Birmingham Conference 2013: Female Carriers

Female Carriers of Fragile X Syndrome

Kim began by saying that women, carriers or not, are complex characters - add a few extra CGG repeats and oh my.

In the last 20 years we have come a long way in terms of understanding issues around being a female carrier of Fragile X Syndrome. Two decades ago everything was believed to be OK for carriers – there were no known behavioural effects for carriers of the fragile X gene. Any anxiety issues were mainly attributed to the stress of having a child with fragile X, rather than inherent to being a carrier.

About a decade ago with the identification of FXTAS, new research has changed this assumption into male carriers and shown that something was different. Clinically the gene expansion was making a difference.

So what do we know in 2013?

  • Men and women premutation carriers are affected clinically in different ways

  • Approximately 40% of male premutation carriers over the age of 55 and a much smaller number of female premutation carriers will go on to develop FXTAS (Fragile X-Associated Tremor Ataxia Syndrome)

  • Approximately 20% of females will have an increased incidence of FXPOI (Fragile X-Associated Primary Ovarian Insufficiency) with many women with the premutation experiencing earlier than normal menopause.

FXTAS

  • FXTAS is a neurological condition that is associated with cognitive decline, anxiety and irritability plus a progressive intention tremor/ataxia and problems with balance

  • Recent studies suggest men most at risk from cognitive decline and perhaps later FXTAS are those who have a CGG repeat number over 100.

In Kim’s research she found that a certain cluster of behaviours especially poor working memory and problems inhibiting responses could be seen in men, who were asymptomatic for FXTAS because they were in their 30’s and 40’s. She suggested that these behaviours may be an early precursor of later FXTAS when they occurred so early in adulthood.

In all studies there has been no evidence of FXTAS in those with a full mutation.

Kim’s Study into Female Premutation Carriers in Victoria and New South Wales

Kim and her colleagues in Melbourne (Professor Sylvia Metcalfe, Dr Jonathon Cohen) and Sydney (Professor Julian Troller) have been funded to examine the clinical and psychological profiles of women with a premutation in Australia. This research was funded by the Australian Research Council and is now completed. Her team looked at a number of issues:

  • Health and physical problems including migraine and early menopause

  • Mental health and wellbeing

  • Behavioural and cognitive functioning – attention difficulties, memory, problem solving

  • Hormonal levels

  • The relevance of the CGG repeat length. Were women at a higher risk of any difficulties if they had a higher CGG repeat number?

Who were the sample?

Women who were premutation carriers and women who were completely clear of fragile X were recruited.

The results were as below:

Cognitive difficulties

Each woman underwent 2 days of testing that looked specifically at executive functioning as this is important for guiding behaviour. Executive functioning affects planning, the ability to switch from one task to another and to multitask, working memory (the ability to hold onto pieces of information in your head) and inhibition (stopping oneself making inappropriate responses). All these are known problem areas for males affected by the full mutation.

  • To test working memory a letter number sequence test (LNS) was used. This is designed to assess the ability to store and manipulate information. Participants were given various sequences of letters and numbers to repeat back. On average the premutation carriers were correct on 12 items and the control women correct on 13 so there was not much difference.

  • The Stroop Colour Word Task was used to measure the ability to inhibit an automatic response. This involves looking at this chart and saying the colour of the word rather than the word. We all had a go at this and it is hard at speed!!

Now Kim began to see a difference between the premutation carrier group and the control group with premutation carrier women poorer at this task than the women in they control group. This was the case irrespective of whether the premutation carrier was caring for an affected child.

  • A further test called The Hayling Response was carried out. This test is sensitive in measuring a person’s ability to inhibit their response and involves people having to complete a sentence with a word that makes no sense. Again it was found that the premutation group had real problems with inhibiting their response and this time the difference between them and the control group was more significant. This was the finding irrespective of whether the lady had other difficulties such as mental health issues or was caring for a child with the full mutation. Response inhibition appears to be a core problem in females with the premutation and indeed similar difficulties have been found in men carrying the premutation

Psychological Factors

Social Anxiety

Many of the premutation carriers described this as a core issue. For them social anxiety encompassed problems like finding being in large groups hard and experiencing fear or discomfort in a social situation. Symptoms included avoidance of social situations.

Depression

Anecdotally many male and female carriers have felt that they have suffered/are suffering from depression. Depression is a feeling of sadness or generally feeling low over a long period of time and can constitute a serious illness. It affects a person’s behaviour, thoughts and can lead to physical problems. There are many causes to depression including drug and alcohol use, personal factors and family history.

Stress

Stress is a commonplace term nowadays. A little stress is OK and helps us cope with situations, but when a person is constantly running on emergency mode, stress can have adverse affects and can impact on a person’s cognitive ability as well as result