Fragile x pre-mutation

[owen]

I have recently been diagnosed with being a Fragile x pre-mutation carrier, my repeat size is 58. i have a very low AMH of 0.7 and am starting IVF in the next two months. I have been warned of the 30% chance of POI/POF that comes with being a carrier and am aware that this could happen to me. Has anyone on this site been diagnosed as a Fragile X carrier and if so how many repeats and have you faced signs of POF?

[anabelle]

I have a repeat of 51- I thought less than 60 was still in the "gray zone" from fragile-x? meaning you're not in the pre-mutation category at 58 repeats, therefore significantly lower risk to passing a mutated gene to offspring? maybe the cutoff is 55? Any how, my doctor warned me of the chances of this and am considering amniocentisis if I can acutally get pregnant....

[owen]

Hello Anabelle
It is strange that someone answered my thread on the day that I received my CVS results. I managed to fall pregnant in April natrually and opted to have a CVS at 12 weeks. The results came back yesterday and the baby does not carry the mutated gene. As you can imagine I am very relieved. The CVS was okay but with your repeat size and amnio would be enough. my repeat size is one away from the 59 repeats that have been shown to mutate in two women, and as the repeats can be of by one I was give a 3% chance of a full mutation.

I did find a link which showed a study of women with intermediate repeat sizes and the expansion of the gene into their offspring, it was very reassuring. You will have to scroll to the bottom of the article to see the repeat sizes.

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http://www.pubmedcentral.nih.gov/art...i?artid=379237

Good luck with everything

Owen

[fragxcarriersyd]

Hi there Owen,

I am a member of the Australian girls thread and only come on here periodically to see if there is anything new in this thread that may help me in my quest. I have between 100-160 trinucleotide repeats, have a 1 in 2 chance of passing on my abnormal gene and have a mother who underwent POF at 27. I am 36 years of age and have done four unsuccessful cycles of IVF with the world class Sydney IVF whose Chief Scientist is a Fragile X carrier with an affected child. Unfortunately I have never made it to embryo transfer.

IVF cycle # 1 - Three occytes ( 2 grade 1, 1 grade 2) retrieved, all fertilised and dividing perfectly day 3.
Outcome - arrested day 4.

IVF cycle # 2 One occyte (grade 2) retrieved.
Outcome - non fertilisation.

IVF cycle # 3
Outcome - Cycle cancelled after nil response to 15 days stimulation.

IVF cycle # 4 One occyte (grade 2) retrieved.
Outcome - Occyte immature and disintegrated overnight.


The first three cycles were all agonist or flare cycles off the OCP.
The fourth cycle was an antagonist cycle and prompted five follicles to grow but only one immature occyte retrieved. I still do not understand what went wrong with the fourth attempt as my specialist is on annual leave at present.

The fourth cycle I was also taking DHEA 25g BD.

I can't tell you what my AMH level is but had a hormone profile done between cycle 3 and 4 so will ask my specialist what the reading was and let you know.

I hope in time I too can fall pregnant with an unaffected child but my reserves of hope are very depleted at present.

Did your RE have a good understanding of Fragile X and put this front and centre in your treatment or just treat you like any other patient with low ovarian reserve? Can you tell me what IVF drugs you were on and what level?

I know a number of fragile x carriers who have gone on to conceive healthy babies using IVF in Australia - just hoping my turn will come soon.

[anabelle]

hi fragxcarriersyd,
my RE tested me right away for this- but before he got the results he explained to me that he wouldn't even let me continue with IVF if I fell into a certain range of mutation. It was very offensive- he was deciding whether or not my genetics were worthy of being passed on. I would not say he had a good understanding of it- he did tell me "I spent an entire hour of my time researching this for you". But I have a whole other slew of issues with that RE - he's an asshole. At least he did test me for it though- so I know why I have DOR at such a young age.

That's great you know of many Fragile X carriers that have healthy kids. It doesn't seem like there's very many posts in the forums about this topic.

And thanks owen for the link- that info was helpful. It's surprising how little data they have - but I guess this gene mutation is pretty rare. Lucky us

[fragxcarriersyd]

Hmm glad I did not have your RE. He held this view despite the option of PGD?

The goal the RE and the clinic I am using in Sydney is to get an embryo to day 5 and then do PGD to exclude embryos with the abnormal gene although given my poor result to date I have also been counselled about transferring back an untested embryo prior to day 5 and having CVS at 12 weeks.

I am finding the emotional toll of back to back IVF failure almost unbearable and I was hoping their might be a US expert who understands more about the mechanisms of altered ovarian function in premutation carriers of FX. I put a post on the US National FX foundation forum but only got a response suggesting Lawrence M. Nelson - an article authored by him says he is Commander in the U.S. Public Health Service, and directs the Gynecologic Endocrinology Unit, Section on omen’s Health Research, at the National Institute of Child Health and Human Development, National Institutes of
Health, Bethesda, MD.

I also found some clinical research through Journals which cites Stephanie Sherman as one of the principal researchers and whom appears to work across the twin departments of Human Genetics and Gynaecology and Obstetrics at Emory University School of Medicine in Atlanta.

I am thinking of e-mailing both but don't know whether any will be motivated to respond or just see me as some deranged woman from Down Under.

A study published in 2008 in Human Reproduction http://humrep.oxfordjournals.org/cgi.../23/5/1220.pdf that I have come across says that

AMH levels are significantly lower among women with longer FMR1 repeat alleles compared to those with shorter repeats, especially at the younger ages.

There are at least two viable mechanisms to explain FXPOI based on our knowledge of the function of FMRP, the protein produced by FMR1, and the molecular consequence of long repeat alleles in the 50 UTR of FMR1. First, the premutation allele produces a messenger RNA (mRNA) that includes a large repeat track. This premutation mRNA may cause a time-related cumulative toxic effect that eventually leads to an increased rate of follicular atresia during a woman’s reproductive life. Fragile X-related tremor/ataxia syndrome, another FMR1 premutation-associated disorder, has now been shown to be due to this type of mechanism (for review, see Hagerman and Hagerman, 2007). Alternatively, the protein may be involved. FMRP regulates translation of a subset of mRNAs using a suppression mechanism (Jin et al., 2004). Perhaps increased levels of FMRP at specific times during development could lead to haploinsufficiency of the proteins needed in oocyte or follicle development. Our preliminary data suggest that whatever the effect, this premutation plays a role early in a woman’s reproductive life, evidenced not by FSH fluctuations but by low AMH levels.

A study published in the Annals of New York Academy of Sciences Vol 1135 pages 99-111 contains the following:-

AMH, also called mullerian-inhibiting substance, is emerging as perhaps the most promising biomarker to date, with numerous studies reporting a strong association between AMH levels and proxy measures of ovarian reserve (including chronological age, antral follicle counts, time to menopausal transition, and response to IVF).49–53 Two studies comparing AMH with other commonly used markers (FSH, inhibin B, E2) found AMH to be more sensitive.50,54

To date, the most comprehensive study of the hormonal profile of FMR1 premutation carrier women was conducted byWelt et al.14 They hypothesized that premutation carriers with ovulatory menstrual cycles would exhibit hormonal changes characteristic of advanced ovarian senescence. They identified 11 regularly cycling premutation carriers, ages 24 to 41 years, and drew daily blood samples across one menstrual cycle. Luteinizing hormone, FSH, E2, progesterone, inhibin A, and inhibin B levels were compared with levels in 22 age-matched, regularly cycling women at each cycle stage. FSH was elevated across the follicular and luteal phases in premutation carriers compared with controls. Inhibin B in the follicular phase and inhibin A and progesterone in the luteal phase were all decreased in premutation carriers compared with controls. Of interest, there was no difference in E2 or LH between groups.Thus, despite regular ovulatory cycles, FSH was increased in premutation carriers compared with controls.The increased FSH was accompanied by decreased inhibin B in the follicular phase and inhibin A and progesterone in the luteal phase. These data are consistent with the hypothesis Welt et al.

Recently, AMH was identified both as an important regulator of early follicular growth and as a potential biomarker of ovarian reserve. The role of AMH in the menstrual cycle involves regulation of the recruitment from the primordial follicle pool and selection for dominance for ovulation (reviewed by von Rooij et al.,45 Visser et al.,50,56 and Nilsson et al.57). AMH, like inhibin and activin, is a member of the transforming growth factor-β family. Using immunohistochemistry in ovarian sections obtained from healthy regularly cycling women, Weenen et al.58 showed that AMH is only expressed in growing follicles and disappears in preovulatory follicles.

To test this hypothesis, we compared AMH levels among women by repeat size group using frozen serum samples that had been previously collected for FSH studies in the study of Sullivan et al.10 Thus, FSH and AMH levelswere measured on serum samples collected during early follicular phase from women who carried higher risk premutation alleles (defined as ≥70 repeats) and those with lower-risk alleles (<70 repeats). In these preliminary data, we found that AMH levels were significantly reduced among higher- versus lower-risk premutation carriers for all age groups studied (P =0.002, P =0.006, and P =0.02 for a one-sided Wilcoxon rank sum test for age groups 18–30, 31–40 and 41–50 years, respectively) (Rohr et al., submitted for publication). Increased FSH, indicative of early ovarian decline, was only significant in the middle age group (P =0.0005), as reported previously.10 Thus, this preliminary studyshowed thatAMHl evels are indicative of early ovarian decline amongwomenwith higher-risk premutation alleles; moreover, AMHis superior to FSH in identifying this decline at an earlier age.

The molecular mechanism and events leading to compromised ovarian function in FXPOI are unknown. However, it may potentially result from any developmental aberration leading to: (1) a smaller ovarian endowment at birth; (2) alterations in initial recruitment (primordial follicles) or in cyclic recruitment (primary, secondary, and tertiary follicles); (3) an increase in oocyte degeneration and follicular atresia; and/or (4) an altered hypothalamic-pituitary-gonadal axis. The toxic effect of the FMR1 premutation could have its influence at any one of these levels. Clinical and epidemiology data on FXPOI, aswell as some early FMR1 transcript and FMRP expression studies, provide some insight into mechanisms. Expression studies indicate that FMRP is highly expressed in the germ cells of the fetal ovary.69,70 Since FMRP regulates mRNA translation through a suppression mechanism,71 perhaps increased levels of FMRP at specific times during development could lead to haploinsufficiency of proteins needed in follicle development and survival. Analyses of X chromosome alterations identified in women with POF provide support for this model.72–74 Rizzolio et al.74 have shown that the most plausible explanation for POF identified in women with balanced X autosome translocations is a position effect of the breakpoints on flanking genes, causing them to be either silenced or downregulated.

Alternatively, the large CGG repeat track in the mRNA produced by the FMR1 premutation allele may cause a cumulative toxic effect, leading to an increased rate of follicular atresia later in a woman’s reproductive life. FXTAS, the other known FMR1 premutation-associated disorder, provides a precedent for this dominant gain-of-function mechanism (for review, see Hagerman and Hagerman75). In addition, early FMR1 expression studies76,77 identified transcripts in granulosa cells of ovarian follicles. Interestingly, Hergersberg et al.76 found that transcripts were present in maturing follicles only, not those in the early stages.

Studies of the hormonal profile of premutation carrier women who are still cycling are consistent with the normal hypothalamic-pituitary-gonadal axis of an aging ovary. However, a recent case report of a man who had FXTAS and reported erectile dysfunction prior to onset of motor symptoms of FXTAS may point to dual involvement at the level of the pituitary as well as the gonad. On neuropathologic exam, intranuclear inclusions were found in neurons of the anterior and posterior pituitary gland and found in the Leydig andmyoid cells of the testicles, possibly leading to neuroendocrine dysfunction.78 Gonadotropic cells from the pituitary gland produce and secrete both LH and FSH. Thus, a dysfunction of these gonadotropic cells as a result of the presence of inclusions and/or elevated FMR1 mRNA levels may lead to an altered hypothalamicpituitary- gonadal axis and consequently to abnormal follicular recruitment. However, similar neuropathologic studies have not been reported for premutation carrier women.

I wish I could find someone at the forefront of understanding around this and with particular expertise in FXPOI and infertility because I feel that I am starting to see my dream of having my own biological children evaporate before me and the heartache and internal disquiet is almost more than I can bear.

I would be interested in the protocols and drugs that both you and Owen have been using. Thanks for your reply.

[anabelle]

I wasn't really given very much information about fragile x and POI by my doctor. He did say genetic testing was available through amniocentisis- but he mentioned that he's Catholic and against terminating any kind of pregnancy so I think that's where his string opinions come from.

The impression I get from reading med journals is that the link between POI and FragileX in the medical community is relatively new.. I have heard of Dr. Nelson as being an expert on POI..but I'm not sure about Fragile X.
Have you tried to enroll in a Fragile X study? It seems like that would be a great way to get more information and more personalized feedback. There's a request for patients listed on the Internation POF Association website at
http://pofsupport.org/research/fragilex.htm.

Here's the info they list.
Charles E. Schwartz, Ph.D., the Director for the Center for Molecular Studies at the Greenwood Genetic Center is conducting a study on Fragile X. If you have POF and a family member with Fragile X contact him at:

864-941-8140
Or via email schwartz@ggc.org
(No geographic restriction).

I'm not sure what the name of the protocol was that my doctor used for my IVF. He said it was the strongest stim protocol he used. I was started on BCP's, then on Lupron for 10 days, then the highest dose of Menopur (75IU) for about 9 days. I only got 3 follicules from this and the embyos were poor quality, so it didn't work out.

I'm sorry you have to go through this. It feels really unfair and I know the pain... I'm trying to come to terms about not having a biological child. I am open to adoption but not so much donor egg. I feel like with adoption I can take my negative situation and use it to help a child that needs a home... but I'm defintely not completely there yet, or ready to stop trying with my own eggs.
Let us know if you enroll in a study.

[cmondwn]

Just wanted to give you all a glimmer of hope. I had a pituitary tumor when I was younger so I knew that it would be difficult for me to conceive. After 6 failed IUIs I moved on to IVF. Of the five follicles I produced only one egg fertilized. Amazingly, she implanted. Just as I entered my second trimester, my OB called that I was a fragile x carrier with 76 repeats. It was too late to do CVS, so I just had to wait for the amnio. I can't even begin to tell you what a wreck I was for those 5 weeks.

I now have a beautiful 16-month old daughter who is not a carrier for the disease.

Now I'm planning on doing IVF with PGD for #2. I totally think conceiving is possible if you find the right RE...

Much love and luck to you all-
Lori

[anabelle]

Thanks Lori! It's great to hear stories like yours

[fragxcarriersyd]

I am struggling after four unsuccessful cycles of IVF - it seems like all the other fragile x carrier patients in my circle are pregnant with healthy unaffected babies and I am finding it hard to remain hopeful that my turn will come. I am with one of the leading clinics in Sydney and the RE who has had the most success with Fragile X carrier patients says that he has never had success with someone with my poor ovarian reserve. I have between 100 - 160 trinucleotide repeats. I wish we understood more about the mechanisms of altered ovarian function. I not only have an egg quantity problem but an egg quality problem. If the medical fraternity understood more about primary ovarian insufficiency maybe we would be empowered with the means to tweak and optimise my response more.

A friend of mine forwarded this article (see below) to me today. It seems like the US National Institute of Health is attempting to break new ground with our understanding of primary ovarian insufficiency - I fear though that the results won't be in time for me but feel heartened nevertheless that perhaps women in future won't have to go through what I have done.

National Institutes of Health develops research plan on Fragile X syndrome and associated disorders
20. July 2009 18:29


The National Institutes of Health has developed a research plan to advance the understanding of fragile X syndrome and its associated conditions, fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency. Fragile X syndrome causes intellectual and developmental disabilities and results from a mutation in a gene on the X chromosome.
The plan puts forward goals to guide future research, setting research priorities for each of the conditions. A major priority of the plan is to investigate the biological processes underlying all three disorders and how to better diagnose and treat them. Other priorities are studying how widespread the gene variations are in the population and how the three conditions affect families.

"NIH's research efforts have made great strides in understanding these conditions," said Raynard S. Kington, M.D., Ph.D., acting director of NIH. "We now intend to build on these advances."

Although the three disorders have very different symptoms, all result from variations in the same gene, known as the Fragile X Mental Retardation 1 (FMR1) gene. Full mutation of the gene means that cells do not produce a protein involved with communications between neurons in the central nervous system. The resulting disorder, Fragile X syndrome (FXS), occurs in approximately one in 2,500 births. People with FXS often have intellectual disabilities ranging from mild to severe. They may also have emotional and behavioral problems, including attention problems, hyperactivity, anxiety, aggression, and autism or autism spectrum disorder.

People with a less dramatic change in the gene have what is called a pre-mutation, which increases their chance of having a child with FXS. These people may not have any apparent health problems or may have symptoms of Fragile X-associated Tremor/Ataxia syndrome or Fragile X-Associated Primary Ovarian Insufficiency.

Fragile X-associated Tremor/Ataxia syndrome (FXTAS) occurs primarily in older men. The principal symptoms are tremor and gait problems, but the condition also includes cognitive decline, anxiety, and depression. Fragile X-associated Primary Ovarian Insufficiency (FXPOI) occurs in women of childbearing age. Women with FXPOI may experience early infertility and increased risk of osteoporosis and heart disease.

"Collectively, these disorders represent a major health burden and have far-reaching implications for individuals as well as their family members," said Tiina Urv, Ph.D., of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, chair of the trans-NIH Fragile X Research Coordinating Group. It is possible, Dr. Urv explained, for the gene to be abnormal in multiple family members. For example, the mother of a child with FXS may eventually show symptoms of FXPOI, and her father, and the child's grandfather, may develop FXTAS.

"These disorders may affect multiple family members, and multiple generations," Dr. Urv said.

To develop the plan, the NIH convened three working groups of experts, one for each of the conditions. Members of each group included experts from the scientific community, members of advocacy groups for individuals and their families affected by the disorders, and other federal agencies. The research plan identifies research goals for each of the three conditions, and outlines strategies for better diagnosis, treatment and prevention of the three disorders.

"The goals were designed to be used by the NIH and FXS, FXTAS, and FXPOI research communities and to be shared with other federal agencies to facilitate coordinated research activities that will lead to timely detection, diagnosis, treatment, and prevention of the targeted disorders," the report stated.

Studies funded by the NIH have been instrumental in contributing to the understanding of Fragile X syndrome, including the discovery of the fragile X expansion mutation in 1991 by 3 groups of scientists, two of which benefited from funding by the NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). NIH-funded researchers also played a pivotal role in identifying FXTAS and FXPOI.

The report also highlights ongoing research, including collaborative efforts from several NIH institutes: the NICHD, the National Institute of Neurological Disorders and Stroke, the National Institute of General Medical Sciences, the National Institute of Mental Health, and the National Institute on Aging. The NIH funds a network of centers devoted to Fragile X syndrome and its associated conditions, as well as studies by independent scientists.

http://www.nih.gov