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Fragile X Syndrome

parrotlady parrotladyREMOVE at hyperactivesw.com
Thu Oct 21 13:46:24 EST 2004


I am hoping that some of you would be willing to help me decipher an
article I found that discusses a possible treatment for the genetic
disability called Fragile X Syndrome. I have just recently found out
about this research and I want to understand it. Someone suggested that
I try asking on this list.

The women in my family have been carriers of Fragile X for generations
and I have many relatives who are affected. My own son is among the
worst. He is almost 18 years old, still in diapers, doesn't really
talk, and is profoundly autistic. He is basically untestable, but his
teachers estimate his IQ to be something under 50. He requires
supervision 24/7. He is subject to severe seizures and has a variety of
obsessive-compulsive behaviors.

Over the years we have heard of many "treatments". We have always been
wary and in most cases we were right -- whatever the current fad was,
it never panned out to anything. We had largely accepted that there is
nothing that will really change things, until I heard about this new
research. This one is based on some hard science. I tracked down the
researcher's publications and started to read, but I have no training
in this field and it may as well have been Chinese. I can't make heads
or tails of anything he says, except for part of his conclusions which
I believe I understand -- but I am not sure. I do not necessarily care
if I understand the biology stuff; what I want to understand is how it
might affect my son. I'd like to know these things:

1. Do the findings sound legitimate to you? They do to me, but I do not
want to go off on a wild goose chase that will get my hopes up without
good reason.

2. The researcher mentions that treatment could reduce the cognitive
capabilities of the Fragile X patient. Then he mentions some other
things that might cause cognition to be unaffected after all. This is
part of what I don't understand, but I think I get the gist: treatment
could make my son dumber, but other factors might offset it so that it
might not. What I would like to know is whether you have any opinions
or information on what the cognitive effects of this treatment might
be. To be honest, I doubt we would even notice if my son had minor
cognitive setbacks; there isn't much coming out of him to begin with so
there is little to lose. On the other hand, he can do a few things on
his own and we don't want him to lose those abilities. Finally, he does
have all the other symptoms the paper talks about (seizures,
compulsions, etc.), all of which this treatment would probably help.

I understand that this research is preliminary and that it might be
years before any treatment is available. I'd still like to know what
you think.

The link below is to an online pdf file as there is no html source. It
is not light reading. I have extracted an excerpt below in case you
don't want to read the whole paper.

<http://bearlab-s1.mit.edu/BearLab/PDFs/bear04.pdf>

Here is an excerpt from the conclusion of the paper. I hope this isn't
a gross copyright violation and that it is enough to go on:

> First, as mentioned previously, recent research suggests that although some
> proteins are overexpressed in the absence of FMRP (e.g. Arc and MAP1b) [44],
> others appear to be under-expressed or misexpressed [42,43,52]. A revision of
> our model to account for these recent findings is shown in Figure 3(b).
> According to this scheme, mGluR activation stimulates the translation of two
> pools of mRNA, those that are negatively regulated by FMRP (pool I) and those
> that are not (pool II). Competition between the pools for the translation
> machinery leads to a yin­yang, or push­pull, type of regulation. By inhibiting
> translation of messages in pool I, FMRP promotes translation of messages in pool
> II. Conversely, in the absence of FMRP increased translation of pool I inhibits
> translation of pool II. Such a model might be a better fit to available data,
> but it does raise concern about the quality of mGluRs as a target for treatment
> of fragile X. If aspects of the fragile X phenotype are attributable to
> decreased translation of mGluR-stimulated synthesis of proteins in pool II, it
> is difficult to see how an mGluR antagonist would be useful (selective blockers
> of pool I translation would be an alternative). The second (possibly related)
> caveat is that animals lacking mGluR5 [93] show cognitive deficits. Thus,
> blocking mGluR5 could potentially exacerbate the cognitive impairments in
> fragile X.
> 
> Despite these potential concerns, the known actions of Gp1 mGluR antagonists
> clearly suggest considerable therapeutic potential in fragile X. Most attention
> has been directed to mGluR5 antagonists, because mGluR1 blockers cause ataxia by
> disrupting cerebellar function. The prototypical mGluR5-selective antagonist is
> MPEP [94]. In animal models, systemically administered MPEP has been shown to
> have broad and potent anticonvulsant and anxiolytic actions without causing
> overt effects on locomotor activity. MPEP can reverse inflammation-induced
> mechanical hyperalgesia by inhibiting mGluR5 receptors in the C-fibers of the
> skin. And, by inhibiting mGluR5 receptors in the gut, MPEP can reduce bowel
> motility. Even the most skeptical would agree it is astonishing that a single
> compound could target such disparate symptoms of human fragile X syndrome as
> epilepsy, anxiety, hyperalgesia, and loose bowels.
> 
> As for the first caveat raised above, it is possible that we are correct about
> the utility of mGluR5 antagonists in fragile X for the wrong reasons, or this
> concern might simply be unwarranted. Regarding the second caveat, proper
> cognitive function appears to require synaptic plasticity within a finite
> dynamic range. Mutations that cause this range to be exceeded in either
> direction (e.g. by too much or too little LTP) impair learning and memory [95].
> Antagonists of mGluR5 might correct the mild cognitive deficits seen in the Fmr1
> knockout by bringing synaptic plasticity back into its proper range. Thus, two
> wrongs (cognitive impairment in Fmr1 and mGluR5 knockout mice) could make a
> right.

There is much more in the full paper. Again, mainly what I'd like to
know is whether you think this research sounds promising (I'm pretty
sure it is,) and any information or discussion you may have about the
caveats the author mentions. Or maybe you can think of some caveats of
your own.

Thanks very much for any information or discussion you can provide.

-- 
There are 247 real people in the world and the rest are ducks.



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