It is only through genetic testing that we know which ones we carry. Some genes are on the non-sex chromosomes numbered , which are the same in males and females, and some are on the sex chromosomes, which are the X and Y chromosomes.
Traditionally, a carrier of a genetic mutation is defined as a person who inherits an altered form of a gene but shows no effects of that mutation. Learn more about the International Fragile X Premutation Registry and join individuals with the premutation and their families to help advance — and encourage — deeper understanding and research into the premutation condition. A premutation carrier is an individual, male or female, who has between CGG repeats in the Fragile X.
FMR1 gene. The full mutation is defined as over CGG repeats. These are alleles with CGG repeats. These alleles are identified as such because there is a small chance that they are mildly unstable and may expand to a premutation in future generations.
There is no reported risk for an individual with an intermediate sized allele to have a child with a full mutation. Often in these disorders, only females are carriers and only males are affected. However, in Fragile X, both males and females can be carriers, and both can be affected by the condition.
This occurs because the changes in the FMR1 gene go through stages as it is passed down in a family. These stages start with the normal gene and then proceed to the premutation and then the full mutation. Females with a premutation are at risk to have a child, male or female, with Fragile X syndrome. Further, it will encourage researchers to explore the interactions between these conditions. It is important to highlight that many of the FXPAC symptoms are also common in the general population.
However, the emerging research suggests that people with the premutation may be at higher risk of some of the symptoms.
In addition, for many, these traits may present in subtle ways that do not affect day-to-day life. Though, a proportion of people who are Fragile X premutation carriers will experience symptoms to the extent it has a negative impact for them.
Being a carrier does not mean that these symptoms are inevitable, and treatment should be sought for these symptoms as for anyone in the general population. In conclusion, there is a need for a term which encompasses conditions affecting Fragile X premutation carriers.
The EFXN, covering a population of over million people throughout Europe, has worked together to come up with new terminology. This has been welcomed by European researchers and clinicians. FXPAC will aid researchers who wish to explore the many ways the premutation affects carriers, allowing for the fact we do not yet understand how these may be interlinked.
FXPAC will help carriers who experience a range of conditions and wish to have a medical diagnosis. FXPAC will be a one-stop shop for doctors who need to explore the various conditions which may affect their patient.
The network of European Fragile X family organizations very much hopes these ideas will be widely adopted outside Europe and around the world. Information on the work of the European Fragile X Network may be found at www. This is a group of charitable organizations who support families and those affected by Fragile X across Europe. This article was written on behalf of the European Fragile X Network, a group of charities representing families and those affected by Fragile X and the Fragile X premutation.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The authors are grateful for the support of all the organizations and their representatives which are part of the European Fragile X Network; and for the support of European researchers and clinicians in refining these ideas. Particular thanks to Dr. Hagerman PJ. The fragile X prevalence paradox. J Med Genet. Epidemiology of fragile X syndrome: a systematic review and meta-analysis.
Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Closing the gender gap in fragile X syndrome: review of females with fragile X syndrome and preliminary research findings. Brain Sci. In: F. Tassone, D. Hall, editors. Cham: Springer Front Genet. Movem Dis. Such similarities in pragmatic language profiles could suggest that the differences between these groups stem from similar underlying factors, supporting a link between FMR1 and autism-related phenotypes in carrier relatives.
In support of this possibility, the study also found that premutation carriers displayed elevated rates of personality traits associated with the broad autism phenotype, rigid or inflexible traits and socially reticent dispositions.
The presence of broad autism phenotype traits was associated with greater expression of autism symptoms in their children with FXS. Other studies have also found increased rates of both social aloofness [ 83 ] and a rigid perfectionism [ 84 ] among carrier women.
Studies have shown that amygdala dysfunction in viewing social stimuli seen in carriers correlates with clinical findings of social deficits and both FMRP deficits and elevated FMR1 mRNA levels [ 85 ]. The largest and most recent study of life-time mood and anxiety in the premutation population was completed by Bourgeois et al.
In that study, carriers both suffering and not suffering from FXTAS were compared in the prevalence of anxiety disorders to a very large age-matched national dataset. When separated out, this was similarly true for panic disorder, post-traumatic stress disorder and specific phobia.
Generalized anxiety disorder and obsessive compulsive disorder failed to demonstrate any difference between carriers and controls. Only social phobia was found to have higher levels in premutation carriers without FXTAS compared to controls. Chronic anxiety has also been associated with radiological signs on MRI; specifically, the higher the anxiety score the smaller the size of the hippocampus in women with the premutation [ 86 ].
Other reports have not found high levels of mental health problems; however, differences in measurements life-time versus state traits, interview versus self-report , age of participants, ascertainment of participants, etcetera , will all play a role in explaining such differences. Irrespective, continued research to identify vulnerable women is essential. Psychosis, given its relative rarity in the general population, has been challenging to study in premutation carriers.
Initial linkage analysis failed to show a clear relationship of schizophrenia to the FMR1 gene [ 87 ]. Prevalence studies have found the overall rate of psychotic disorders to be low [ 83 ]. There have, however, been several case reports of combined psychotic illnesses and the premutation, including schizoaffective disorder [ 88 ] and a subject with combined schizophrenia and schizoid personality disorder [ 89 ].
Interestingly, as opposed to frank psychotic disorders, multiple studies have found increased prevalence of schizotypal personality traits in the carrier population [ 83 , 90 ]. Attention regulation difficulties have been proposed to be a problem in people with the premutation.
Notably, when compared with their control siblings, premutation carriers had significantly more issues with attention than their noncarrier siblings [ 91 ]. Inattention and impulsivity amongst FMR1 carriers can be problematic through adulthood [ 55 ], although hyperactivity was not noted to be increased in prevalence.
This suggests that the premutation acts in concert with additional genetic loci to influence the severity of ADHD symptoms [ 92 ]. Sleep issues have recently been studied in carriers, and common measures such as the Pittsburgh Sleep Quality Index and the Insomnia Severity Index have shown significant pathology.
These findings may be related to higher rates of Restless Legs Syndrome and sleep apnea, both of which have shown multiple-fold increases in subsets of the premutation population [ 93 , 94 ]. In a study of males and females with the premutation, including with FXTAS and controls, sleep apnea occurred in These issues may be contributing to the development of significant fatigue, which is a common complaint of adult carriers [ 95 ].
Two hypotheses have been advanced to account for elevated psychiatric, cognitive, and somatic symptoms in premutation carriers [ 96 ]: first, that such symptoms are a primary biological feature of FMR1 CGG expansions in the premutation range, and second, that such symptoms may be exacerbated by the stress associated with parenting a child with FXS. Importantly, stress may interact with the biological vulnerabilities caused by the premutation, and thus it is important to incorporate biological markers when exploring stress effects in this population.
It has been well established that many individuals with FXS have severe behavior problems, including inattention, hyperactivity, aggression, anxiety, and autism symptoms [ 97 ], which result in high levels of stress exposure for their families [ 96 , 98 — ].
In one study, exposure to child behavior problems was investigated in the context of a biomarker of the premutation, namely the activation ratio. Hartley et al. Such episodes occurred, on average, about every other day.
They examined the association of genetic variation in the corticotrophin releasing hormone receptor 1 locus CRHR1 in women, including premutation carriers with and those without a child with FXS and non-carriers. These preliminary data suggest that there may be a subgroup of premutation carriers who are more susceptible to the effects of stress.
Stressful life events are a source of stress quite distinct from child behavior problems, and include experiences such as divorce, death of a family member or close friend, caring for an aging parent, or negative changes in financial or health status.
These life events have been shown to compromise psychological well-being in the general population [ ] and in parents of children with developmental disabilities [ , ]. Although exposure to child-related stress is a common characteristic of premutation carrier mothers of children with FXS, these mothers vary with respect to their exposure to other types of stress.
Only one study has been conducted investigating general life stress effects in premutation carrier mothers of children with FXS. However, the other mothers did not experience any of these sources of life stress during the previous year. The variation in exposure to life events made it possible to investigate the effect of exposure to this type of stress on premutation carrier mothers of children with FXS.
Specifically, Seltzer et al. They found that the higher number of stressful life events experienced during the previous year, the greater the level of depression and anxiety, and the lower the level of cortisol. However, variation in the biology of the premutation was critical to understanding the pattern of stress effects. A curvilinear association was observed between stress exposure and CGG repeat length.
Premutation carrier mothers with mid-range CGG repeat lengths approximately 90 to had the highest levels of depression, anxiety, and the most abnormal cortisol parameters if they had recently experienced stressful life events, but mothers in the same CGG repeat range had the lowest level of depression and anxiety, and the most normal cortisol parameters if their life had been free from stressful events in the previous year.
This divergence was most prominent in the mid-CGG range, whereas those with low CGG repeat numbers or repeats closer to the full mutation cut-off were less reactive to stress. A curvilinear pattern of vulnerability in CGG repeat effects has been previously shown for reproductive outcomes in carrier females [ 5 , 26 , 27 ] and for depression [ 56 ].
This study implicates exposure to stressful life events and CGG repeat length in the manifestation of psychiatric symptoms in premutation carrier mothers.
A large number of studies have shown that autism is an extremely stressful developmental disorder, arguably the disorder posing the greatest level of parenting stress [ , ]. A few studies have contrasted parenting stress in mothers who have a child with autism and mothers whose child has FXS [ 17 , ]. These studies generally have found similar patterns for premutation carrier mothers of children with FXS and mothers of those with autism. These findings of similarity between premutation carrier mothers of children with FXS and mothers of children with autism are similar to earlier work in which it was found that the most consistent predictor of maternal depression across disability groups FXS, ASD, and Down syndrome was child behavior problems [ ].
Only when research that separates the effects of the biology of FMR1 expansions from the effects of stressful parenting will there be a complete understanding of the premutation phenotype and how stress may alter it. Table 4 summarizes nominations for psychiatric features in premutation carriers. At this point there is strong evidence to suggest that females with an FMR1 premutation may be variably at risk for multiple medical, reproductive, cognitive, and psychiatric difficulties.
Several recent papers have described significance and breadth of concerning features reported to be associated with the FMR1 premutation [ 6 , 11 , , ], thus capturing the importance of better describing phenotypes associated with the premutation.
While the rates of many medical and psychiatric problems are significantly increased in aging carriers who have FXTAS [ 79 ], the onset of some of these problems has been reported well before the onset of an official diagnosis [ ]. The emergence of some problems, such as ADHD, anxiety disorders and autism traits are noted to occur in some premutation carriers in childhood [ 91 , , ].
However, little is known about the early developmental phenotype of individuals with a premutation, and those studies that have focused on features in children with a premutation are virtually all based on clinically referred children or siblings of an individual with FXS.
Additional longitudinal studies are needed to determine at what point some of these features may develop, whether they are developmental or degenerative and what protective factors might reduce risks for more negative outcomes. CGG repeat length has been implicated in the onset and severity of several of these features. This is most notable in the literature on FXPOI, with a nonlinear association greater severity among those with midrange repeats being reported in multiple studies [ 5 , 27 , 28 , 30 ].
Similar nonlinear findings have been reported for psychiatric [ 12 , 56 , 78 , ] symptoms, while other studies report linear associations between repeat length and severity of neurological symptoms [ 22 , 49 , ]. There may be a variable degree of RNA toxicity in carriers due to elevation of the FMR1 mRNA, which can lead to oxidative stress and neuronal hyperexcitability [ ]. These later two proteins are necessary for maturing the miRNA, which regulate both transcription and translation in the CNS [ ].
The RNA toxicity is thought to be related to miRNA dysregulation which can jeopardize survival of the neuron and glia containing the premutation [ , ].
Additional research is needed to examine the relationship between these biomarkers and phenotypic features. Also, cumulative effects of multiple risk factors may occur.
Those individuals with the premutation and either intellectual disabilities, seizures or autism traits are also likely to have a second genetic hit [R Lozano, RH, and F Tassone, unpublished data]. Hypertension and hypothyroidism, irrespective of the strength of the association with the premutation, should be evaluated medically and if present, treated, since the lack of treatment may aggravate CNS dysfunction.
Neurological problems including migraines, neuropathy, sleep apnea and psychiatric problems should be considered and if present and sufficiently symptomatic then treatment should be initiated. Exercise, stress reduction techniques such as therapy, biofeedback or meditation, avoidance of toxins, such as excessive alcohol use or illicit drugs, avoidance of vitamin deficiency and healthy eating should be recommended for all carriers [ 6 ]. Thus, the literature may be skewed toward larger repeats, and more serious symptoms, as well as substantial ascertainment bias toward patients and families who are more likely to seek medical care for themselves or their child with FXS, and thus are more likely to have clinical symptoms.
Studies of premutation carriers who do not have children with FXS and even who are not aware of their genetic status would make it possible to address a central unanswered question namely whether, in an unbiased sample of individuals with FMR1 CGG expansions who, for example, are not exposed to stressful parenting, and are not aware of literature related to their genetic status , there are increased risks of clinical or sub-clinical symptoms neurocognitive, health, and psychiatric and whether the severity of such symptoms is associated with their FMR1 genotype.
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