Tuesday, October 22, 2013
It's Not Just About Walking: Q&A with Katherine Mathews
Q: Is limb-girdle muscular dystrophy one disease or many diseases?
A: It's a clinical description of a pattern of muscle weakness, and there are many different genetic causes of that pattern of weakness. It's used as a term for some patients when there's weakness but we don't know what it is; and for others it's much more specific, with a known genetic cause.
Q: Does the term have any significance in itself?
A: It implies that the weakness started in the proximal muscles, either in the hip girdle, which means the muscles around the hips, or in the shoulder girdle, which means the muscles around the shoulders, or both.
Most of the time it's hips first, with trouble walking and trouble going up stairs, trouble standing up. Hip girdle as opposed to distal limbs. Trouble standing on toes, trouble walking on heels.
Shoulder girdle weakness causes trouble lifting your arms over your head, such as when brushing your hair or reaching into cupboards. For most people, it comes later than the hip weakness.
Getting a diagnosis
Q: Is it important for someone who has a diagnosis of LGMD to seek a more precise diagnosis?
A: I think it is. My bias as a muscular dystrophy doc and geneticist is yes. We won't always come up with a more specific diagnosis. The reasons for trying to come up with a more specific diagnosis are, number one, that it might modify your care. For example, if you come up with a diagnosis that virtually never involves the heart, you don't need to have regular cardiac monitoring after a baseline screening.
Q: How feasible is it for people to find out what kind they have?
A: Most people with limb-girdle muscular dystrophy will have had a muscle biopsy, and that insurance generally covers. Sometimes — not always, but often — the muscle biopsy can help direct genetic testing so that you don't go through everything [a full panel of genetic testing].
The muscle biopsy often will help guide diagnosis. If the biopsy was done a number of years ago, it's probably worth sending it to an experienced neuropathologist to have it re-assessed.
Q: How expensive is genetic testing for LGMD?
A: It’s so dependent on your insurance company and so many other things. We have a limb-girdle panel here that is less than $1,000. It's $500 to $700.
My diagnostic algorithm, if they come with limb-girdle muscle weakness, is first to check the serum CK. Some forms of limb-girdle don't have an elevated CK, so that takes you down a different route. If they have an elevated CK, then I’ll test for dystrophin testing. Strictly speaking, Duchenne muscular dystrophy and Becker muscular dystrophy are limb-girdle muscular dystrophies [because they start with limb-girdle weakness]. They’ve been pulled out as a different category, but they are limb-girdle muscular dystrophies.
Then, if the dystrophin is normal, I’ll usually do our screen for the common LGMD mutations. We estimate that dystrophin testing and testing for the common LGMD mutations allows a specific diagnosis to be made about 30 percent of the time.
After that, if those are normal and they haven’t yet had a muscle biopsy, I’ll do a muscle biopsy.
MRI is also being used to help direct genetic testing. The pattern of the skeletal muscle involvement on MRI can help guide genetic testing.
Let’s go back to the other reasons for getting a specific diagnosis. Number one is to modify your treatment. Number two is for family planning, for yourself and for other family members. Number three is that there's some peace of mind that often comes with knowing the exact type and being able to compare yourself with others with that type. And four, clinical trials are becoming available for which you need to know your specific LGMD subtype. If you don’t know your subtype, you can’t know whether you’re eligible for a specific trial.
It takes a while, often, to come up with a type, so you're better off starting sooner, rather than later.
Q: Would you say that most people, if they have the resources, can find out their type now, in the U.S.?
A: I would say yes, most, because most is more than 50 percent. I would say that there's probably still a significant portion who, despite doing everything we know how to do right now, don't have a diagnosis. Maybe that's 30 percent, something in that ballpark.
Q: Is pain something that comes up a lot?
A: Cramps are a common complaint. Usually we try to treat those with heat and cold. In fact, most of the musculoskeletal pain we try to treat with heat, cold, stretching, massage or a TENS unit and not with medicines. I will try physical therapy and everything non-medicine first. [Editor's note: Transcutaneous electrical stimulation is the use of electrical current to stimulate nerves through the skin; it can be used to treat pain.]
For a lot of people, that’s enough. There are some in whom it’s not.
Q: Do some people take anti-inflammatory medications, like ibuprofen?
A: Yes. Those sorts of things, definitely. And for a lot of people, it’s a matter of thinking about their lifestyle. Are there things that we can change in your lifestyle that are causing pain? Do you need a wheelchair at work rather than walking? Are you carrying too many heavy things? Are you positioning yourself in a bizarre way that's causing musculoskeletal pain?
Heart and respiratory concerns
Q: What do people need to know about that they might not notice themselves?
A: Cardiac and respiratory problems.
Q: And how to you manage those?
A: First and foremost, I try to get a diagnosis. If I don’t have a diagnosis, I will do an electrocardiogram and an echocardiogram about every other year as long as the results are completely normal. If the results start to be abnormal, or it’s a type of LGMD that’s known to involve cardiomyopathy, I’ll do these more often.
If I have a patient with a muscular dystrophy that I know is associated with a high probability of cardiomyopathy — not rhythm disturbance, but contractile disturbance — I will generally start them on an ACE inhibitor, even if they have a normal echocardiogram. We know that by the time the echocardiogram turns abnormal, there’s already been injury to the heart, so we try to start the medication before it becomes abnormal.
Q: Do you refer to a cardiologist?
A: It depends. I work closely with the cardiologists.
Q: Is cardiomyopathy a factor for most people with LGMD?
A: Yes, it’s a risk for the majority.
Q: Are there some LGMD patients where you do see cardiac rhythm disturbances?
A: Yes. In general, for most forms of LGMD, rhythm disturbance comes late in the disease. It’s a sign that the heart is in the end stage of failure. By then, of course, I have a cardiologist involved.
But some patients can get rhythm disturbance first. These patients may require anti-arrhythmic medications or a pacemaker. I have a cardiologist handle that, and they do that only after the abnormality shows up. I’ve never seen anybody do that prophylactically.
A: Respiratory function is obviously critical, so we measure respiratory function annually, whether or not I know the diagnosis. At a minimum, we measure forced vital capacity. Measuring cough function and expiratory pressure are good to do as well.
I’ll do a lot of the preliminary testing. If they start to have problems, then I call in a pulmonologist.
Q: What therapies are prescribed for respiratory difficulties?
A: Almost always BiPAP and CoughAssist.
Q: Is respiratory muscle impairment common in LGMD?
A: LGMD is such a heterogeneous [mixed] collection of things that I think it would be very hard to answer that question. But the bottom line is, cardiomyopathy is the most likely cause of death in LGMD, and the second most likely is respiratory impairment, so respiratory function needs to be monitored. If I have a patient with a sarcoglycan deficiency or a dystroglycan abnormality, I will monitor their respiratory function very closely. [
Therapies in the pipeline
Q: What therapies do you see coming down the pipeline for any form of LGMD?
A: For LGMDs that have to do with dystroglycan, there is probably going to be a trial of corticosteroids coming up.
There is anecdotal evidence that they might be helpful in some of the LGMDs that have to do with dystroglycan – the dystroglycanopathies.
A: If gene therapy or if exon skipping work for Duchenne muscular dystrophy, I think we’re going to see people looking at whether a similar treatment will work for forms of LGMD where the problem is a deficiency of a protein — the type 2, or recessive, LGMDs.
For the dominant forms of LGMD — the type 1 forms — people are looking at blocking toxic proteins with antisense or other kinds of genetic manipulation.