X-inactivation in the clinical phenotype of fragile X premutation carrier sisters

Abstract

Objective:The purpose of this study is to describe a case series of 4 sisters with discordant clinical phenotypes associated with fragile X–associated tremor/ataxia syndrome (FXTAS) that may be explained by varying CGG repeat sizes and activation ratios (ARs) (the ratio of cells carrying the normal fragile X mental retardation 1 [FMR1] allele on the active X chromosome).Methods:Four sisters with premutation size FMR1 gene repeats underwent detailed clinical characterization. CGG repeat length was determined by PCR, and AR was determined using a newly developed commercial methylation PCR assay and was compared with the results from Southern blot with densitometric image analysis.Results:Sister 1 had the largest CGG expansion (82) and the lowest AR (12%), with the most severe clinical presentation. Sister 2 had a lower CGG expansion (70) and an AR of 10% but had a milder clinical presentation.Sister 3 had a similar CGG expansion (79) but a slightly higher AR of 15% and less neurologic involvement. Sister 4 had a similar CGG expansion size of 80 but had the largest AR (40%) and was the only sister not to be affected by FXTAS or have any neurologic signs on examination.Conclusions:These results suggest that premutation carrier women who have higher ARs may be less likely to show manifestations of FXTAS. If larger studies show similar patterns, AR data could potentially be beneficial to supplement CGG repeat size when counseling premutation carrier women in the clinic.

Molecular Correlates and Recent Advancements in the Diagnosis and Screening of FMR1-Related Disorders

“…In addition, the neuropathological hallmark of FXTAS, i.e., numbers of intranuclear inclusions in neurons and astrocytes of affected individuals are associated with the number of CGG triplets, which highlights the clinical utility of repeat size analysis in predicting the extent of neurological involvement in PM carriers [38]. The penetrance of FXTAS is generally low in PM females, with the severity of clinical symptoms being directly proportional to the extent of skewed XCI of the NL FMR1 allele [39,40,41,42]. …”

Epigenetics of fragile X syndrome and fragile X‐related disorders

“…One might expect that premutation phenotypes would be more prominent in women in whom a higher proportion of cells harboured the premutation on the active X chromosome. This seems to be the case in relation to the clinical and radiological features of FXTAS; however, in contrast, there is no evidence for a relationship between skewed X‐inactivation and fragile X‐associated primary ovarian insufficiency . Interestingly, in premutation females, FREE2 methylation, which is sensitive to X‐inactivation changes, has been found to be correlated both with poorer performance on tasks of executive function and with increased grey matter volume of cortical structures that have known roles in executive function, such as frontal and parietal gyri …”

Fragile X‐associated Tremor/Ataxia Syndrome in an Adolescent Female

“…However, some individuals have skewing of this ratio, with a higher percentage of active premutation allele, which may result in substantial phenotypic heterogeneity. This variation in the activation ratio (the ratio of cells carrying the normal FMR1 allele on the active X chromosome) could explain the young onset of her symptoms . Early diagnosis of FXTAS is helpful in young patients, who can subsequently undergo genetic testing and receive counselling.…”

“…They have a higher prevalence of hormonal, psychiatric, and medical conditions, such as central pain sensitivity syndrome, sleep disturbances, thyroid dysfunction, fibromyalgia, and migraine. 10,11 Females were thought to be protected from this disorder due to the presence of the second X chromosome, however, females with this syndrome have been reported. 12 X chromosome inactivation is the transcriptional silencing of 1 X chromosome in the somatic cells of women.…”

“…This variation in the activation ratio (the ratio of cells carrying the normal FMR1 allele on the active X chromosome) could explain the young onset of her symptoms. 11 Early diagnosis of FXTAS is helpful in young patients, who can subsequently undergo genetic testing and receive counselling. This case emphasizes the need to consider FXTAS in both men and women of all ages who present with tremor and ataxia.…”