This is a continuation of our Q&A session with Rabi Tawil, MD, co-director of the MDA Neuromuscular Disease Clinic at the University of Rochester, New York, and lead author of the first evidence-based care guideline for FSHD, a project the FSH Society supported through consultations and advocacy. Summaries of the guideline can be downloaded at https://www.fshdsociety.org/resources/.
Part 1 of our session was published in FSH Watch 2016, Issue 1, and is available here.
Q: I was wondering if you could give us some options that are available for FSHD Type 1 females who may be interested in starting a family?
Dr. Tawil: One of the difficulties with FSHD is that the genetic test for FSHD needs a lot of DNA, and so this precludes doing what we call pre-implantation genetic diagnosis (PGD), except in certain situations.
A pre-implantation diagnosis is when you can take eggs from the female and fertilize them in vitro, and grow the embryos to the eight-cell (day 3) stage. You can then take one cell from each embryo and test it, and you’d be able to determine if that very early embryo has FSHD or not. You can then implant the FSHD-free embryos into the mother, and you can be certain that the baby won’t have FSHD.
The problem is that you cannot do standard genetic testing on DNA from just one cell, but you can do it in a different way. You can do PGD based on what we call linkage, and it’s a little bit complicated to explain, but for that to happen, you need multiple members of the family who have FSHD―and preferably from more than one generation―to donate blood to get tested, and then by looking at the pattern of the DNA of all the affected family members, you can figure out, based on DNA from one cell, what the probability of that embryo is to develop FSHD. So in FSHD, to do pre-implantation genetic diagnosis, the bottom line is that it only works if you have multiple affected members of the family in more than one generation that can be tested.
Q: I understand that the care guidelines are based on FSHD Type 1 (FSHD1). Would it make sense for an FSHD Type 2 (FSHD2) patient to share the guidelines with my care team?
Dr. Tawil: Again, the problem is that FSHD2 is really kind of a new type of FSHD that’s only been known for the last six or seven years. I think we know that both FSHD Type 1 and 2 eventually have the same mechanism; they’re caused by the same thing, even though they’re genetically different. Both of them are caused by the expression of DUX4 in muscle cells. What we know is that in general, FSHD2 looks very much like FSHD1.
What I have not seen in FSHD2 myself or have seen published anywhere are some of the more severe forms of FSHD, like infantile-onset FSHD, which you see with FSHD1. I don’t think it has been reported in FSHD2. Similarly, the complications of hearing loss and retinal vascular disease have not yet been reported in FSHD2.
So I think the care guideline recommendations, by and large, apply for both Types 1 and 2. Some of the predictors―for example, the size of the D4Z4 deletion―obviously do not apply to FSHD2. There may be certain factors that we’re going to be able to measure, and which we’re looking at now, that may tell us if somebody is more predisposed to getting more severe disease with FSHD2. This has to do with the methylation levels of the DNA. The methylation level basically reflects how tightly bound the DNA is around the D4Z4 repeat; the less tightly bound it is, the more likely you’re going to get DUX4 expression. The more tightly bound it is, the more it’s suppressed, and so we’re looking at identifying the best marker for methylation in FSHD2 and see if it may be helpful in making a prognosis in patients who have FSHD2. But again, in general, as far as recommendations like exercise and everything else, I think the guideline recommendations apply for both types of FSHD.
Q: Are cardiac arrhythmias and atrial flutter typically related to FSHD, and, I guess clinically, what’s their significance?
Dr. Tawil: It’s very hard to tease out from the reports of FSHD patients who have these arrhythmias whether they have them because of other cardiovascular risk factors, or whether the cardiac issues are connected to FSHD. But if there’s anything that happens with FSHD, it’s some of those atrial arrhythmias, and they’re usually very benign.
Now, atrial fibrillation is not necessarily benign, because it can predispose to clots, and so somebody who has chronic atrial fibrillation may need to be on anticoagulation. But again, I don’t think that there’s enough evidence from what we’ve looked at to suggest that people with FSHD need to be screened for these arrhythmias because most people will have symptoms if they have atrial fibrillation or atrial flutter. Again, while there are potentially dangerous arrhythmias in the long run, they’re not as severe as some ventricular arrhythmias.
Q: Do you anticipate any blood tests that preclude the need for a muscle biopsy? I think maybe the underlying question really is, Why is the muscle biopsy still being done often as part of the diagnostic workup when there is a genetic test that would definitively tell you if you have FSHD?
Dr. Tawil: Yes, so the sequence of events―and again, there is a flow chart in the actual journal article of the guidelines that shows that there’s no need for a biopsy. The only time you would do a biopsy is if people looked like they have FSHD, and you do all the genetic testing, and it comes back negative; then you have to do a biopsy to help guide the physician as to where to go next as far as figuring out what you have. So the first approach is that you don’t need a muscle biopsy to make a diagnosis of FSHD.
Q: If there is breakdown of muscle tissue going on in FSHD, does that put a strain on kidneys and other organ systems, and should there be some kind of therapy to support those systems that are being stressed by muscle breakdown?
Dr. Tawil: I think that the person is referring to what happens in people who have generalized breakdown of their muscle in what we call rhabdomyolysis. That’s when many muscles break down all at the same time, and the muscles leak enzymes and myoglobin proteins which can cause kidney damage. At any one time, the actual muscle damage is not very high in FSHD, and it’s reflected by the CPK enzyme level. Most people with FSHD have either normal or slightly abnormal CPKs, in the 500 to 1,000 range. Those levels don’t result in any kidney problems. It’s the people who have CPKs of 20,000 to 100,000 who get into trouble.
Q: There are some patients who have very severe atrophy, and keeping weight on is a challenge for them. What do you recommend for a patient who just can’t put on weight and need to?
Dr. Tawil: I think it’s a balance. You don’t want to put on too much weight. The question is, Are people who are very thin, who have FSHD because there’s a lot of muscle wasting, but nutritionally they’re eating appropriately? Then I’m not sure that gaining weight in those situations is beneficial for them, especially if they are very weak, because they would have to carry more weight.
But you want to make sure that they’re not continuing to lose weight because of what we call a catabolic process. You can do some blood studies, look at the albumin level, and see if it’s appropriate. If somebody’s not getting enough nutrition, then it would be reflected in some of the blood tests that you can do.
Editor’s note: We thank Dr. Tawil and dozens of FSH Society members for participating in the live chat.