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 in behavioural and emotional symptoms. What causes stress is often our perception of it. For some people the long drive home is a stressful experience, for others it is a time to listen to the music they like and have their own thoughts. People also tend to be much more vulnerable to stress if they do not know how to calm themselves
It was found that premutation carriers may look at stress in a more negative way, so Kim’s research used a number of well known measures over a number of months to look at stress
Distractibility
Distractibility has always been thought to be a feature of female premutation carriers in terms of not being able to stick at a task and also in terms of being overwhelmed by a task.
The Tests
The Liebowitz Social Anxiety Scale (SAS) is a short questionnaire designed to measure social anxiety. The participants scored their stress levels (from uncomfortable to major anxiety) in different social situations like telephoning in public, participating in small groups.
The Depression Anxiety Scale was also used. This is a self report instrument designed to measure the three related emotional states of depression, anxiety and tension/stress.
The Brown Attention Deficit Disorder Scale was used to measure distractibility. This measured how the participants focussed on getting started on a task and the times they drifted away from the task.
Findings
Females premutation carriers were much more anxious than the controls
Female premutation carriers had slight elevation in depressive symptoms when compared to the controls, but this was not significantly different between groups.
Female premutation carriers had significantly higher attention problems when compared with the controls.
As with the cognitive difficulties, female premutation carriers showed anxiety and attention problems irrespective of whether they were caring for a child with fragile X.
Anxiety, attention problems and the poor inhibitive response have a biological/genetic base related to fragile X. More will be known about this when all the data is collected and published.
Increasing age was related to poorer performance in working memory and inhibiting responses, but this relationship was not strong.
There was no relationship between CGG repeat length and either executive functioning or psychological problems
Poor executive functions in terms of response inhibitions and working memory strongly related to self reported psychological symptoms in the carrier females.
A fragile X female premutation carrier profile we call “cognitive-affective” disorder is beginning to emerge in a subset of women.
Fragile X-Associated Primary Ovarian Insufficiency (FXPOI)
20% of female premutation carriers go through the menopause before they reach 40. This is 20 times higher than the general population.
Hormones
Hormones are chemical messengers produced in one part of the body, but having action somewhere else. The ovaries produce oestrogen, progesterone and testosterone. Testosterone is linked with cognition in both men and women. Testosterone levels in females can drop after the menopause and this can link to cognitive decline. In clinical settings adding testosterone has been shown to enhance some cognitive functions. Higher levels of testosterone were particularly linked with a higher performance on spatial and Maths programmes and with better verbal skills in older women.
In Kim’s pilot study half of the premutation carrier females showed a testosterone decline earlier than the control females. This was linked to a poorer score on the Hayling test.
Kim wants to take this very small pilot study further and look for research into what can improve cognitive levels in women.
Professional presentations
Kraan, C., Hocking, D., Bradshaw, J. L., Georgiou-Karistianis, N., Metcalfe, S. A., Archibald A., Fielding, J., Trollor, J., Cohen, J., Cornish, K. (2013). Motor sequence learning in fragile X carrier females: insights into cerebellar dysfunction? Oral Presentation: ACNS-2013 Australasian Cognitive Neuroscience Conference November 30th 2013.
Kraan, C., Hocking, D., Metcalfe, S. A., Cohen, J., Archibald A. D., & Cornish, K. M. (2013). Impaired inhibitory processing is associated with neuropsychiatric phenotypes in female FMR1 premutation carriers. Oral Presentation: 16th International Workshop on Fragile X & other early onset cognitive disorders September 18th 2013.
Cornish, K & Kraan, C. (2013). Carriers of Fragile X. Invited talk - National Fragile X Family Meeting, Birmingham UK September 2013.
Kraan, C., Hocking, D., Georgiou-Karistianis, N., Metcalfe, S. A. Archibald A. D., Fielding, J., Trollor, J., Bradshaw, J. L., Cohen, J., & Cornish, K. M. (2013). CGG-repeat length and age are associated with neuromotor impairments in at-risk females with the FMR1 premutation. Oral Presentation: The 1st International Conference on the FMR1 premutation: basic mechanisms and clinical involvement June 25th 2013.
Kraan, C., Hocking, D., Bradshaw, J., Georgiou-Karistianis, N., & Cornish, K. (2012). Postural control in young female FMR1 premutation carriers. Oral Presentation: ANS-2013 Australian Neuroscience Society Conference.
Kraan, C., Hocking, D., Bradshaw, J., Georgiou-Karistianis, N., & Cornish, K. (2012). New evidence for a complex interaction between executive control and motor functioning in young female FMR1 premutation carriers. Oral Presentation: ACNS-2012 Australasian Cognitive Neuroscience Conference December 1st 2012.
Shelton, A., Kraan, C., Cornish, K., & Fielding, J. (2012). The use of eye movements to detect cognitive changes in carriers of medium expansions of the FMR1 gene. Oral
Presentation: ACNS-2012 Australasian Cognitive Neuroscience Conference December 1st 2012.
Kraan, C., & Hocking, D. & Cornish, K., (2011). The Step Ahead Project: Developmental trajectories in male and female carriers of fragile X syndrome. Oral presentation at the Fragile X Association of Australia Symposium, Brisbane, October 4th 2011.
Journal publications
Kraan, C. M., Hocking, D. R., Georgiou-Karistianis, N., Metcalfe, S. A., Archibald, A. D., Fielding, J., Trollor, J., Bradshaw, J. L., Cohen, J., & Cornish, K. M. (accepted 15/3/2014). Age and CGG-repeat length are associated with neuromotor impairments in at-risk females with the FMR1 premutation. Neurobiology of Aging. [impact factor: 6.166; rank 554].
Kraan, C. M., Hocking, D. R., Bradshaw, J. L., Georgiou-Karistianis, N., Metcalfe, S. A., Archibald, A. D., Fielding, J., Trollor, J., Cohen, J., & Cornish, K. M. (2014). Symbolic sequence learning is associated with cognitive-affective profiles in female FMR1 premutation carriers. Genes, Brain and Behavior. DOI: 10.1111/gbb.12122 [impact factor: 3.597; rank 4357].
Grigsby, J., Cornish, K., Hocking, D., Kraan, C., Olichney, J. M., Rivera, S. M., Schneider, A., Sherman, S., Wang, J. Y., Yang, J-C. (in press). The cognitive neuropsychological phenotype of carriers of the FMR1 premutation. Journal of Neurodevelopmental Disorders. [impact factor: 3.45].
Shelton, A. L., Cornish, K., Kraan, C., Georgiou-Karistianis, N., Metcalfe, S. A., Bradshaw, J. L., Hocking, D. R., Archibald, A. J., Cohen, J., Trollor, J., & Fielding, J. (2014). Exploring inhibitory deficits in female premutation carriers of fragile X syndrome: Through eye movements. Brain & Cognition, 11, 201-208. [impact factor: 2.823; rank 1826].
Kraan, C. M., Hocking, D. R., Georgiou-Karistianis, N., Metcalfe, S. A., Archibald, A. D., Fielding, J., Trollor, J., Bradshaw, J. L., Cohen, J., & Cornish, K. M. (2013). Impaired response inhibition is associated with self-reported symptoms of depression, anxiety, and ADHD in female FMR1 premutation carriers. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics: the Official Publication of the International Society of Psychiatric Genetics, 26(10), 32203. [impact factor: 3.231; rank 1622].
Kraan, C. M., Hocking, D. R., Georgiou-Karistianis, N., Metcalfe, S. A., Archibald, A. D., Fielding, J., Trollor, J., Bradshaw, J. L., Cohen, J., & Cornish, K. M. (2013). Cognitive-motor interference during postural control indicates at-risk cerebellar profiles in females with the FMR1 premutation. Behavioural Brain Research, 26(13), 432-434. [impact factor: 3.327; rank 1202].
Kraan, C. M., Hocking, D. R., Bradshaw, J. L., Fielding, J., Cohen, J., Georgiou-Karistianis, N., & Cornish, K. M. (2013). Neurobehavioural evidence for the involvement of the FMR1 gene in female carriers of fragile X syndrome. Neuroscience & Biobehavioral Reviews, 37(3), 522-547. [impact factor: 9.440; rank 291].
Published conference abstracts
Kraan, C., Hocking, D., Bradshaw, J., Georgiou-Karistianis, N., Sylvia Metcalfe, Alison Archibald, Joanne Fielding, Julian Trollor, Jonathan Cohen & Cornish, K. (2012). Motor sequence learning in fragile X carrier females: insights into cerebellar dysfunction? Front. Hum. Neurosci. Conference Abstract: ACNS-2013 Australasian Cognitive Neuroscience Conference.
Kraan, C., Hocking, D., Bradshaw, J., Georgiou-Karistianis, N., & Cornish, K. (2012). New evidence for a complex interaction between executive control and motor functioning in young female FMR1 premutation carriers. Front. Hum. Neurosci. Conference Abstract: ACNS-2012 Australasian Cognitive Neuroscience Conference.
Shelton, A., Kraan, C., Cornish, K., & Fielding, J. (2012). The use of eye movements to detect cognitive changes in carriers of medium expansions of the FMR1 gene. Front. Hum. Neurosci. Conference Abstract: ACNS-2012 Australasian Cognitive Neuroscience Conference.