Here's the scoop on meds like beta blockers (propranolol, et al) and alpha agonists (clonidine, guanfacine) in young kids with fragile X.
Wednesday, May 19, 2010
Monday, May 17, 2010
Videoblogging fragile X: treatment cocktails
Here's a response to one of the most common questions I get:
Monday, March 29, 2010
Blog for FRAXA
People are always asking me how they can help FRAXA. Obviously, we'd all like to be able to raise tons of money for research, but if you're like me, you probably don't have a lot of extra cash, and you probably don't know anyone who does. But just about anyone with a little free time can blog, and you can use a free blog to help FRAXA. We'd like to set up a network of bloggers around the world to raise awareness of fragile X, and raise money for FRAXA---just email me ( fraxares@verizon.net ) and we can go over the details. It's fun, and if enough of us join together, it really can make a difference!
Tuesday, September 8, 2009
Science Q & A !!!
Q: Something that has been on my mind for some time now and I hope that you will know where to look for an answer. Why do children with Fragile X exhibit a consistent phenotype, large ears, etc.? You will already have thought about this, I am sure. I just can't understand why a single protein deficiency would influence the general development of a human. Does it happen also with the mice? Does the fragile X mouse model exhibit similar phenotypic appearances? If not, then I would start to wonder if the model was accurate, wouldn't you?
A: Of course, we don't know all the details yet, but a few key answers to this question have come from the research. First of all, it is known (especially from drosophila work) that the normal role of FMRP, as an RNA-binding protein, is to help regulate directional growth in most (if not all) cells. This can be seen in fly oocytes, where normal anatomy is severely disrupted by mutations of dFMRP; fertility is also impaired, though this still does not result in sterility (which is very good luck for us, or we'd have no fly model of fragile X.) So, from this perspective we can see that this mutation would cause the greatest disruption in the most spatially differentiated cells: neurons. Other cells are affected, though, and that may explain some of the dysmorphic physical features.
The mice do have some physical phenotype, but I think it's just hard for us, as a different species, to recognize. Human facial recognition is very highly evolved; I doubt that the mice would be able to tell any difference in our faces! They certainly do have larger testes; no one has looked at their connective tissue, but I'm sure it's quite lax (just hard to examine or quantify this.)
Beyond direct effects on directional cell growth, there are the many known indirect effects, for example on hormone regulation. We know from Carolyn Beebe Smith's work at NIMH that protein synthesis is dysregulated in much of the fragile X brain, but the hottest of all the hot spots for excessive protein synthesis is the hypothalamus, with about 32% more activity in fraX vs. normal. That is a huge difference for a whole brain region! The hypothalamus is responsible for regulating a wide range of hormones in the body, and these, in turn, regulate cell growth in a number of ways. Because of the elaborate control mechanisms in the body, with multiple feedback loops, we don't see vast increases in one hormone or another at any one time in fragile X people, but we really haven't looked very hard, either. What is likely happening is that the fine regulation of hormonal response is lost. For example, Alan Reiss showed abnormal response of cortisol to social stress---but the cortisol levels weren't crazy-high, they were just a bit more prolonged than normal. Likewise, many of the facial features are reminiscent of acromegaly, though high levels of growth hormone have not been shown in humans or mice. It may be a more subtle defect than that. Interestingly, Abdeslem El-Idrissi at CUNY Staten Island has found low levels of somatostatin (in some ways, the opposite of growth hormone) in the knockout mouse; this could explain many features of fragile X, and is potentially treatable (somatostatin can be administered via injection, and synthetic analogs are being developed with oral bioavailability).
On a finer level, the excess in activated MMP-9 in fragile X, which was found in the mouse model by Iryna Ethell, could explain many of the CNS and non-CNS phenotypes seen in fragile X. This extracellular enzyme is part of a large and complex system which regulates the stiffness of the extracellular matrix---the foundation for all cell growth. We know that MMP-9 activity can be regulated through mGluR5 (at least in neurons) and that mGluR5 is present on many non-neuronal cell types. Of course, we can block MMP-9 activity directly with minocycline, but the evidence suggests that mGluR5 antagonists could also help with this problem, certainly in neurons, but probably in a great many other cell types as well. I certainly never expected that we would come up with treatments for the physical features of fragile X (and we weren't really looking for this) but it's quite promising. The experience with minocycline suggests that we can fix the lax connective tissue with this drug, and the research suggests that mGluR5 antagonists could work, too. Since most kids with fragile X (at least in the future) will be treated with these drugs well before the majority of physical development, this may modify the phenotype significantly. Time will tell if these findings hold up, or if the story is more complicated/less amenable to treatment.
A: Of course, we don't know all the details yet, but a few key answers to this question have come from the research. First of all, it is known (especially from drosophila work) that the normal role of FMRP, as an RNA-binding protein, is to help regulate directional growth in most (if not all) cells. This can be seen in fly oocytes, where normal anatomy is severely disrupted by mutations of dFMRP; fertility is also impaired, though this still does not result in sterility (which is very good luck for us, or we'd have no fly model of fragile X.) So, from this perspective we can see that this mutation would cause the greatest disruption in the most spatially differentiated cells: neurons. Other cells are affected, though, and that may explain some of the dysmorphic physical features.
The mice do have some physical phenotype, but I think it's just hard for us, as a different species, to recognize. Human facial recognition is very highly evolved; I doubt that the mice would be able to tell any difference in our faces! They certainly do have larger testes; no one has looked at their connective tissue, but I'm sure it's quite lax (just hard to examine or quantify this.)
Beyond direct effects on directional cell growth, there are the many known indirect effects, for example on hormone regulation. We know from Carolyn Beebe Smith's work at NIMH that protein synthesis is dysregulated in much of the fragile X brain, but the hottest of all the hot spots for excessive protein synthesis is the hypothalamus, with about 32% more activity in fraX vs. normal. That is a huge difference for a whole brain region! The hypothalamus is responsible for regulating a wide range of hormones in the body, and these, in turn, regulate cell growth in a number of ways. Because of the elaborate control mechanisms in the body, with multiple feedback loops, we don't see vast increases in one hormone or another at any one time in fragile X people, but we really haven't looked very hard, either. What is likely happening is that the fine regulation of hormonal response is lost. For example, Alan Reiss showed abnormal response of cortisol to social stress---but the cortisol levels weren't crazy-high, they were just a bit more prolonged than normal. Likewise, many of the facial features are reminiscent of acromegaly, though high levels of growth hormone have not been shown in humans or mice. It may be a more subtle defect than that. Interestingly, Abdeslem El-Idrissi at CUNY Staten Island has found low levels of somatostatin (in some ways, the opposite of growth hormone) in the knockout mouse; this could explain many features of fragile X, and is potentially treatable (somatostatin can be administered via injection, and synthetic analogs are being developed with oral bioavailability).
On a finer level, the excess in activated MMP-9 in fragile X, which was found in the mouse model by Iryna Ethell, could explain many of the CNS and non-CNS phenotypes seen in fragile X. This extracellular enzyme is part of a large and complex system which regulates the stiffness of the extracellular matrix---the foundation for all cell growth. We know that MMP-9 activity can be regulated through mGluR5 (at least in neurons) and that mGluR5 is present on many non-neuronal cell types. Of course, we can block MMP-9 activity directly with minocycline, but the evidence suggests that mGluR5 antagonists could also help with this problem, certainly in neurons, but probably in a great many other cell types as well. I certainly never expected that we would come up with treatments for the physical features of fragile X (and we weren't really looking for this) but it's quite promising. The experience with minocycline suggests that we can fix the lax connective tissue with this drug, and the research suggests that mGluR5 antagonists could work, too. Since most kids with fragile X (at least in the future) will be treated with these drugs well before the majority of physical development, this may modify the phenotype significantly. Time will tell if these findings hold up, or if the story is more complicated/less amenable to treatment.
Tuesday, August 25, 2009
Another Fragile X/Minocycline Blog
Here's another mom blogging her daughter's minocycline trial;
no dramatic effects (yet), but it's nice to see a range of experiences.
Are there any blogs out there featuring fragile X boys and their experiences with minocycline?
no dramatic effects (yet), but it's nice to see a range of experiences.
Are there any blogs out there featuring fragile X boys and their experiences with minocycline?
Monday, July 20, 2009
Shameless Commerce
The Medication Guide for Fragile X is now available as a download; faster and cheaper than the CD; exact same info from start to finish! This isn't an automated download service (we're definitely not that fancy!) so you'll get email instructions from me after ordering which will tell you how to download. It's not a huge file, but at over 15 MB, you'll definitely want broadband for this one. Ideal for all the folks in far-flung corners of the fragile X universe. I'll gladly refund your money if you're unable to accomplish the download, so don't be afraid of the technical stuff!
Wednesday, July 8, 2009
More Q & A with Dr. Mike
Q: Our son is eight years old and has the full mutation Fragile-X gene, as well as autism (he is a mosaic). He is (essentially) non-verbal, with only one or two word sentences that are mostly not understandable and just express a need (food, water, etc.). Since his diagnosis in 2004 we have tried many different medications to address his main issues of anxiety, aggressive behavior (hitting people & things), impulse-control, perseveration, attention-deficit, & hyperactivity. We suspect his frustration from his lack of verbal abilities is causing a lot of his aggressiveness. He has been on Adderall for the ADHD symptoms and Zoloft for the anxiety for a few years. Then we read your medication book more carefully, and found out about your blog, and read your opinion about the stimulants' side effect of increased aggressiveness. At that time, about four months ago, we started reducing the Adderall and began the guanfacine (continued the Zoloft). He has now been off of the Adderall completely for about two months, and takes the guanfacine three times daily, which we gradually ramped up over time. About a month ago he started having some extreme meltdowns about twice per week that were uncontrollable, destructive, and lasting about 45 minutes each. We don't know what caused them, although we suspect one was due to getting scared from a cartoon. We literally had to hold him down to prevent him from hurting himself, others, or property. These episodes were frightening, especially since he's quickly getting bigger (after stopping the Adderall). That's when we started the Abilify to try to stabilize his moods. We started on 1mg at bedtime, but after a week we realized he was so tired all of the time, we backed off to .5mg. He was still very tired, so we also halved his guanfacine at bedtime, thinking the cumulative side effects of the Abilify and guanfacine were causing the sleepiness... Still sleepy. One problem is that when he's sleepy, that's a time when he starts hitting his four-year-old sister relentlessly. He is physically strong, quick, and agile, so we need to get a handle on this quick.
Here is my question: Your book says Stimulants and Abilify work well together, but what about guanfacine, Abilify, & Zoloft together? Could the side effect of drowsiness with the Abilify and Guanfacine be cumulative?
A: This sounds like a fairly common progression of events as hyperactivity gives way to aggression as a young boy with fragile X gets older. Stimulants can certainly aggravate this, and it's probably a good thing that the Adderall is gone. Abilify (aripiprazole) can duplicate some of the effects of stimulants and sympatholytic agents like guanfacine (Tenex), and it's no secret that I think Abilify is a great treatment for fragile X, though it's a powerful drug which probably shouldn't be anyone's first-line treatment. In this case, you are using it appropriately to treat severe agitation, and it should be helpful, though most likely at a higher dose (2-5 mg/d would be typical for an 8 year old boy.)
By itself, Abilify isn't especially sedating. However, drugs like guanfacine and clonidine block the body's ability to compensate (via the autonomic nervous system) for sedation caused by other drugs, thus intensifying the sedation. This effect can be more than additive---it can be synergistic in some cases. The good news is that you could probably lower the guanfacine as you increase the Abilify, and this would decrease the overall sedation; hopefully, the Abilify will take over the useful functions of the guanfacine (as well as provide a little stimulant-like boost in attention). You may want to reconsider the timing, too. You mention that you cut the guanfacine dose at bed time, but you need to remember that Abilify is ultra-long-acting (half life is 75 hours!) so it's in there all the time, regardless of when the pill is swallowed. Guanfacine is much shorter acting (half life around 12 hours) and causes most of its sedation in the first couple of hours after a dose. So, usually you'd keep a higher dose at bedtime (since you want him to sleep well) and reduce the daytime doses to minimize sedation. I should say that I am continually amazed at how sensitive people with fragile X are to drug withdrawal effects, and guanfacine causes significant withdrawal effects; I always recommend cutting doses very slowly, so think of this as a long-term proposition.
You didn't note the dose of Zoloft, but as I've mentioned many times, all the evidence is that higher doses of SSRIs are required for the best effect in treating fragile X and developmental disorders. This has been reinforced by a couple of high-profile failed trials of SSRIs in autism (most recently citalopram and fluoxetine) where the doses were, IMHO, way too low and the trial drug was no better than placebo. It's quite true that some kids simply can't tolerate high enough doses of SSRIs to get this benefit, but in your case, the guanfacine and Abilify should both offset the activation which is the main dose-limiting side effect. In other words, a higher dose of Zoloft will cause activation (basically, the opposite of sedation) which could be useful in this case, and the therapeutic effect of the SSRI will add to the overall efficacy of the regimen. Zoloft, guanfacine, and Abilify can all work quite well together; I've actually seen a number of kids who did very well on this exact combination. I generally think of meds like clonidine and guanfacine as being most useful earlier in life, when kids are most hyperactive; most will eventually decrease the use of these meds (and also stimulants) as they go through puberty and grow in size. Eventually, gravity takes over, and you simply can't be as hyperactive at full size. However, many people with fragile X benefit from the calming effects of clonidine or guanfacine as adults, and there's no problem continuing the treatment as long as it helps.
Here is my question: Your book says Stimulants and Abilify work well together, but what about guanfacine, Abilify, & Zoloft together? Could the side effect of drowsiness with the Abilify and Guanfacine be cumulative?
A: This sounds like a fairly common progression of events as hyperactivity gives way to aggression as a young boy with fragile X gets older. Stimulants can certainly aggravate this, and it's probably a good thing that the Adderall is gone. Abilify (aripiprazole) can duplicate some of the effects of stimulants and sympatholytic agents like guanfacine (Tenex), and it's no secret that I think Abilify is a great treatment for fragile X, though it's a powerful drug which probably shouldn't be anyone's first-line treatment. In this case, you are using it appropriately to treat severe agitation, and it should be helpful, though most likely at a higher dose (2-5 mg/d would be typical for an 8 year old boy.)
By itself, Abilify isn't especially sedating. However, drugs like guanfacine and clonidine block the body's ability to compensate (via the autonomic nervous system) for sedation caused by other drugs, thus intensifying the sedation. This effect can be more than additive---it can be synergistic in some cases. The good news is that you could probably lower the guanfacine as you increase the Abilify, and this would decrease the overall sedation; hopefully, the Abilify will take over the useful functions of the guanfacine (as well as provide a little stimulant-like boost in attention). You may want to reconsider the timing, too. You mention that you cut the guanfacine dose at bed time, but you need to remember that Abilify is ultra-long-acting (half life is 75 hours!) so it's in there all the time, regardless of when the pill is swallowed. Guanfacine is much shorter acting (half life around 12 hours) and causes most of its sedation in the first couple of hours after a dose. So, usually you'd keep a higher dose at bedtime (since you want him to sleep well) and reduce the daytime doses to minimize sedation. I should say that I am continually amazed at how sensitive people with fragile X are to drug withdrawal effects, and guanfacine causes significant withdrawal effects; I always recommend cutting doses very slowly, so think of this as a long-term proposition.
You didn't note the dose of Zoloft, but as I've mentioned many times, all the evidence is that higher doses of SSRIs are required for the best effect in treating fragile X and developmental disorders. This has been reinforced by a couple of high-profile failed trials of SSRIs in autism (most recently citalopram and fluoxetine) where the doses were, IMHO, way too low and the trial drug was no better than placebo. It's quite true that some kids simply can't tolerate high enough doses of SSRIs to get this benefit, but in your case, the guanfacine and Abilify should both offset the activation which is the main dose-limiting side effect. In other words, a higher dose of Zoloft will cause activation (basically, the opposite of sedation) which could be useful in this case, and the therapeutic effect of the SSRI will add to the overall efficacy of the regimen. Zoloft, guanfacine, and Abilify can all work quite well together; I've actually seen a number of kids who did very well on this exact combination. I generally think of meds like clonidine and guanfacine as being most useful earlier in life, when kids are most hyperactive; most will eventually decrease the use of these meds (and also stimulants) as they go through puberty and grow in size. Eventually, gravity takes over, and you simply can't be as hyperactive at full size. However, many people with fragile X benefit from the calming effects of clonidine or guanfacine as adults, and there's no problem continuing the treatment as long as it helps.
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