Fragile X syndrome: An aging perspective

Schneider, Andrea; Ligsay, Andrew; Hagerman, Randi J.

doi:10.1002/ddrr.1129

Cited by 20 publications

(27 citation statements)

References 133 publications

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“…FXS was described over 35 years ago, but clinical research continues to concentrate on young patients, with few clinical reports of adult patients available . While the scope of our data is modest, we were successful in following and charting the personality as well as cognitive and adaptive skill development of FXS men over a relatively long time‐period.…”

Section: Discussionmentioning

confidence: 90%

Fragile‐X syndrome – a 20‐year follow‐up study of male patients

Arvio

2015

Clinical Genetics

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In 1994, a multi-professional team examined clinically 34 males with fragile X syndrome (FXS). Since then, these patients have been clinically evaluated twice at a 10-year interval. With the aid of the Portage method we were able to chart the course of their adaptive skills. The FXS males learned new abilities on average up to the age of 25; this was followed by a plateau stage until they reached 50, after which time, physical symptoms evidencing weakened overall motor skills were apparent. During follow-up, a total of 10 men died, 9 of them suddenly. Of these, three were under the age of 40 at death, and the oldest was 77. The FXS men were socially interactive, helpful, but shy. Typical symptoms of FXS boys such as poor eye contact, tactile defensiveness, and perseverative speech did not disappear with age. At the end of the study, 75% of the study subjects had long-standing health problems. Most aged over 50 suffered from symptoms arising from an enlarged prostate; one fourth were on psychotropic-, and one fifth on antiepileptic drug treatment.

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Section: Discussionmentioning

confidence: 90%

Fragile‐X syndrome – a 20‐year follow‐up study of male patients

Arvio

2015

Clinical Genetics

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“…In addition, individuals with both lowered FMRP and elevated FMR1 mRNA can also be at greater risk for psychotic symptoms (Schneider et al, 2013). …”

Section: Discussionmentioning

confidence: 99%

Clinical and molecular implications of mosaicism in FMR1 full mutations

et al. 2014

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Expansions of more than 200 CGG repeats (full mutation) in the FMR1 gene give rise to fragile X syndrome (FXS) through a process that generally involves hypermethylation of the FMR1 promoter region and gene silencing, resulting in absence of expression of the encoded protein, FMRP. However, mosaicism with alleles differing in size and extent of methylation often exist within or between tissues of individuals with FXS. In the current work, CGG-repeat lengths and methylation status were assessed for eighteen individuals with FXS, including 13 mosaics, for which peripheral blood cells (PBMCs) and primary fibroblast cells were available. Our results show that for both PBMCs and fibroblasts, FMR1 mRNA and FMRP expression are directly correlated with the percent of methylation of the FMR1 allele. In addition, Full Scale IQ scores were inversely correlated with the percent methylation and positively correlated with higher FMRP expression. These latter results point toward a positive impact on cognition for full mutation mosaics with lower methylation compared to individuals with fully methylated, full mutation alleles. However, we did not observe a significant reduction in the number of seizures, nor in the severity of hyperactivity or autism spectrum disorder, among individuals with mosaic genotypes in the presentation of FXS. These observations suggest that low, but non-zero expression of FMRP may be sufficient to positively impact cognitive function in individuals with FXS, with methylation mosaicism (lowered methylation fraction) contributing to a more positive clinical outcome.

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“…In FM mosaics partial expression of the unmethylated PM/NL FMR1 allele accounts for the milder cognitive involvement and less severe clinical presentation of FXS. However, mosaicism for a PM allele, which is usually associated with ~2–10-fold higher FMR1 mRNA and slightly lower FMRP levels [20], can increase the risks of developing psychotic symptoms [21] and a late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS, OMIM 300623) [22]. Methylation mosaicism, the presence of both fully methylated and unmethylated FM alleles, as opposed to the presence of methylated FM alone has been associated with better clinical outcomes and higher IQ levels in FXS individuals [17], and the subset of these methylation mosaics and unmethylated FM males who display moderate or normal phenotypes are referred to as high-functioning fragile X males [23,24,25].…”

Section: Molecular Determinants Of Fxsmentioning

confidence: 99%

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

Rajan‐Babu

Chong

2016

Genes

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Fragile X syndrome (FXS) is the most common monogenic cause of intellectual disability and autism. Molecular diagnostic testing of FXS and related disorders (fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS)) relies on a combination of polymerase chain reaction (PCR) and Southern blot (SB) for the fragile X mental retardation 1 (FMR1) CGG-repeat expansion and methylation analyses. Recent advancements in PCR-based technologies have enabled the characterization of the complete spectrum of CGG-repeat mutation, with or without methylation assessment, and, as a result, have reduced our reliance on the labor- and time-intensive SB, which is the gold standard FXS diagnostic test. The newer and more robust triplet-primed PCR or TP-PCR assays allow the mapping of AGG interruptions and enable the predictive analysis of the risks of unstable CGG expansion during mother-to-child transmission. In this review, we have summarized the correlation between several molecular elements, including CGG-repeat size, methylation, mosaicism and skewed X-chromosome inactivation, and the extent of clinical involvement in patients with FMR1-related disorders, and reviewed key developments in PCR-based methodologies for the molecular diagnosis of FXS, FXTAS and FXPOI, and large-scale (CGG)n expansion screening in newborns, women of reproductive age and high-risk populations.

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Fragile X syndrome: An aging perspective

Cited by 20 publications

References 133 publications

Fragile‐X syndrome – a 20‐year follow‐up study of male patients

Fragile‐X syndrome – a 20‐year follow‐up study of male patients

Clinical and molecular implications of mosaicism in FMR1 full mutations

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

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