’t like waste and in each cell one or other of the X chromosomes is “turned off”. This is a random process, so on average in one-half of a woman’s cells one of the X chromosomes is turned off, and in the other half it is the other X chromosome. For a female carrier, this means that half of her cells produce normal dystrophin and half produce the mutated dystrophin. Female carriers therefore would seem to have one-half of the production capacity for normal dystrophin as women who don’t carry the mutation. Muscle is more complicated, because it is produced by the fusion of many cells – it therefore has multiple nuclei, the structures that contain the genetic material (DNA). Although, on average, only one-half of the nuclei are producing normal dystrophin, the dystrophin can diffuse throughout the muscle fibres and for most women that is sufficient for normal muscle function. In some women, the X-inactivation process is “skewed”, meaning that instead of there being a 50:50 inactivation of X chromosomes, the ratio might be, for example 90:10. If the balance is in favour of the mutated dystrophin, then the woman may develop features of muscle disease, typically milder than in an affected male because she still has some capacity to make normal dystrophin, which the male doesn’t.
It must be remembered that not all mothers of boys with DMD or BMD are carriers. This is so in about 70%, but in the remaining 30% the mutation arises for the first time during the creation of the embryo. Therefore, when a new diagnosis of DMD or BMD is made, it is extremely important to determine whether or not the mother is a carrier, and this will also carry implications for other family members.
Overall, about 10% of female carriers may show symptoms or signs of muscle disease and it can be shown that this relates to non-random inactivation of the X chromosome, as outlined above. They are referred to as “manifesting carriers”. Symptoms are what the patient complains of; signs are what the doctor finds on examination. The two do not always go together. It is possible for the doctor to find an abnormality (sign) on examination, but the patient has no awareness of any problems (symptoms). This can relate to the limb muscles or, as noted below, to the heart muscle. The reverse is also true, in that a patient may have a symptom without the doctor being able to find a certain abnormality on examination. Sometimes the patient may complain of something which they are convinced relates to them being a carrier, and the doctor doubts the relationship. In my experience the commonest bones of contention relate to the complaints of muscle pain and fatigue.
A relatively common observation is that of enlargement of the calf muscles, without any complaints of weakness or pain. But casual observation in the street will make it obvious that there are many women with large calves who are not MD carriers!
There may be weakness around the shoulders or the hips, or both. Complaints might include difficulties using the arms above shoulder height, or difficulty climbing stairs, running, or getting out of low chairs. Such weakness can come on at any age. If it does develop it will slowly worsen with time. In only a very small proportion of the 10% of manifesting carriers is it severe.
Males with DMD and BMD may develop heart involvement (cardiomyopathy). There is evidence that a small number of female carriers, even if they have no other symptoms, may also develop cardiomyopathy, although it is very rarely severe. Although there is still debate as to the frequency of this complication, we currently advise all carriers to have a simple heart assessment (ultrasound scan of the heart). In middle-age heart problems become more common in the general population so there may be doubt as to whether or not an identified abnormality relates to the woman’s carrier status or not.
It is important, particularly for non-specialist doctors, to realise that a manifesting carrier may come from a family with no known history of DMD/BMD, and that can present a diagnostic challenge.
Interested readers are strongly advised to look at the fact sheets produced by the Muscular Dystrophy Campaign, particularly:
These, and further useful information, can be found at: www.muscular-dystrophy.org
In addition, the DFSG has an information leaflet available for Manifesting Carriers. Please contact our office if you would like a copy, or if you would like to be put in touch with another manifesting carrier.