Thanks to everyone who bought tickets in our Awareness Day raffle which was drawn today.
We had a morning tea in the office for some local FXAA members and John Kelleher drew the winning ticket for us. Congratulations to Bianca Buckman.
Bianca is the winner of our day sail on Team Australia, Sean Langman’s Orma 60 trimaran. The fastest boat in the southern hemisphere!
We raised $3,400 and a huge thank you to our member Ricky Crowe who sold over 200 tickets!
Advances and setbacks in our understanding of the fragile X-associated tremor/ataxia syndrome (FXTAS): Current research
By Danuta Z. Loesch, MD, PhD; Senior Research Fellow, School of Psychological Science, La Trobe University, Melbourne.
Since the discovery of Fragile X Syndrome (FXS) associated with large expansions of the CGG repeat (>200) in the non-coding portion of the FMR1 gene, the main focus for the majority of clinicians and genetic researchers has been on this genetic disorder, where severe neurodevelopmental disability is apparent from a very early age. The parents and grandparents of the affected children, who were carriers of small repeat expansions (55-200 CGGs) termed ‘premutation’, were initially thought to be clinically unaffected, especially as any emotional, cognitive or health problems in those carriers appeared relatively minor in comparison with the severity of the FXS, and were often largely attributed to the stress of raising children with this syndrome. However, the 1991 report of a higher (20%) incidence of premature ovarian failure (menopause before the age of 40 years) in females carrying the premutation, followed by the discovery, a decade later, of FXTAS (fragile X-associated tremor/ataxia syndrome) in older male premutation carriers, led to closer investigation of these and some other changes, including psychiatric and cognitive problems, or immune-mediated conditions such as thyroid dysfunction and fibromyalgia, all of which were grouped under the term of the ‘premutation associated disorders’.
The main focus of our research during the last decade, conducted in collaboration with the team from the M.I.N.D. Institute of the University of California (UC) lead by Prof Randi Hagerman, has been on the spectrum of clinical manifestations of FXTAS and the pathological mechanisms which underlie the progressive brain changes (neurodegeneration) in this severe neurological condition. The core features of FXTAS are intention tremor, impaired balance (ataxia), memory problems, and loss of brain cells associated with white matter disease manifesting as ‘hyperintensities’ on T2 Flair MR images in certain brain areas, with hyperintensity of the middle cerebellar peduncle (MCP sign) being the most characteristic MRI feature of this syndrome. The presence of intranuclear deposits (inclusions) in the brain and some other tissues is another major diagnostic feature of FXTAS. The onset of these manifestations is typically between the ages of 60 and 65 years in most individuals, with the tremor usually being the first observable symptom. Because parkinsonism (resting tremor and muscle rigidity) occurs in more than a half of individuals with FXTAS, this syndrome may be mistakenly diagnosed as idiopathic Parkinson’s disease by neurology specialists.
The frequency of a fully symptomatic (‘definite’) FXTAS has been estimated at an average of ~40% in male premutation carriers in both US and Australian cohorts. However, it is lower in men aged between 50 to 60 years and much higher (over 70%) in men aged over 80. Female premutation carriers can also develop FXTAS, but the risk is much lower (~16%) than in males and, although we do not yet have an accurate estimate, it seems even less prevalent in the Australian than in the US females. The accurate estimate of the risk of FXTAS in both male and female carriers is problematic because of an extensive inter-individual variability of both progress and clinical presentation of this syndrome. We (and others) found the discrepancy, in some proportion of patients, between typical brain changes on MRI and minor clinical manifestations, or typical clinical manifestations with minimal MRI changes, or predominance of cognitive decline or depression that, in some cases, may precede the onset of neurological symptoms. These variable manifestations suggest that the frequency of the FXTAS spectrum (in contrast with the traditional concept of ‘definite’ FXTAS) may be higher than previously estimated; however, longitudinal (follow up) studies are needed to accurately assess this variability and its relevance to the risk and diagnostic criteria of FXTAS.
The most intriguing and clinically meaningful aspect of FXTAS is that it occurs only in some premutation carriers, while a proportion of individuals remain symptom-free till the very old age. To address this problem our teams have tried to unravel the pathological mechanisms underlying progressive loss of brain tissue in the affected carriers. An important breakthrough was a discovery of the elevation of the levels of the FMR1 transcript, termed ‘messenger RNA’ (mRNA), in nearly all premutation carriers, both affected and non-affected. We also found this elevation in carriers of smaller expansions overlapping with normal CGG size termed ‘grey zone’ or ‘intermediate size’ alleles (45-54 CGG repeats). This is in contrast with the much larger (>200 CGGs) expansions, where the gene switches off, with consequent absence of the FMR1 mRNA, which normally determines the synthesis of the FMR1 FMRP- the protein important for brain development. Thus, it has become clear that, while a deficit of the FMR1 mRNA and of the relevant protein causes abnormal brain development in FXS, the elevation of this transcript in premutation is likely to have some causal link with the late-onset neurodegenerative disease, FXTAS.
In order to better understand the link between the RNA changes and the loss of brain cells in FXTAS, the UC team studied the composition of the intranuclear inclusions in this disorder. The results have suggested that the elevated FMR1 mRNA with the expanded repeat may change the properties of some important proteins which come in contact with this RNA. These proteins then become dysfunctional and are deposited in the inclusions. Although deficit of those proteins combined with their deposition are not directly responsible for the destruction of brain cells, these changes may lead to other yet unknown processes which cause further damage to these cells. An important step was a discovery, by both our teams in Australia and UC, of the changes concerning important cellular organelles known as mitochondria, which were more obvious in the affected than in non-affected carriers. These changes, in their severe form, are lethal to the cell.
Thus, in the future study, we need to relate the severity of the mitochondrial alterations in the affected premutation carriers to the loss of brain cells as seen on MR images and clinical involvement, on the one hand, and to genetic changes, especially the elevation of FMR1 mRNA with an expanded CGG repeat, on the other. Amongst several possible pathways leading from the elevated RNA via mitochondrial changes to severe cellular pathology in premutation we chose to test one particular pathway which, if confirmed, may open the possibility of targeted treatment. Moreover, because each of the individual elements tested along this pathway provides a potential biomarker for disease, their identification and relevance to clinical involvement may help to predict which premutation carriers will be affected, and will therefore help in accurate prognosis and thus in any early intervention/treatment strategies. We rely mainly on the results from blood cells, since they are fair (though not ideal) representation of what’s happening in the brain. We have recently applied for NHMRC funds to allow us to carry out this series of studies.
However, in addition to adequate funding, a large number of participants, as well as collaboration between the relevant research centres are also essential for the success of studies of the FXTAS spectrum and other premutation-associated disorders. The relatively low participation rate of premutation carriers in this country, especially those from older generations, has been a serious problem in our research. Another factor which also affects research participation is inadequate information about FXTAS amongst relevant medical specialists, who may misclassify this condition as idiopathic Parkinson’s disease or other forms of parkinsonism, or else confuse FXTAS with FXS. Although these two syndromes are associated with mutation in the same (FMR1) gene, they have different underlying mechanisms, different symptoms, and concern different age groups.
There is no targeted treatment of FXTAS or any other premutation-associated condition as yet. This is a long process requiring substantial funds and wide carrier participation. Although further research on risk factors contributing to FXTAS is still required, several factors such as smoking, alcohol and other substance abuse, prolonged anaesthesia, chemotherapy, have already been identified. Avoiding these factors, where possible, combined with diet rich in antioxidants may constitute some preventative measures, or an important addition to existing treatments for tremor or ataxia in the affected carriers.
For additional information, including participation in our studies, please contact: Dr Danuta Z Loesch, ph (03) 94791382; e-mail: firstname.lastname@example.org, or Ms Eleanor Hammersley, ph: (03) 9479 2329; email: email@example.com
(This article was submitted to the Fragile X Association of Australia in April 2014)
Recommended review publications:
-. Loesch DZ & Hagerman RJ. ‘Unstable mutations in the FMR1 gene and the phenotypes’. In: Hannah AJ, eds. Tandem Repeat Polymorphisms: Genetic Plasticity, Neural Diversity and Disease., Texas, USA: Landes Bioscience, 2011.
- Hagerman RJ & Hagerman. ‘Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome’. Lancet Neurology, 12, 786-98, 2013.
Fragile X Association has prepared a series of Fact Sheets with information about Fragile X-associated disorders which include Fragile X syndrome, Fragile X-associated tremor/ataxia syndrome (FXTAS) and Fragile X-associated primary ovarian insufficiency (FXPOI).
Fact Sheet 2: What is Fragile X syndrome?
FXAA Fact Sheet 2_What is Fragile X_June 2014
Fact Sheet 4: Carriers of Fragile X
FXAA Fact Sheet 4_Carriers of Fragile X_June 2014
Fact Sheet 6: Fragile X-Associated Tremor Ataxia Syndrome (FXTAS)
FXAA Fact Sheet 6_FXTAS_June 2014
Evidence-based Medical and Therapeutic Intervention? Who Needs It?
A discussion for parents of children with special developmental needs about evidence, consensus and anecdotal-based interventions.
by Robert M. Miller (former Executive Director of the National Fragile X Foundation in the US)
After more than four decades of working with parents of children with special developmental needs, I’ve learned that they often find it difficult to know what the best approaches or interventions are to help their children. Conflicting statements, recommendations and opinions from fellow parents and/or from professionals involved in the child’s treatment can cause confusion and uncertainty. Understanding why there can be such variation within always well-meaning advice may help parents make the difficult decisions that confront them.
Earlier in my career, the idea of “evidence-based” interventions or even “consensus-based” interventions was little understood, particularly for those with an intellectual disability. Things were done because we (the special educators) or someone we respected, had a good idea. It was the caring and helping that were important. And tracking the long-term benefits of an intervention, though talked about, was not integral to the process.
Much, if not most, of our disability work in the early days was based on “anecdotal evidence.” That is, we were told, heard about, or read that so-and-so had done such-and-such and there had been an improvement in a child’s skills or behavior—at least as reported by the person who had provided or supervised the intervention. All well and good, considering that up until that time many people with special developmental needs received little to no intervention at all! Indeed, some children did seem to improve. But, as we now understand, the questions that should have been asked at the time were whether or not the improvement was the result of the intervention, or unintended actions by the interventionist (e.g. more attention given to the individual), or maturation (growth and development—even when delayed), or not real at all except in the eyes of those working with the individual.
No blame is assigned here. People wanted to help and they used what seemed to be common sense and their own life experiences to try and do so. Just the act of helping and caring sometimes did produce desirable results—results that should not be discounted. For example, if parents believed and/or had been told that their child with a disability was incapable of learning, and, through the act of caring and help from others the child became a focus of that help and care, learning may have occurred that was the result of nurturing. This is something we now know to be crucial to the healthy development of all humans, and not merely the direct result of the techniques being applied by the parents or interventionist.
Anecdotal-based intervention is still practiced today and, while it should never be entirely discounted (What’s anecdotal-based today could be the basis for evidence-based intervention tomorrow!), it is not the foundation on which to build a good intervention plan. Families should always inquire about and look for interventions that have a history of being used by mainstream professionals and, at minimum, have a body of literature from numerous practitioners that attempts to describe the mechanisms that make the interventions successful. That is, look for some “consensus” by professionals that the intervention may be helpful.
Consensus-based interventions develop over time, as enough people work with enough children for a consensus to develop about what works and what doesn’t. That is, a large number of people who are trained to provide intervention, whether anecdotal-based or not, begin to agree that they have seen improvements in the behavior, self-help skills, communication, and other factors in children they have worked with, and that these improvements are, or likely are, the result of the intervention.
In many ways, consensus can be equated to “professional opinion.” It is based on the notion that if a significant number of professionals, particularly from a variety of relevant disciplines, agree about a particular topic, it may indicate that there is some validity to the matter on which they agree. Coming to consensus can be a time-consuming process, involving much discussion and a critical review of any literature that already exists regarding the intervention.
Is consensus-based intervention based on scientific proof that it was the intervention itself that was producing the results? It is not, but I will note here the extreme difficulty (and expense) of meeting a standard of scientific proof in educational interventions (more on that below), and that in the absence of such proof, often the best we can do is to rely on the training, expertise and insight of the relevant professionals who have concluded it is a given intervention itself, and not some other variable, that is causing improvement in a child’s performance. As we often do when it comes to matters that we don’t fully understand, we tend to trust the “experts” in their expertise. Over time, consensus-based intervention has become the mainstay of much of special education.
We’ve all heard of the scientific process. Over the past few hundred years, scientists/researchers have developed and refined a system of checks and balances to try to accurately separate fact from fiction. Much of what we take for granted in this day and age exists thanks to the scientific method. Common medications used for a variety of medical and mental health reasons are just one example. All of these medications are approved, at least in the U.S., by the Food & Drug Administration, based on the best scientific evidence available at that time.
The process of controlled studies for new drugs, in which some of the participants in the study receive only a sugar pill (placebo), and even the professionals running the study don’t know who is receiving the real drug and who the placebo (meaning all parties are “blinded”), can also be used to study non-drug interventions used in the disability field. These types of studies are designed to eliminate bias in the researcher, whether conscious or unconscious, as well as the aforementioned seeing of improvement where none actually exists.
At minimum, when looking for evidence to substantiate interventions, researchers look for signs of improvement that are measurable, replicable and that are sustained over time in a significant percentage of those being studied. If an intervention produces only short-term results that don’t appear to “stick” (when reassessed at some point in the future), that particular intervention may not be fully developed nor ready for use in an evidence-based intervention plan. Evidence of long-term results is an important variable to consider when determining the best intervention for a child with special needs.
When Professionals Disagree
Sometimes—make that often—intelligent, committed and well-meaning professionals are unable to agree on what constitutes evidence. Some propose a halfway point between consensus and evidence called “evidence-informed.” Unfortunately, this can make life difficult for parents, who may get caught between opposing camps and, as a result, end up not making any decisions or, even worse, jumping from intervention to intervention depending on who makes the latest or most strident claim.
There are many examples of disagreements about the evidence for certain interventions, including those having to do with medical treatments. Such disagreements are common in the use of medications, and in educational, therapeutic or counseling interventions.
So what is a parent to do? Common sense suggests that one should do what anyone does when presented with conflicting advice: get a variety of opinions. Ask questions. Listen carefully. Read up on the topic. Weigh what you learn against your own experience. Work with your child’s intervention team. Make informed choices.
One important caution is to always question the comments of self-appointed experts, i.e. those whose training or experience doesn’t’ qualify them to be making definitive statements about an intervention, and whose statements are significantly different than the majority of others in the field. While it is true that a lone individual can have a critical insight that the majority has missed, an abundance of caution is still encouraged when evaluating the “evidence” that a given “expert” is citing.
“Do No Harm”
Most everyone knows of the Socratic Oath, first documented in ancient times, modified over the years, and taken by most doctors at the conclusion of their training. It says in essence that one should first and foremost “do no harm” when providing a medical intervention. That is, sometimes it may be better to do nothing than to risk causing harm. This point is particularly relevant when it comes to the use of drug treatments, but it can also have relevance for other types of interventions. For example, interventions that might cause a child to experience undue fear, anxiety or stress may do more harm than good.
The concept of doing no harm includes the harm that might be caused by doing nothing. In human development there appear to be windows of opportunity in which interventions have the greatest chance of success. Ignoring those windows may result in harm sometime in the future. One of the best examples of this within the disability field has to do with the original legislation that mandated the states to provide special education services. Originally, these services were required to be provided for children above the age of 5. But with a growing body of evidence showing that the greatest window of opportunity existed earlier in life, the requirements were subsequently modified to mandate services be offered for those birth to 5. (What we now call “early intervention.”) So, one could argue, doing nothing from birth to five could be harmful. (At least that was the consensus of the experts.)
Why is any of this important and what is the right answer?
Whether you are parent, teacher, doctor, therapist or counselor, everyone who chooses to work with children who have special needs does so to help make a difference in the quality of life for those children. Understanding that there are different standards when considering interventions, and varying opinions about what constitutes evidence, will help with the decision-making process. I strongly recommend that you always favor evidence-based interventions, and if there is no evidence or the evidence is unclear, then look for consensus-based approaches. Then, assuming that an intervention passes the “do no harm” standard, proceed with what feels right for you, your child, and your family, but always in full consultation with the professionals who, like you, truly have your child’s best interests at heart.
Special thanks to Elizabeth Berry-Kravis, MD, PhD and Marcia Braden, PhD for their feedback and input, and to Andrew Hidas for his always helpful and always needed editing.
The author is the former Executive Director of the National Fragile X Foundation and can be reached at firstname.lastname@example.org.
[note: reproduced in full on the Fragile X Association of Australia website from robmillerconsulting.com with the author's permission]
BetterStart Early Days Workshops
Are you in the early days of the journey with your child with a disability? The Better Start Early Days workshops are for parents of children with a disability in the early years before school. These FREE workshops will help you to understand how the funding works, learn more about services and supports, meet other parents and build confidence.
Inaugural Fragile X Association
Fundraising Gala Dinner in Queensland
The Fragile X Association of Australia is holding a Gala Dinner
on 5 July 2014 at Everton Park Hotel.
Tickets are $60 p/p or $450 p/table of 8.
RSVP by Friday, June 6, 2014 to Candy Stingel on 0421 694 483
For more information:
Facebook Queensland Fragile X Family Network https://www.facebook.com/fxaaqldgala
or email Candy at email@example.com
Fragile X Association Membership Renewal for 2014-2015
Thank you for your support over the past year
It has been a busy and successful year for the team in the office and the Board:
* Fragile X seminars and assessment clinics were conducted in Adelaide, Brisbane, Launceston and Sydney in late 2013. Around 400 people took part to learn more about Fragile X—families, medical professionals, teachers, carers and disability support service providers. We were extremely fortunate in having experts from the US here to share their unique insights and experience at the seminars. The assessment clinics provided a special opportunity for some families to discuss their children’s needs and progress with professionals knowledgeable about Fragile X
* Our counselling service, provided at no cost to members, goes from strength to strength and provides important support to many of our families and their carers
* Our website www.fragilex.org.au continues to be a first port of call for families seeking information and help
* Our facebook sites including www.facebook.com/fxAus connect us with more than 800 people and provide a discussion base for members
* Members’ participation in major runs and other events has helped to raise funds and awareness
What will the coming year bring?
* Our goal is to continue supporting our members and actively raising awareness of Fragile X–associated disorders. A major focus will be an awareness raising campaign targeting health professionals. This initiative has been very generously sponsored by a donor to the Association.
* We also aim to provide a Fragile X workshop and mobile clinic in each capital city over the next 3 years. We’re actively seeking grant funding to achieve this.
We’re especially keen to see our membership grow to a size more representative of the estimated 90,000 people in Australia who are affected by FX-associated disorders. Please do encourage others you know to join the Association.
Please continue your own support by renewing your $25.00 annual membership for 2014-2015
It’s an easy and essential way to support the Association. Your membership fee helps fund the services and support we can provide. And a growing member base is needed to give us a stronger voice in lobbying government for support for our members.
To renew your membership:
* Send us a completed membership form (below) - by post or email to firstname.lastname@example.org
* Call us to renew your membership over the phone – 1300 394 636
Your membership and support are important to us, and we look forward to working with you over the coming 12 months.
FXAA Membership Form 2014 to 2015_individuals and families
FXAA Membership Form 2014 to 2015_professional