Manifesting carriers of Duchenne md

Dr Kate Bushby is a clinician and researcher based at our Newcastle Muscle Centre (Department of Human Genetics at the University of Newcastle upon Tyne).

Heidi Short: “I started falling over when I was about 12. I went to different doctors but as there was no family history of the disorder, they thought it was just a phase I was going through. I felt awful through my school years. I hated PE and missed several weeks from each term. It felt like having permanent flu. When my middle child – Sam – was diagnosed with DMD, one of the family care officers suggested I should be tested. It has helped a great deal to know. I feel that I’ve got some credibility now. People won’t think it’s all in my mind”.

Tracy McMahan: “I always had a peculiar walk – my pelvis sticks out and my back arches – but when people commented on it I couldn’t explain. It was just me! After my son Liam was born, I became a lot weaker; I couldn’t climb the stairs and lift him up. The condition was diagnosed at Oxford by Doctor Hilton-Jones’ team. I was much happier after that, knowing what I had. Now if I have any questions there are people to ring, like Jane my family care officer, and that’s so comforting”.

These are quotations from two women who are now known to be ‘manifesting carriers of Duchenne MD’. Until recently, this condition has been little understood and rarely diagnosed. Women and girls have struggled to get their symptoms recognised and accurately identified. However, with new genetic technology and increasing knowledge about Duchenne and Becker muscular dystrophy, the situation is improving. Dr.Kate Bushby of Newcastle explains:

“The most usual situation in Duchenne and Becker muscular dystrophy is that women carry the faulty gene and pass it on to their children, but only their sons show symptoms. Some women we know, however, do show symptoms relating to the genetic fault themselves and we call this being a manifesting carrier. Amongst women known to be carriers of Duchenne and Becker muscular dystrophy (DMD and BMD), one in ten might fall into this category”.

What symptoms does a manifesting carrier have?

There are as wide a variety of presentations of manifesting carriers as there are of males with DMD and BMD. Some girls may have a muscular dystrophy that is as severe as boys with DMD. Other women may only have very mild problems with muscle weakness late in adult life. Some women get aches and pains in their muscles as their first complaint and may notice enlargement of their calves and other muscles.

There are other manifestations of Duchenne muscular dystrophy, for example involvement of intellectual function and of heart muscle. Problems in these areas can be the only signs that someone is a manifesting carrier. These presentations are less common than a woman noticing a mild but progressive weakness involving usually first her legs but later on the arms as well. Most manifesting carriers notice some progression of their muscle problem with time; however it is rare for there to be any sudden deterioration.

Do all manifesting carriers come from families where people are known to have Duchenne or Becker muscular dystrophy?

No. It is very important to note that the diagnosis of a manifesting carrier may be made in someone who has absolutely no family history of DMD or BMD at all. In the days before it was possible to look at the dystrophin gene and protein by special laboratory tests, a female could only be suspected of being a manifesting carrier of Duchenne or Becker muscular dystrophy if she had a definite family history of the condition or had an affected son herself. Now that it is possible to look at muscle biopsy samples directly with dystrophin staining, the diagnosis has been made in women and girls who were previously thought to have a form of limb-girdle muscular dystrophy.

These people usually have no family history of any muscle problems whatsoever. It is an important diagnosis to make in these cases because, unlike most of the forms of limb-girdle muscular dystrophy, the risk of having a child who may be affected with DMD or BMD is relatively high. Like any carrier of Duchenne or Becker muscular dystrophy, a manifesting carrier has a one in four chance of having an affected son in any pregnancy. There is no clear evidence to suggest that being a manifesting carrier tends to run in families. So if one carrier in any family has muscle problems this does not seem to make it any more likely that other members of the family will also manifest any problems relating to being a carrier.

Why do some women run into problems like this?

It is thought that people who are manifesting carriers of any X-linked condition such as DMD and BMD generally have some problem in the mechanism which we know as ‘X-inactivation’. Because men only have one X-chromosome and women have two, one copy of the X-chromosome in every cell in a woman’s body is ‘switched off’ very early in development. The process is usually random; on average half the cells have one X-chromosome active and the other half the other. In people who are manifesting carriers of Duchenne and Becker muscular dystrophy most cells have the faulty X-chromosome active. The X-inactivation patterns can be studied in blood and most manifesting carriers show a non-random pattern. Some manifesting carriers may show an apparently random pattern in blood. It is thought that these women may have skewed inactivation only or mainly in their muscle cells.

How can the condition be diagnosed?

It is best to try and perform a number of tests to be absolutely sure that someone is a manifesting carrier. A muscle biopsy can be extremely helpful because it is relatively easy to look at patterns of dystrophin in muscle using antibodies to dystrophin. The sort of pattern which we often see in manifesting carriers is that of a mixture of staining patterns in different muscle fibres, some labelling nearly normally for dystrophin, others labelling weakly and sometimes others which can be completely negative. The finding of this without a major disruption of the proteins that link in with dystrophin can be diagnostic of a manifesting carrier of Duchenne or Becker muscular dystrophy. As additional proof one can also look at X-inactivation patterns in blood because most manifesting carriers have a non-random pattern. It is also possible though not as easy to look for the problem in the dystrophin gene itself in manifesting carriers. This usually requires relatively specialised tests which are not available everywhere.

What follow-up should manifesting carriers be getting?

This really depends on how much they are affected by their problem: For children who are affected with muscular dystrophy, whether they are boys or girls, it is appropriate for them to be seen at a muscle clinic. Adults may also find it helpful to attend a specialist clinic where they will find physiotherapy and family care officer back-up which may help them with their problems. However, adults with relatively minor problems may not need regular follow-up, providing their family doctor is aware of their problems and can refer them to the appropriate clinic should their symptoms get worse.

Are there other problems?

In DMD and BMD there is a chance that heart muscle may be involved as well as skeletal muscle. Manifesting carriers can have their hearts checked over by having an ECG and if necessary an echocardiogram. It must be stressed, however, that the actual incidence of heart problems in manifesting carriers is not yet known.

Please note: In its milder form, Duchenne muscular dystrophy is known as Becker muscular dystrophy. All references to manifesting carriers in this article, therefore, are relevant to both Becker and Duchenne muscular dystrophy. If you would like to know more about the inheritance pattern of Duchenne and Becker muscular dystrophy, please ask for our Fact Sheet. This explains about the X and Y chromosomes.