Fragile X Premutation Carriers

A carrier has an altered form of a gene that can lead to having a child or grandchild with a genetic disorder.

We are all carriers of gene mutations, many of which are “silent.” This means we can pass the gene on but suffer no ill effects from it ourselves. It is only through genetic testing that we know which ones we carry. Some genes are on the non-sex chromosomes (numbered 1-22), which are the same in males and females, and some are on the sex chromosomes, which are the X and Y chromosomes where males have XY, and females XX.

Both males and females can both be Fragile X carriers

In Fragile X, unlike some other X-chromosome linked disorders, both males and females can be carriers and both can be affected by Fragile X syndrome.

It is estimated that about 1 in 250 women and about 1 in 800 men are carriers of the Fragile X premutation.

What does it mean to be a Fragile X premutation carrier?

The changes in the FMR1 gene can go through stages as that gene is passed down in a family. These stages start with the normal FMR1 gene, and can expand to the premutation and then the full mutation. The differences in the stages are determined by the number of CGG repeats (repeats of a DNA pattern) in the FMR1 gene as it is passed on to offspring. In female carriers of Fragile X, the repeat size can be unstable and increase in size as it is passed on to future generations.

A normal range of this gene for an unaffected person is between 1-54 CGG repeats.

A person who is a carrier of the Fragile X premutation has between 55-200 CGG repeats. A person with the full mutation, often leading to Fragile X syndrome, has over 200 CGG repeats.

Female carriers have a 50% chance of having a child, male or female, with either the Fragile X premutation (carrier) or Fragile X full mutation (Fragile X Syndrome). They have a 50% chance of having an unaffected child. Male carriers will pass the premutation on their X chromosome to all of their daughters, and none of their sons.

diagram

Diagram source: Women’s Health and the Fragile X premutation, Espinel & Sherman, Emory University, Georgia, USA, 2015.

Conditions associated with the Fragile X premutation

Traditionally, a carrier of a genetic alteration (mutation) is defined as a person who inherits an altered form of a gene but shows no effects of that alteration.

However, in Fragile X this definition does not exactly fit, as some carriers are at risk of developing disorders which are associated with the Fragile X premutation, but the exact connection between the Fragile X premutation and these associated conditions is not yet known.

It is important to note that only some women and men who carry the premutation experience related health concerns, and the experiences of individuals will differ. Researchers are seeking to understand why this is the case.

Females

Potential health concerns include Fragile X-associated Primary Ovarian Insufficiency (FXPOI) which is characterised by fertility issues and early menopause, and is experienced by 25% of female premutation carriers. Other health concerns that have been reported to be more frequent among premutation carriers who are women include anxiety, depression, thyroid problems, auto-immune issues, fibromyalgia (chronic pain and tiredness), migraines, sleep disturbance, and auto-immune issues. Prof Randi Hagerman has proposed the diagnostic term FXAND (Fragile X-associated Neuropsychiatric Disorders) to promote research, recognition and treatment for these problems.

Fragile X-associated Tremor Ataxia syndrome (FXTAS) is less common and the symptoms are generally less severe in women.

diagram

Diagram source: Women’s Health and the Fragile X Premutation, Espinel & Sherman, Emory University, Georgia, USA. 2015.

Males

In older males, the most significant issue for men with a Fragile X premutation is the risk of developing Fragile X-associated Tremor Ataxia syndrome (FXTAS), which affects about 45% of male carriers over 70 years of age. It has been reported that some boys with the premutation have an additional diagnosis of autism, ADHD, or other learning/behavioural disorders.

Health and wellness for premutation carriers

It is important for any Fragile X carrier experiencing any health problems to consult with their general practitioner, or a specialist. Advice and treatments should be sought for any specific health issues. A healthy lifestyle and minimizing stress can increase health outcomes for everyone.

Treatments for premutation carriers

Dr Randi Hagerman (UC Davis MIND Institute) talks about health and wellness perspectives in her presentations and lectures about Fragile X, and this is covered in several videos.

diagram

Figure 2: Recommendations and treatments to support healthy aging and support for FMR1 premutation carriers including medications, complementary and alternative treatment methods, and lifestyle changes as evidenced by similar neurodegenerative disorders.

Diagram source: Molecular Advances Leading to Treatment Implications for Fragile X Premutation Carriers, J Polussa, A Schneider, R Hagerman, Brain Disorders and Therapy, Vol 3 Issue 2, 2014


To Learn more:

There are many information sources online which cover the Fragile X premutation. This list is not exhaustive.

Health Issues Fragile X Premutation Carriers can Experience. Q&A with Dr Randi Hagerman

Video filmed for Fragile X Association of Australia, September 2018. (viewing time 5 minutes)

Health and Wellness for Carriers of the Fragile X Premutation, Q&A with Prof Randi Hagerman

Video filmed for Fragile X Association of Australia, September 2018 (viewing time 6 minutes)

Women’s Health and the Fragile X Premutation booklet

Espinel and Sherman, Emory University, Georgia, USA, 2015.

Premutation Carriers, National Fragile X Foundation (US) website

Fragile X Association of Australia YouTube channel

Has several video presentations by Profs Randi and Paul Hagerman on Fragile X, including premutation carriers.

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