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What Does It Mean To Be a Carrier?
By Liane Abrams
Certified Genetic Counselor
Special Acknowledgment to the University of North Carolina's Fragile X Information Center website for contributions to the following information.
Introduction
It is not uncommon to find out that you or someone in your family is a "carrier" for a fragile X mutation and to have questions about what this means. Do I have a premutation or full mutation? What does this mean for my health, my family and my future?
Definition of Carriers
Unlike other X-linked genetic disorders,
both males and females can be carriers of a Fragile X mutation. A carrier is an individual who carriers an altered form of a gene which can lead to having a child or offspring in future generations with a genetic disorder. We are
all carriers of three to five gene mutations, many of which are "silent;" it is only through genetic testing that we know which ones we carry. Some genes are on the non-sex chromosomes which are the same in males and females
and some are on the sex chromosomes, namely the X or Y chromosome.
The gene for Fragile X (the FMR1 gene) is on the X chromosome and therefore fragile X syndrome is called an X-linked genetic disorder. Often in X-linked disorders only females are carriers and only males are affected. However, in Fragile X both males and females can be carriers (and both males and females can be affected). This occurs because the changes in this gene go through different stages as it is passed down in a family. These stages are commonly called a premutation and a full mutation. The differences in the stages are determined by the number of CGG repeats (repeats of a DNA pattern) and the degree of methylation (whether the gene is turned on or off). An FMR1 gene that is methylated is turned off and does not make an adequate amount of an important brain protein called FMRP. Fragile X syndrome occurs due to the fact that FMRP is absent or significantly reduced in an individual with a full mutation.
A premutation carrier is typically defined as an
individual, male or female, who has between 55-200 CGG repeats and has a normal methylation pattern. The full mutation is defined as over 200 CGG repeats with some degree of methylation. A female can be a carrier of a premutation
or full mutation. Females with either a premutation or full mutation have a risk to have a child, male or female, with fragile X syndrome. The magnitude of this risk is related to the number of CGG repeats identified. A male can be
a carrier of a premutation; however, the vast majority of males with a full mutation have fragile X syndrome. A male premutation carrier will pass this premutation (as a premutation, not a full mutation) on to all of his daughters
and none of his sons, and therefore, is at negligible risk to have a child with fragile X syndrome. However, there is a risk for fragile X syndrome in his grandchildren through his daughters.
The specific number of CGG
repeats and methylation status of each persons' gene is identified as the individual's "allele". An allele is defined as the various forms a given gene can take (like the various types of potatoes that exist).
Traditionally, a carrier of a genetic mutation was defined as an individual who inherited an altered form of a gene but had no effects or symptoms of that gene change or mutation. However, in Fragile X this definition does not
exactly fit, as carriers of a premutation have a risk to develop fragile X- associated tremor ataxia syndrome (FXTAS) (an adult onset neurological condition more common in males), and fragile
X-related premature ovarian failure (POI) (a cause of early menopause or infertility). Females with a full mutation may have features of fragile X syndrome, or exhibit few, if any, effects of the
gene, as described below. We consider this latter group of females "full mutation carriers", as their primary concerns may focus on reproductive issues and the risk for passing on fragile X syndrome to their children.
There
is a subgroup of individuals who have what is now called an "intermediate" or "grey area" sized allele. These are alleles with 45-55 CGG repeats. These alleles are not considered to be mutations and do not appear to be associated
with any clinical features, medical issues, developmental disabilities or social/emotional difficulties. These alleles are identified as such because there is some unknown chance that they are unstable and may expand to a
premutation in generations to come. There is no known risk for an individual with an "intermediate" sized allele to have a child with a full mutation.
A full mutation carrier would be defined as a female with over 200 CGG
repeats with mild or no significant effects of the full mutation. Some females have difficulties in some areas of function or during certain times of their life. However, if a female required minimal or no intervention in school
and is able to maintain a stable and independent adult life, it is appropriate to include them in this definition of carriers.
Females with a premutation
The premutation is defined by an abnormality of the FMR1
gene associated with an expansion of CGG repeats between ~55 and 200. Early research findings suggested that there were few, if any, effects observed in premutation carriers; however, recent evidence suggests that some individuals
with the premutation may experience physical, medical, cognitive, or social-emotional effects.1,2
Physical Effects
One of the first effects reported in
premutation carriers was an increased rate of twin births and premature ovarian failure (POI) in some women.8 Approximately 22% of women with a premutation experience POI, which is characterized by infertility, decreased ovarian reserve or onset of menopausal symptoms prior to age 40. Interestingly, women with the full mutation, which is defined as an expansion of CGG repeats greater than 200, do not experience POI or increased twinning rates. Another medical effect of the premutation is the discovery of a fragile X-associated tremor ataxia syndrome (FXTAS) in individuals with the premutation.2,9 FXTAS is characterized by a progressive intention tremor, ataxia, cognitive decline, and generalized brain atrophy. FXTAS is hypothesized to be related to elevated levels of mRNA (a molecule similar to DNA) and much research on this is underway. While first found only in males with the premutation, some females with the premutation have also been diagnosed with FXTAS.9
Cognitive Effects
In general, studies report that males and females with the premutation have IQ scores that fall within the average range.3,10 As in the general population, there is variability with some individuals falling in the mildly impaired range and some falling in the superior range of cognitive functioning. Research
studies looking at more specific cognitive skills have shown that some women with the premutation may score lower on measures of vocabulary and arithmetic than women without the premutation.11 In
terms of attention, some work has shown that women with the premutation do well on measures of sustained attention (can focus on one activity for an adequate amount of time) but may have difficulty on selective attention tasks
(more easily distracted when more than one activity is going on).12
In all females one X chromosome in each cell is activated and one is inactivated. This is
a random process, and typically, in approximately 50% of a woman's cells her maternal X chromosome is activated and in 50% her paternal X chromosome is activated. The ratio of affected/unaffected activated X chromosomes is called
the activation ratio. Preliminary evidence suggests that women with the premutation who had lower activation ratios (lower number of unaffected X chromosomes activated) and longer CGG repeat lengths performed poorer on IQ and
attention tasks.13,14 .15
Social-Emotional Effects
Keeping in mind the stresses and emotional aspects of parenting a child with disabilities, as well as
stresses that can accompany the various reproductive issues associated with having a premutation (risks for an affected child, fertility and prenatal issues), it can be difficult to establish emotional effects which are a direct
biological result of the premutation versus those as a result of the concerns of those carrying a premutation. Though most women with a premutation have normal social skills and emotional resources, increased shyness and social
anxiety have been reported in some women with the premutation. In addition, there is evidence that women with the premutation are at increased risk for major depression with evidence suggesting that up to 70% of women with the
premutation have experienced at least one major depressive episode in their lifetime.13,14,17 In a study that looked at the relationship of clinical effects to CGG length,
results suggested that women with the premutation who had CGG repeat lengths of 100 or greater reported increased interpersonal sensitivity, withdrawn behavior, and depressive feelings but no greater symptoms of anxiety.18
Female carriers with a full mutation
Physical Effects
Females with a full mutation do not appear to be at risk for fertility issues including
premature ovarian failure, early menopause or increased twinning. The physical effects of fragile X syndrome such as joint hypermobility, long face, high arched palate, large ears, flat feet, mitral valve prolapse and other
physical features may occur in female full mutation carriers.
Cognitive effects
As described in other sections, the cognitive effects of the full mutation in females is extremely variable. In this section we
are focusing on the cognitive effects of females who are not identified as having a significant cognitive disability. A number of areas of cognitive functioning have been identified as areas of possible difficulty in female full
mutation carriers. These include:
- Visual-spatial skills- skills involved in placing objects accurately in space. This can affect map reading, locating objects in diagrams, instruction guides, etc.
- Executive functioning- this is the ability for problem solving and modifying incorrect strategies when the elements of the situation change. This can affect planning ability, organization skills and adaptation to unfamiliar
environments or new systems.
- Visual memory – this can affect the memory/understanding of diagrams, figures, tables and mathematical information.
- Non-verbal communication- this is the recall and interpretation of non-verbal information. This can affect interpretation of non-verbal "body language" and communications, or the ability to closely follow a complex story, joke,
etc..
- Mathematical computation and comprehension
Social-emotional effects
Though many female carriers with a full mutation have adequate social and emotional development, depression, anxiety, shyness and social avoidance occur more frequently in female full
mutation carriers. This may affect interpersonal communication, difficulties in new social situations, adaptation to new environments (such as college, moving, etc)
Males with a premutation
The most significant
issue for males with a premutation is the risk for FXTAS, an adult onset neurological disorder. The onset of this condition, which occurs in an unknown proportion of males with a premutation (55-200 CGG repeats), occurs in men over
50. The most common features are ataxia (balance or gait problems) and an intention tremor (a tremor which occurs during activity- but not at rest). Additional features may include short-term memory loss, Parkinson's-like symptoms,
loss of cognition, lower limb weakness or loss of sensation, decline of organizational and planning skills and moodiness/anxiety. The initial symptoms may progress slowly over years and may be misdiagnosed as Parkinson's disease.
Other than FXTAS in older males, most males with the premutation are clinically unaffected. There have been a number of reports of rare males with a premutation who had an additional diagnosis of autism or other developmental disorder. There have been a small number of case reports of males with a premutation who have learning disorders, ADHD, or mild physical features of fragile X syndrome. One recent study looked at six individuals with the premutation that had also been diagnosed with autism. Physical, psychological, and behavioral features found in males with the full-mutation, including perseveration of speech and poor eye contact (but far fewer that what is typically seen in the full mutation), were present in individuals with the premutation and autism. While autism and the premutation may be unrelated, it is unlikely. The authors hypothesized that autism may be caused by an interaction of genes and environmental factors in those individuals with the premutation.16
Though these cases are rare, there may be some association between the premutation in some boys and a risk for autism or other developmental disorders.
References:
1.Jin, P., & Warren, S. T. (2003). New insights into fragile X syndrome: From molecules to neurobehaviors. Trends in Biochemical Sciences, 28(3), 152-158.
2.Hagerman, P. J., & Hagerman, R. J. (2004). The fragile X premutation: A maturing perspective. American Journal of Human Genetics, 74, 805-816.
3.Loesch, D. Z., Huggins, R. M., Bui, Q.,M., Taylor, A. K., Pratt, C., & Hagerman, R. J. (2003). Effect of fragile X status and FMRP deficits on cognitive profiles estimated by robust pedigree analysis. American
Journal of Medical Genetics, 122A(1), 13-23.
4.Loesch, D. Z., Huggins, R. M., & Hagerman, R. J. (2004). Phenotypic variation and FMRP levels in fragile X. Mental Retardation and Developmental Disabilities Research Reviews, 10, 31-41.
8.Sherman, S. (2000). Premature ovarian failure in the fragile X syndrome. American Journal of Medical Genetics, 97(3), 189-194.
9.Hagerman, R. J., Leavitt, B. R., Farzin, F., Jacquemont, S., Greco, C. M., Brunberg, J. A. et al. (2004). Fragile-X-Associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation. American Journal of Human Genetics, 74, 1051-1056.
10.Bennetto, L., & Pennington, B.F. (2002). Neuropsychology. In R.J. Hagerman, & P.J. Hagerman (Eds.), Fragile X syndrome: Diagnosis, treatment, and research, third edition (pp. 206-248). Baltimore: Johns
Hopkins University Press.
11.Reiss, A.L., Freund, L., Abrams, M.T., Boehm, C., & Kazazian, H. (1993). Neurobehavioral effects of the fragile X premutation in adult women: A controlled study. American Journal of Human Genetics, 52, 884-894.
12.Steyaert, J., Legius, E., Borghgraef, M., & Fryns, J.P. (2003). A distinct neurocognitive phenotype in female fragile X premutation carriers assessed with visual attention tasks. American Journal of Medical
Genetics, 116A, 44-51.
13.Franke, P., Leboyer, M., Hardt, J., Sohne, E., Weiffenbach, O., & Biancalana, V., et al. (1999). Neuropsychological profiles of FMR-1 premutation and full mutation carrier females. Psychiatry Research, 87,
223-231.
14.Franke, P., Maier, W., Hatuzinger, M., Weiffenback, O., Bansicke, M., & Iwers, B. et al. (1996). Fragile X carrier females: Evidence for a distinct psychopathological phenotype? American Journal of Medical
Genetics, 64, 334-339.
15.Moore, C.L., Daly, E.M., Schmitz, N., Tassone, F., Tysoe, C., Hagerman, R.J., et al. (2004). A neuropsychological investigation of male premutation carriers of fragile X syndrome. Neuropsychologia, 42(4), 1934-1947.
16.Goodlin-Jones, B.L., Tassone, F., Gane, L.W., Hagerman, R.J., et al. (2005). Autistic spectral disorder and the fragile X premutation. Developmental and Behavioral Pediatrics, 25(6), 392-398.
17.Abbeduto, L., Seltzer, M. M., Shattuck, P., Krauss, M. W., Orsmond, G., & Murphy, M. M. (2004). Psychological well-being and coping in mothers of youths with autism, Down syndrome, or fragile X
syndrome. American Journal of Mental Retardation, 109(3), 237-254.
18.Johnston, C., Eliez, S., Dyer-Friedman, J., Hessl, D., Glaser, B., Blasey, C., et al. (2001). Neurobehavioral phenotype in carriers of the fragile X premutation. American Journal of Medical Genetics, 103, 314-319.
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