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Predictors and risk model development for menopausal age in fragile X premutation carriers.

ABSTRACT: Women who carry a fragile X mental retardation 1 premutation are at risk for fragile X-associated primary ovarian insufficiency and should be counseled for a potentially reduced fertility. Multiple factors can affect the age of onset and severity of fragile X-associated primary ovarian insufficiency. In this study, we assessed the predictive power of several factors with menopausal age, a surrogate measure of onset of fragile X-associated primary ovarian insufficiency.Genetic, environmental, and reproductive factors were analyzed by Cox proportional hazard models in 1068 women, 385 of fragile X families ascertained through the Nijmegen study and 683 of fragile X families or general population families ascertained through the Atlanta study.The highest association with menopausal age among fragile X mental retardation 1 premutation carriers was found for risk index by CGG repeat size (hazard ratio, 1.43) and smoking (hazard ratio, 1.34). Women from the Nijmegen cohort showed an overall lower age at menopause onset, for which a correction was made. A prediction model based on these two parameters, mean menopausal age of first-degree relatives with the same mutation status and the correction for ascertainment site, estimated the probability of becoming postmenopausal for premutation carriers, with a margin of 7-10%.We conclude that this model serves as a first step toward clinical application of fragile X-associated primary ovarian insufficiency prediction.

SUBMITTER: Spath MA

PROVIDER: S-EPMC3132284 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Predictors and risk model development for menopausal age in fragile X premutation carriers.

Spath Marian A MA Feuth Ton B TB Smits Arie P T AP Yntema Helger G HG Braat Didi D M DD Thomas Chris M G CM van Kessel Ad Geurts AG Sherman Stephanie L SL Allen Emily G EG

Genetics in medicine : official journal of the American College of Medical Genetics 20110701 7

<h4>Purpose</h4>Women who carry a fragile X mental retardation 1 premutation are at risk for fragile X-associated primary ovarian insufficiency and should be counseled for a potentially reduced fertility. Multiple factors can affect the age of onset and severity of fragile X-associated primary ovarian insufficiency. In this study, we assessed the predictive power of several factors with menopausal age, a surrogate measure of onset of fragile X-associated primary ovarian insufficiency.<h4>Methods ...[more]

PMID: 21597380

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Project description:The FMR1 premutation confers a 40-60% risk for males of developing a neurodegenerative disease called the Fragile X-associated Tremor Ataxia Syndrome (FXTAS). FXTAS is a late-onset disease that primarily involves progressive symptoms of tremor and ataxia, as well as cognitive decline that can develop into dementia in some patients. At present, it is not clear whether changes to brain function are detectable in motor regions prior to the onset of frank symptomatology. The present study therefore aimed to utilize an fMRI motor task for the first time in an asymptomatic premutation population. Premutation carriers without a diagnosis of FXTAS (n = 17) and a group of healthy male controls (n = 17), with an age range of 24-68 years old, were recruited for this cross-sectional study. This study utilized neuroimaging, molecular and clinical measurements, employing an fMRI finger-tapping task with a block design consisting of sequential finger-tapping, random finger-tapping and rest conditions. The imaging analysis contrasted the sequential and random conditions to investigate activation changes in response to a change in task demand. Additionally, measurements were obtained of participant tremor, co-ordination and balance using the CATSYS-2000 system and measures of FMR1 mRNA were quantified from peripheral blood samples using quantitative real-time PCR methodology. Premutation carriers demonstrated significantly less cerebellar activation than controls during sequential versus random finger tapping (FWEcorr < 0.001). In addition, there was a significant age by group interaction in the hippocampus, inferior parietal cortex and temporal cortex originating from a more negative relationship between brain activation and age in the carrier group compared to the controls (FWEcorr < 0.001). Here, we present for the first time functional imaging-based evidence for early movement-related neurodegeneration in Fragile X premutation carriers. These changes pre-exist the diagnosis of FXTAS and are greatest in older carriers suggesting that they may be indicative of FXTAS vulnerability.

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Predictors and risk model development for menopausal age in fragile X premutation carriers.

Publications

Predictors and risk model development for menopausal age in fragile X premutation carriers.

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