18th International Fragile X Conference session presenters: Randi J. Hagerman, MD, Deborah Hall, MD, David Hessl PhD, Emily Allen, PhD

Summarized by Dr. Connor Maltby, a 2022 Jr. Investigator

On Saturday afternoon of the NFXF’s 18th International Fragile X Conference, we heard insightful discussion regarding the FMR1 premutation from four highly regarded experts whose backgrounds span a diverse range of fields including psychiatry, neurology, basic science, and reproductive biology. Chaired by Hilary Rosselot, questions put forward from the in-person and virtual audiences were discussed and debated by Dr. Randi Hagerman, Dr. Deborah Hall, Dr. David Hessl, and Dr. Emily Allen. Below we have outlined the key questions as an overview of the topics covered by our panelists.

Three females sitting in front of microphones, one female is speaking while the other two listen.

What is the distinction between a Fragile X premutation “carrier” and those with intermediate or grey zone repeat numbers?

Individuals with the Fragile X premutation sometimes called “premutation carriers” are, by definition, individuals who possess between 55-200 CGG repeats within their FMR1 gene on the X chromosome. Females possess two X chromosomes, while males have only one X chromosome, meaning that females can be either homozygous premutation carriers, where both FMR1 genes contain expansions between 55-200 repeats, or heterozygous premutation carriers, where one FMR1 gene contains the premutation expansion and one remains within what is considered the ‘normal’ range of CGG repeats. On the contrary, males who possess just one FMR1 gene are either carriers or not.

These definitions are however challenging, as the conditions that arise from FMR1 CGG expansions present as a spectrum, rather than a clear cut yes or no based on the repeat number. This is further confounded by what we consider ‘grey zone’ carriers, which are individuals who possess between 40-54 CGG repeats. Many people fall into this intermediate grey zone area, with estimates ranging from between 1 in 20 to 1 in 100 individuals (up to ~23million in the U.S. alone). Our panelists discussed the potential risks that the individuals in the grey zone may face, which may be different health issues compared to those with smaller CGG repeats and those who fall more conclusively within the ‘premutation range’ of 55-200. The clearest risk for these individuals is the potential for this repeat to expand further in their children and grandchildren, and so increasing the chances of their children inheriting Fragile X syndrome or developing Fragile X premutation-associated conditions like Fragile X-associated tremor/ataxia syndrome (FXTAS) and Fragile X-associated primary ovarian insuffiency (FXPOI). The increased risk of developing Parkinson’s disease was also discussed for those in the grey zone. Research has shown that there is a small but significant increase in the prevalence of Parkinson’s disease in both male and females in the grey zone (Ref 1&2). There is, however, no observable increase in the risk of developing FXPOI or ovarian dysfunction in females in the grey zone as well as females with the Fragile X Premutation with up to ~65 repeats.

How do premutations affect males and females differently?

This is a very important question, and the answers point largely back to the previous point of females being more protected from FMR1 CGG expansions due to possessing two X chromosomes compared to the one X chromosome in males. Dr Hessl called on his experience in psychiatry to discuss the increased risk of males with the Fragile X premutation developing FXTAS, ADHD-like symptoms, autism, as well as lower FMRP expression levels seen in higher repeat number carriers, which is more commonly seen in young males compared to young females and may explain some of these increases in neuropsychiatric symptoms. Next, Dr Allen discussed the evidence for females with the Fragile X premutation reporting an increased prevalence of anxiety and depression symptoms when compared to males, with reports of up to 35% of females with the Fragile X premutation exhibiting these symptoms. This was affirmed by Dr Hagerman, who explained that she sees a wide range of premutation carriers in the clinic exhibit what she termed Fragile X-associated neuropsychiatric disorders (FXAND) and others call Fragile X-associated neuropsychiatric conditions (FXANC). This can also be hugely confounded by those individuals with the Fragile X premutation who are the parents of children with Fragile X syndrome due to the nature of caring for these children, making it difficult to separate symptoms from being associated with having the Fragile X premutation vs the potential challenges at home.

 What symptoms should female premutation carriers be aware of?

For those females who are aware that they have the Fragile X premutation, there are key symptoms that they should be aware of and steps that can be taken to mitigate the effects of these on their life. Irregular, skipped, and abnormal menstruation cycles should be looked for and could be a sign of ovarian insufficiency. Females with the Fragile X premutation should inform their OB/GYN about their premutation status, as this can allow for the tracking of hormone levels. Anti-Mullerian Hormone (AMH) and Follicle-Stimulating Hormone (FSH) can be tested and used as a marker of fertility and distance from menopause. This allows females with the premutation to make informed and early choices about their fertility and any potential family planning later in life if these symptoms arise early.

The presence of tremor or ataxia symptoms in your 50s is not always indicative of FXTAS development in females with the premutation, but it is always worth seeing a neurologist for a baseline neurological exam as they can track subsequent symptoms. The presence of a tremor in males with the premutation in their 50s is more likely to be sign of FXTAS development and should be acted on accordingly.

 Do women who develop FXPOI early have an increased risk of developing FXTAS?

Yes, but they are still a lot more protected from developing FXTAS than equivalent males with the Fragile X premutation.

What vitamins or dietary supplements do you suggest that do not cross into the brain?

It has been shown that individuals with the premutation show elevated levels of iron deposition in the brain, particularly within the cerebellum which is a region of the brain affected in FXTAS (Ref3). These individuals, as well as those with FXTAS, also exhibit increased rates of anemia and reduced iron levels. Finding the balance between supplementing your iron intake without increasing the risk of triggering increased iron deposits within the brain can therefore be hard. Dr Hagerman suggested that there may be iron infusions available that show reduced uptake into the brain and may help alleviate anemia symptoms, but that this should be carried out in consultation with a clinician. Alcohol consumption is known to increase iron deposition in the brain, so cutting out or reducing alcohol is a great non-supplementation way to increase iron in the body and reduce iron in the brain. Other supplements that were discussed and suggested to have clinical or anecdotal benefits to FXTAS and individuals with the Fragile X premutation included:

  • The MIND diet established by the Rush Alzheimer’s Center.
  • Turmeric and curcumin – Preclinical data suggest that these may help reduce RAN translation in cells.
  • General multivitamins that include vitamin C and vitamin D.
  • Hormone replacement therapy for those with FXPOI , which could help alleviate peripheral body symptoms associated with ovarian insufficiency.
  • Supplements for mitochondrial health, such as MitoQ.

Should all individuals with the Fragile X premutation see a neurologist to get a neurological baseline examination with regular follow-up visits to identify FXTAS onset early?

It is always good to have a relationship with a neurologist who understands the spectrum of Fragile X conditions if you or a family member has the Fragile X premutation, especially if a family member also suffers with FXTAS or FXPOI. Having this relationship ensures that as individuals reach the age where FXTAS symptoms may begin, they will be in a position to identify symptoms early.

What is the best way to support individuals with the Fragile X premutation?

There are enormous benefits of counseling and exercise for individuals with the Fragile X premutation who are suffering from anxiety, depression or other conditions, whether that be due to clinical implications of having the premutation or through the stresses of life. Exercise is known to stimulate new brain cell growth, so it is very good for individuals with the premutation. Dr Hall stressed that this is not the individual’s fault, rather a fundamental imbalance of chemicals in the brain and that sometimes patients do need to try different SSRIs or types of anxiolytic medications in combination with counseling to find the right balance. Some individuals report their depression and/or anxiety is made worse by less sunlight, long winters, cold temperatures etc., known as seasonal affective disorder (SAD). This can be aided through the use of light therapy boxes, which can boost vitamin D during the winter as well as overall mood.

There were many other great questions also answered in this session. Watch or re-watch the entire panel discussion here.


  1. Loesch et al 2018 – Evidence for the role of FMR1gray zone alleles as a risk factor for parkinsonism in females. Movement Disorders.
  2. Hall et al 2011 – FMR1 grey zone alleles: Association with Parkinson’s disease in women? Movement Disorders.
  3. Rogers et al 2016 – Cerebellar Mild Iron Accumulation in a Subset of FMR1 Premutation Carriers with FXTAS. Cerebellum

Thanks to panelists, Randi J. Hagerman, Deborah Hall, David Hessl, and Emily Allen for the lively and informative discussion!

Author Hilary Rosselot

Hilary Rosselot
Hilary joined the NFXF team in 2019. Prior to joining the NFXF team, she worked at the Cincinnati Fragile X Research and Treatment Center for over five years. She has experience as a clinical research coordinator across many types of clinical trials and served as the clinical research manager for the Cincinnati program. She earned a bachelor’s degree in psychology, a master’s, and is a SOCRA certified clinical research professional (CCRP). She enjoys time with family and friends, a great book, a strong cup of coffee and, of course, a good laugh!

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Every conference year, the NFXF facilitates a Jr. Investigator program. You can learn more about the program and our 2022 Jr. Investigators here:

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